Novel Biological Properties of Peptides Arising from Basement Membrane Proteins

CHAPTER 13 Novel Biological Properties of Peptides Arising from Basement Membrane Proteins

I. Matrikines and Matricryptines A. Definition B. EVects of Matrikines II. Matrikines Formed from Type IV Collagen A. Formation of Type IV Collagen Fragments B. EVects of Type IV Collagen Matrikines on Blood Cells C. EVects of Type IV Collagen Matrikines on Angiogenesis D. EVects of Type IV Collagen Matrikines on Neoplastic Cell Adhesion and Metastasis III. EVects of Matrikines Derived from Collagens XV and XVIII A. Structures B. Biological Properties of Endostatin C. Biological Properties of Restin D. Generation and Role of Endostatin and Restin IV. EVects of the Matrikines Formed from Laminin and from Other Proteins, and Proteoglycans of the Basement Membrane A. Laminin Matrikines B. Protein SPARC Matrikines C. Proteoglycan Matrikines V. Conclusion References

Current Topics in Membranes, Volume 56 Copyright 2005, Elsevier Inc. All right reserved.

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I. MATRIKINES AND MATRICRYPTINES A. Definition During the last decade, several papers have demonstrated that some peptides formed in the degradation of proteins may exert biological eVects on certain cells similar to those of cytokines. This is the case with hemoglobin, whose catabolic peptides, the so‐called hemorphins, are active as atypical opioids and as inhibitors of the angiotensin‐converting enzyme (Davis et al., 1989; Zhao et al., 1994a, 1997; Nyberg et al., 1997). This is also the case for peptides liberated by the degradation of several proteins of connective tissue or obtained by experimental preparation, such as expression of recombinant DNA into specific sequences of matrix proteins. These peptides have been termed ‘‘matrikines,’’ a neologism coined from ‘‘matrix’’ (extracellular matrix) and ‘‘kine’’ for active molecules. A matrikine is defined as ‘‘a matrix‐originating peptide with a cytokine activity’’ (Maquart et al., 1999; Hornebeck et al., 2002; Pasco et al., 2004a). The usefulness of this term arises from the fact that it defines a group of peptides that are specifically related to the connective tissue proteins. Other authors proposed the name matricryptines, active sites in matrix proteins that become accessible after a conformational change or a limited proteolysis (Davis et al., 2000). Basement membrane proteins (type IV collagen, type XV collagen, type XVIII collagen, laminin, core protein of perlecan) and basement membrane–associated proteins (type XV collagen, type XVIII collagen, and protein SPARC) can generate such active peptides during their normal catabolism. The many active peptides liberated from basement membranes have been given various names such as arresten, canstatin, tumstatin, oncothanin, endostatin, and restin (Table I). It must be mentioned that the eVects of matrikines have been mostly studied in vitro, and that the demonstration of their physiological activity in vivo is still under discussion. Basement membrane macromolecules are capable of binding growth factors such as fibroblast growth factor (FGF) and transforming growth factor‐b (TGF‐b). Then, during the catabolism of these macromolecules, growth factors are released. For instance, the cleavage of perlecan by collagenase (MMP‐1) or by stromelysin (MMP‐3) is capable of liberating FGF that not only acts as a growth factor but also activates the expression of these matrix metalloproteinases MMP‐1 and MMP‐3, forming a catabolic amplification loop (Dumin et al., 2001; Ntayi et al., 2001).

B. Effects of Matrikines The eVects of matrikines are multiple (Table I): they exert an inhibitory eVect on the inflammatory cells such as polymorphonuclear leukocytes or

TABLE I Names of Matrikines Formed from Basement Membrane Protein Catabolism Name of peptide

Protein of origin

Location in the protein

Biological effects

References

383

Arresten

a1 chain of type IV collagen

NC1 domain of a1(IV) chain

Anti‐angiogenic, Inhibits tumor growth Anti‐metastatic in prostate carcinoma

Colorado et al., 2000

Canstatin

a2 chain of type IV collagen

NC1 domain of a2(IV) chain

Anti‐angiogenic, Inhibits tumor growth and metastasis

Colorado et al., 2000. Kamphaus et al., 2000; Panka and Mier, 2003; He et al., 2003 and 2004

Tumstatin

a3 chain of type IV collagen

Recombinant NC1 domain of a3(IV)

Inhibits melanoma cell growth (effect on cyclin D1 expression)

Han et al., 1997. Maeshima et al., 2000a Sudhakar et al., 2003; Floquet et al., 2004; Pasco et al., 2004

Tum‐5

a3 chain of type IV collagen

Sequence 54–132 of NC1 domain

Antiangiogenic Inhibits tumor proliferation

Maeshima et al., 2001b

Oncothanin

a3 chain of type IV collagen

Sequence 179–208 and 185–203 of NC1 domain

Antiangiogenic Antitumoral

Shahan et al., 2004

Unamed peptides

a5 and a6 chains of type IV collagen

Peptides from domains NC1 of a5 and a6 chains

Slight effects antiangiogenic and melanoma growth inhibitor

Petitclerc et al., 2000

Unamed Peptides

Triple helical domain from type IV collagen

a1(IV)531–543 sequence of the C‐ terminal domain a1(IV)

Increase of melanoma cell adhesion

Miles et al.; 1994, 1995

Vastatin

Collagen VIII

C terminal domain

Anti‐angiogenic

Ricard‐Blum, 2003 (Continued )

384 TABLE I (Continued ) Name of peptide

Protein of origin

Location in the protein

Biological effects

References

Restin

Collagen XV

NC1 domain

Antiangiogenic but not antiproliferative

Ramchandran et al., 1999

Endostatin

Collagen XVIII

C terminal region of NC1 domain

Antiangiogenic Antitumor effect

O’Reilly et al., 1997

Unamed Peptides

Laminin.

YIGSR

Inhibit metastatic effect in melanoma cells

Kleinmann et al., 1989; Nomizu et al. 1998; Kuratomi et al., 2002

b1 chain

LQVQLSIK

Promotes cell adhesion

g1 chain

KAFDITYRLRF

Increases melanoma cell metastases

Endorepellin

Perlecan

C‐terminal end of core protein

Angiostatic

Oligosaccharides

Perlecan

Oligosaccharide

Angiogenic

Peptide 4.2

Protein SPARC (osteonectin)

From EC module

Inhibits endothelial cell proliferation Stimulates cell proliferation and angiogenesis

Peptide KGHK

From folistatin‐like domain

Mongiat et al., 2003, Biz and Iozzo, 2005 West et al., 1985; Rooney et al., 1995; Noble, 2002 Yan and Sage, 1999; Brekken and Sage, 2001; Ricard‐Blum et al. 2003

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macrophages (by inhibiting superoxide formation and proteolytic enzyme secretion); they also exert an antiangiogenic activity on endothelial cells, and they inhibit tumor cell progression, particularly in the case of melanoma cells; they have been shown to increase the adhesion of melanoma cells onto the extracellular matrix; and to a lesser extent to inhibit progression and metastatic activity of tumors such as prostatic adenoma. Another important eVect of basement membrane protein fragments is the inhibition of several proteolytic pathways, such as that of pro‐MMP‐2 activation and that of MT1‐MMP expression. In the sections that follow, we describe the properties of matrikines derived from various ECM proteins. II. MATRIKINES FORMED FROM TYPE IV COLLAGEN A. Formation of Type IV Collagen Fragments The proteolytic pathways responsible for the degradation of type IV collagen are not yet clear, although diVerent fragments can be detected in the serum (Ortega and Werb, 2002). It is known that the proteinase MMP‐ 2 extensively degrades type IV collagen, following reduction of disulfide bonds, but it is less active in vivo (Hornebeck and Maquart, 2003). Fragments from both the helical and the NC1 domains are liberated, with the latter exerting greater biological eVects. Proteinase MMP‐9 can liberate NC1 domains, particularly the active peptide termed tumstatin, from the NC1 domain of the a3(IV)chain (Hamano et al., 2003). B. Effects of Type IV Collagen Matrikines on Blood Cells Blood cells were the first cells on which the eVect of type IV collagen and derived peptides was tested. Physiological interactions between blood cells and vascular basement membranes are multiple and unavoidable: (a) in the case of normal blood cells, such as human lymphocytes, polymorphonuclear leukocytes (PMNs), or macrophages, which have to cross the vessel wall to get to peripheral tissues; and (b) in the case of wounds, where blood leaks out of the injured vessels. Initial studies demonstrated that type I collagen stimulates some biological functions of PMNs, more particularly on the oxidative burst (fast and intensive formation and liberation of oxygen free radicals, essentially superoxide), and proteolytic enzymes secretion (Monboisse et al., 1987, 1990). It was shown later that type IV collagen, through several peptide domains, also exerted a biological eVect on blood cells, such as PMNs. The complete type IV collagen molecule extracted from EHS tumor had no significant eVect on superoxide production; however, it caused an increase in elastase and type IV collagenase production by PMNs. By

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contrast, type IV collagen prepared from bovine anterior lens capsule inhibited the activation of PMNs induced by addition of the bacterial peptide f‐Met‐Leu‐Phe. There was no inhibition if the latter collagen had been previously treated with pepsin (Monboisse et al., 1991a,b; Borel et al., 1992). A PMN suspension was first incubated for 30 minutes at 37
C in test tubes with type IV collagen from EHS tumor, with type IV collagen prepared from bovine lens capsule (Monboisse et al., 1990), or with synthetic peptides corresponding to sequences derived from the NC1 domain of type IV collagen (Kefalides et al., 1993). Then, PMNs were transferred to a second test tube and incubated for a further period of 15 minutes in the presence of the stimulating agent, such as f‐Met‐Leu‐Phe, phorbol myristate acetate, or collagen I, using saline as a control. The amount of O2 formed was measured in this medium at the end of the second incubation, by the SOD‐inhibitable reduction of ferricytochrome c method (Monboisse et al., 1987, 1990, 1994). Pepsinization of bovine lens capsule type IV collagen, which destroyed the NC1 domain, did not exhibit any inhibitory eVect. However, previous treatment of the same molecule with bacterial collagenase, which destroyed the collagenous domain, left the NC1 domain intact and capable of inhibiting PMN activation. It was deduced that the inhibitory activity was located in the NC1 domain. An important diVerence between the type IV collagen extracted from EHS tumor and that extracted from bovine lens capsule is the presence of only a1(IV) and a2(IV) chains in the former, whereas in the latter, additional chains a3, a4, a5, and a6(IV) are present. The biological activities of the whole a3(IV)NC1 domain and of the synthetic peptides derived from it were tested and compared with the sequences from the NC1 domains of the other a(IV) chains. The synthetic peptides had been prepared in a separate attempt to identify antigenic epitopes capable of giving rise to autoantibodies in disorders such as Goodpasture syndrome, and the particular sequences were selected based on the presence of b‐turns and on the degree of hydrophilicity and aromaticity. Comparison of the secondary structure of the a1(IV), a2 (IV), and a3(IV) NC1 domains revealed the presence of a‐helices, b‐turns, and b‐sheets (Kefalides et al. 1993). The exact location of the biological activity was found in a peptide of the a3(IV) chain comprising residues 185–203 of the NC1 domain of both human and bovine molecules (Monboisse et al., 1994). This sequence is CNYYSNSYSFWLASLDPKR. An additional feature that distinguishes the a3(IV) peptide 185–203 from those arising from a1(IV) and a2(IV) chains is the presence in the former of the triplet SNS corresponding to residues 189–191. Substitution of the serines with alanines in either position 189 or 191 of the peptide reduced the inhibitory activity, and substitution of both abolished it altogether. It was concluded that the sequence SNS is an absolute necessity for the biological activity. In addition, deletion of the cysteine in position 186 also resulted in

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a complete loss of the inhibitory activity. As mentioned above, in the complete type IV collagen molecule, as the sequence 185–203 of the a3 chain is contained within two b‐turns, the SNS triplet must reside within the two b turns (Kefalides et al., 1993; Monboisse et al., 1994). It is possible that in vivo, this sequence presents itself as a region that is exposed outside the molecule, a fact that is specific for the a3(IV) chain. It is also of interest to note that, in the case of inhibition of PMN activation, the full molecule of type IV collagen exhibits this type of inhibition as long as it contains the a3 chain. Type IV collagen extracted from lens capsule, or its NC1 domain, as well as the peptide a3(IV)185–203, elicit a rapid threefold increase in the PMN intracellular concentration of cAMP, whereas Ca2þ levels remain unchanged (Fawzi et al., 2000). Treatment of PMNs by forskolin, which activates adenylate cyclase, also abolishes the respiratory burst. The formation of cAMP by the NC1 domain is inhibited by pertussis toxin, demonstrating that a Gi protein might serve as an intermediate between a ‘‘receptor’’ for the a3(IV)185–203 peptide and adenylate cyclase. Cyclic AMP triggers the activation of protein kinase A. The peptide a3(IV)185–203 acts like a cytokine capable of preventing the activation of PMNs. The pathway is complicated by the fact that the binding of peptide a3(IV)185–203 to PMNs also induces a release of adenosine (or ATP) outside the cell. This adenosine binds back to an A2 membrane receptor, which activates adenylate cyclase and forms intracellular cAMP (Monboisse et al., 1998; Fawzi et al., 2000). The ability of the a3(IV) NC1 domain and of the a3(IV)185–203 peptide to inhibit superoxide production and proteolytic enzymes secretion by PMN could have a physiological eVect; namely, that the migration of PMNs from the lumen of the blood vessels toward an inflamed area occurs without producing too severe damage to the vascular BM. During transmigration, PMNs are likely to come in contact with the NC1 sequence a3(IV)185–203, temporarily preventing these cells from being fully activated. By contrast, any significant degradation of the vascular wall could induce the destruction of the inhibiting sequence, thus triggering a local activation of PMNs and contributing to the defense of the organism at the vessel wall level. The biological eVect of the peptide a3(IV)185–203 was also reproduced on monocytes (J. C. Monbasse, unpublished data) but has not been studied on other blood cells, except for red blood cells, where no eVect was found.

C. Effects of Type IV Collagen Matrikines on Angiogenesis Type IV collagen plays an important role in angiogenesis. Studies by Maragoudakis et al. (1993) demonstrated that the presence of type IV collagen in vascular basement membranes is an absolute necessity in the

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process of angiogenesis. The NC1 domains obtained from the a1 and the a2 chains induce adhesion and spreading of the endothelial cells (Koliakos et al., 1989; Tsilibary et al., 1990; Maragoudakis et al., 1993; Haralabopoulos et al., 1994). Attempts to identify specific domains of the type IV collagen that may influence angiogenesis led Kalluri and collaborators to identify antiangiogenic properties in recombinant peptides corresponding to the NC1 domains of a1(IV), a2(IV), and a3(IV) chains, which they named arresten, canstatin, and tumstatin, respectively (Colorado et al., 2000; Kamphaus et al., 2000; Maeshima et al., 2000a). These peptides inhibit endothelial cell proliferation and migration, with tumstatin being the most eYcient. They also inhibit in vitro angiogenesis, as shown in experiments in which formation of the tubular structures of mouse aortic endothelial cells embedded in Matrigel was blocked. Similarly, in vivo experiments demonstrated that arresten blocked formation of capillaries in Matrigel plugs inserted under the skin of mice. Antiangiogenic eVects have also been demonstrated in the chorio‐allantoic membrane model. Moreover, it was found that the recombinant NC1 domain of the a6(IV) chain shared the same inhibiting activity, whereas the a5(IV)NC1 domain had no eVect (Petitclerc et al., 2000). The sequence responsible for the inhibiting eVect of tumstatin on endothelial cell proliferation was located at residues 54–132 of the a3(IV)NC1 domain and was termed Tum‐5 (Maeshima et al., 2001a,b). This sequence, 54–132 (Tum‐ 5), is capable of inhibiting angiogenesis in vivo and in vitro by increasing apoptosis of endothelial cells, and it is far more active than tumstatin. As regards the membrane receptors involved in the action on endothelial cells of the peptides obtained from the type IV collagen NC1 domain, it is known that tumstatin binds to integrin avb3 (Maeshima et al., 2000a, 2001a). Peptide Tum‐5 also binds to the integrin avb3. It triggers a transduction pathway that blocks p125‐FAK, PI3‐kinase, protein kinase B (Akt), and mTOR. It prevents the dissociation of the eukaryotic initiation factor 4E from its inhibiting binding protein (Maeshima et al., 2002). The role of these integrins was confirmed in experiments in which the corresponding genes in the mouse were silenced, thus inducing inhibition of angiogenesis (Reynolds et al., 2002). In recent studies, Shahan et al. (2004) and Pasco et al. (2004a) presented data demonstrating that the a3(IV)185–203 peptide, and the longer analogue, a3(IV)179–208, inhibit angiogenesis through a mechanism that regulates endothelial cell proliferation, adhesion, and motility. Shahan et al. (2004) designated these two peptides as oncothanin because of their ability to inhibit tumor growth. The researchers’ data also indicate that oncothanin, when used as a chemo‐attractant, greatly enhances endothelial cell chemotaxis. By contrast, pre‐treatment of endothelial cells with oncothanin inhibits chemotaxis toward several diVerent chemo‐attractants. When oncothanin is

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used as a substrate, it enhances endothelial cell adhesion. Oncothanin inhibits angiogenesis in several assay systems, including endothelial cell diVerentiation (tube formation), aortic ring microvessel formation, and the chorioallantoic membrane assay. In the endothelial cell diVerentiation assay, oncothanin completely inhibits tube formation at 25 mg/mL, whereas peptides with comparable sequences from the NC1 domains of a1(IV) and a2 (IV) chains that lack the ‐SNS‐ triplet fail to inhibit tube formation. The complete a3(IV)NC1 domain and the sequence 185–203 both bind onto the avb3 integrin (Maeshima et al., 2000a; Pasco et al., 2000b; Shahan et al., 2000; Hamano et al., 2003). Data presented by Maeshima et al. (2001a) indicate that peptides derived from the a3(IV)68–88 region of the NC1 domain induce apoptosis of endothelial cells through binding with the integrin avb3 in an RGD‐independent manner. The more recent studies of Shahan et al. (2004), however, demonstrate that neither the intact type IV collagen molecule nor the NC1 domain or the oncothanin peptides promote endothelial cell apoptosis or death. The reason for the disparity between these two sets of results is at present unknown. These biological eVects on blood vessel formation are intimately linked to the problems of tumor growth and their metastatic propensity, as will be discussed in the next section.

D. Effects of Type IV Collagen Matrikines on Neoplastic Cell Adhesion and Metastasis 1. Cancer Cells Cross Vascular Basement Membranes Tumor progression is a complex phenomenon in which basement membranes are the target of cancer cells. During the local invasion by the tumor, or during the process of metastasis, individual cells or clusters of cells must get through the vascular basement membranes and into the blood circulation and, from there, cross other vascular membranes to enter the various target organs. The propensity of PMN to traverse vascular basement membranes is shared by neoplastic cells, which traverse epithelial as well as vascular basement membranes. This process requires that these cells, through their cell surface receptors, interact with components of the basement membranes. In addition, tumor growth is directly dependent on the process of angiogenesis because the formation of new vessels is necessary for the nourishment of cancer cells. It was therefore logical to test whether the components of basement membranes had any physiological eVects on the cancer cells from primary tumors as well as metastatic ones. Type IV collagen induces adhesion, spreading and migration of melanoma cells to a diVerent extent, depending in vitro on the cell lines and in vivo on

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the location and the type of tumor. Intact type IV collagen molecules, whether from EHS tumor or the lens capsule, induce adhesion, spreading, and migration of melanoma cells; however, they diVer on a number of other cellular reactions, including PMN activation, cell replication, motility, and metastatic propensity (Starkey et al., 1984; Han et al., 1997; Setty et al., 1998; Shahan et al., 2000; Xu et al., 2001). Partial degradation or denaturation may also modify the eVect of type IV collagen on melanoma cells, as is the case with the eVects of oxygen free radicals that may reveal a cryptic epitope (Kalluri et al., 2000). Actually, there are multiple sites along the molecules, with a major diVerence in the activities between the helical domains and the NC1 domains: the triple‐helical domain triggers cell adhesion and motility of tumor cells, whereas the NC1 domain, when it contains the sequence of the a3(IV) chain, 185–203, has a significant eVect of inhibiting cell divisions, motility, and metastatic propensity toward normal tissues. 2. EVects of the NC1 Domain of the a3(IV) Chain on Melanoma Cell Growth Several studies cited in the above discussion on the adhesion of melanoma cells to whole type IV collagen molecules also describe the inhibiting eVects of the individual NC1 domains (Maragoudakis et al., 1993; Tsilibary et al., 1990; Xu et al., 2001). It is well known that tumor growth is repressed when angiogenesis is inhibited locally. Using comparable techniques previously used for the study of the action of lens capsule–derived a3(IV)NC1 domain and the related peptides originating from that domain on PMNs, an inhibiting eVect of that NC1 domain of the a3(IV) chain extracted from bovine lens capsule was demonstrated on several types of metastatic tumor cells (Han et al., 1997). The biological activity of peptide 185–203 from the NC1 domain of the a3 (IV) chain was studied on a mouse melanoma model, in vivo (Floquet et al., 2004; Pasco et al., 2004b) as well as in vitro (Han et al., 1997; Shahan et al., 1999a; Pasco et al., 2000a; Floquet et al., 2004). It exerts a clear inhibiting activity on the in vitro replication of melanoma cells and the in vivo progression of a melanoma tumor. The medical interest of such studies is evident. Melanoma is a very aggressive and common cancer, whose incidence increases every year, as a result of prolonged exposure of the skin to the sun. It would be of interest to know whether one could inhibit its development through a drug as simple and as physiological as a peptide originating from normal tissues. Han et al. (1997) examined the ability of the complete a3(IV)NC1 domain and of the peptide a3(IV)185–203 to influence adhesion and proliferation of human metastatic melanoma cell lines such as WM9, WM164, and WM1361A, as well as HT‐144, UACC‐903, and a fibrosarcoma cell line

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(HT‐1080) and an osteosarcoma cell line (MG‐63). Cell binding assays on plastic plates coated with the synthetic peptides and cell proliferation assays after incubation with the peptides were performed. These studies demonstrated that the peptide a3(IV)185–203 not only promotes the adhesion of human melanoma cells but also inhibits their proliferation. Melanoma cell proliferation was inhibited by 40% when cells were grown in a medium containing the peptide. Normal skin fibroblasts used as a control did not show any significant inhibition of cell proliferation. As in the case of the eVect of the peptide on angiogenesis, replacement of serine in position 189 or 191 with alanine in the ‐SNS‐ triplet significantly reduced the biological activity on cell adhesion or proliferation (Han et al., 1997; Pasco et al., 2004a; Floquet et al., 2004). Melanoma cell adhesion was inhibited to an extent of 53–60% by addition of the monoclonal antibody to peptide a3(IV) NC1 179–208, a longer analogue of the peptide 185–203 (Han et al., 1997). A structural study of the peptide a3(IV)NC1 185–203 was made by circular dichroism, homology modeling, molecular dynamics simulations, adiabatic map calculation, and the clustering method (Floquet et al., 2004). It demonstrates that the b‐turn formed at the sequence YSNS is crucial for biological activity (Fig. 1). There appears to be a strong structure–function relationship. Two important questions were raised as a result of the above studies: what is the tumor cell membrane receptor for the peptide a3(IV)NC1 185–203, and what are the systems of intracellular signal transduction of the binding message, which work inside the cell? These questions were examined in a series of experiments that demonstrated that, although the

FIGURE 1 Structural figuration of the backbone atoms of the a3(IV)NC1 185‐203 peptide. Obtained by Monte‐Carlo simulations. From Floquet et al. J. Biol. Chem. 2004, 279, 2091. With permission of the American Society for Biochemistry and Molecular Biology.

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binding of collagen type IV helical domains occurs through cell membrane receptors such as the proteoglycan CD 44 or the b1 integrins, the NC1 domains of several a chains of type IV collagen do not bind to the same receptors. The avb3 integrin is largely responsible for melanoma progression. It binds the matrix metalloproteinase MMP‐2 and retains it on the cancer cell surface (Brooks et al., 1996). This association plays a great role in tumor angiogenesis and transendothelial migration of cancer cells. AYnity chromatography studies demonstrated that the a3(IV)NC1 185–203 peptide was capable of binding strongly to the integrin avb3 and the protein CD 47, which is usually associated with it (Shahan et al., 1999a). When cells were pretreated with monoclonal antibodies to this integrin, the biological eVect of the peptide was abolished. It was suggested that this integrin was the specific receptor for the a3(IV)NC1 domain 185–203. Further work using cells that express the integrin avb3 and the protein CD 47 separately demonstrated that the peptide was specifically binding onto the b3 chain, independent of the subunit av and the associated CD 47 protein (Pasco et al., 2000b). The binding site does not contain the RGD sequence. The binding causes a change in the conformation of the whole integrin, as demonstrated by the appearance of new epitopes LIBS 1 and 2 on the integrin (Pasco et al., 2003). The intracellular transduction pathway stimulated by the a3(IV) peptides comprises several mechanisms, among them the phosphorylation of cytoplasmic proteins such as p125FAK and PI3‐kinase (Shahan et al., 1999b, 2000; Pasco et al., 2000b). Wortmannin, a specific inhibitor of PI3‐kinase blocked the action of the peptide on melanoma cells. These findings have prompted an attempt at using an antiangiogenic peptide for therapeutic purposes (Van der Schaft et al., 2002). The recombinant NC1 domain from the a3 chain, tumstatin, exhibits antitumor properties. A recombinant sequence of tumstatin was shown to induce apoptosis of tumor cells and inhibition of neovascularization in vivo (Maeshima et al., 2000b). By contrast, the limited sequence 54–132 of tumstatin (peptide Tum‐5) has no influence on melanoma cell proliferation. It seems that the site of binding of Tum‐5 on the integrin avb3 is diVerent from that of the sequence 185–203 of the same a3(IV)NC1. Nevertheless, the peptide Tum‐5 may inhibit the tumor growth by limiting its vascularization. The avb3 integrin binds a complex of MMP‐14‐TIMP‐2, which acts as a pro‐ MMP‐2 receptor, and activates it, promoting cell migration. It is possible that the binding of the NC1 domain of a3(IV) chain prevents these eVects by inhibiting the avb3 integrin from binding to MMPs (Colorado et al., 2000; Marneros and Olsen, 2001; Hornebeck et al., 2002, Hornebeck and Maquart, 2003). Some studies pointed out a sequence homology between a region of the NC1 domain and the matrix metalloproteinases inhibitors

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TIMP (Netzer et al., 1998). These sequence homologies might explain the inhibiting eVect of NC1 on the activity of MMP‐2 and MMP‐3. Recombinant NC1 domains of a5(IV) and a6(IV) chains not only were slightly antiangiogenic but also slightly inhibited the CS1 melanoma tumor growth (Petitclerc et al., 2000). Arresten and canstatin have not been reported to have any eVect on melanoma cells. 3. EVect of Collagen IV and Derived Peptides on Other Types of Cancer Cells a. EVects of the a3(IV)‐NC1 Domain. Comparable studies were performed on other cancer cell lines isolated from tumors, such as fibrosarcoma, osteosarcoma, and stomach, pancreas, or breast cancers. It was found that the peptide a3(IV)NC1 185–203 also inhibits the proliferation of these types of cells, but with a lower intensity than for melanoma cells (Shahan et al., 1999a; Pasco et al., 2000a; Hornebeck et al., 2002). In fibrosarcoma cells of the type HT‐1080, and in the bronchial cells BZR, type IV collagen also exerts an inhibition of MMP‐14 (Martinella‐Catusse et al., 2001). In contrast, type IV collagen extracted from human placenta (which does not contain the a3 chain) activates proMMP‐2 in HT 1080 fibrosarcoma cells, a fact that might explain the increase of invasiveness of these tumor cells, as determined in an assay using this type of collagen (Maquoi et al., 2000). It has also been demonstrated that the expression of the a3(IV) chain is triggered in bronchogenic and alveolar tumors, although this chain is undetected in normal bronchi (Polette et al., 1997). The expression of this chain may represent a defense mechanism on the part of the host toward the neoplasm. Other experiments indicated that the a3(IV) chain may protect the lung against bronchial cancer extension, as the intact NC1 domain and the a3(IV)NC1 185–203 peptide inhibited the expression of MMP‐14 in bronchial tumor cell lines (Martinella‐Catusse et al., 2001). In contrast, in the case of stromal invasion by lung adenocarcinoma, a marked remodeling of type IV collagen occurs, leading to a progressive and specific loss of the expression of the a3, a4, and a5 chains (Nakano et al., 2001). It is remarkable that the progression of solid tumors may be aVected in a positive or a negative way, depending on the variable composition of type IV collagen molecules or on the composition of the various laminins. b. EVects of the NC1 Domains of the Other a Chains on Tumor Growth. Both arresten and canstatin, which derive from the NC1 domains of a1(IV) and a2(IV) chains, respectively, have been shown to inhibit tumor proliferation and metastasis in a prostatic adenoma model (Colorado et al., 2000). Canstatin inhibits endothelial cell proliferation and induces apoptosis

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(Kamphaus et al., 2000). The antiangiogenic eVect of canstatin was also described in papers by Panka and Mier (2003) and by He et al. (2003, 2004). 4. EVects of the Triple‐Helical Domains of Type IV Collagen on Melanoma Cells There are, along the triple‐helical domain of the type IV collagen molecules, multiple nonoverlapping sites capable of acting on melanoma cells. Some induce their adhesion, and others trigger their motility in a RGD‐ dependent or RGD‐independent manner (Chelberg et al., 1989). Several sequences such as a1(IV)531–543 and a1(IV) 1263–1277 have been found to increase the adhesion of melanoma cells on the basement membrane, and specifically on type IV collagen; similar eVects were demonstrated with cyanogen bromide peptides such as CB3(IV) (Chelberg et al., 1990; Vandenberg et al., 1991; Fields et al., 1993; Kern et al., 1993; Miles et al., 1994, 1995; Lauer et al., 1998; Lauer‐Fields et al., 2003). These sequences are recognized by receptors such as the transmembrane chondroitin sulfate proteoglycan CD 44 or by integrins of the b1‐group such as a3b1 (Knutson et al., 1996). The intracellular events following the binding of these ligands have not yet been fully characterized. Some experiments have shown the intervention of a pertussis toxin–sensitive G‐protein and an increase of calcium ion (Savarese et al., 1992). Other experiments have demonstrated that Ras and Rac GTPases followed by PI3‐kinase and protein kinase C participate in the melanoma cell migration on type IV collagen. In other cases, the pathway of NF‐kB seems to be involved, with an increase in the nuclear translocation of this mediator (Hodgson et al., 2003).

III. EFFECTS OF MATRIKINES DERIVED FROM COLLAGENS XV AND XVIII A. Structures The NC1 domains of the XV and XVIII basement membrane collagens display a structural homology. They are composed of three subdomains—a C terminal, an intermediate, and a trimer (See chapter 7 for the description of types XV and XVIII collagens). They have been perfectly conserved throughout evolution, and even more, their functions seem to have remained identical. For instance, in the invertebrate Hydra vulgaris, their NC1 domain has an inhibiting eVect on cell development and morphogenesis (Sarras et al., 1993; Zhang et al., 1994). A collagen of the same type exists in C. elegans where it serves to guide axons during development, as long as

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the trimeric NC1 domain has not been separated into peptide chains, which by themselves are without eVect (Ackley et al., 2001). In rodents, the complete trimeric NC1 domain of type XV collagen participates in the morphogenesis of the kidney and ureteric buds; however, the monomer has an inhibiting eVect (Karihaloo et al., 2001). It seems that the full trimeric domain participates in the association of the key components of basement membrane, whereas the separated chains competitively inhibit the process. The C‐terminal subdomain (20 kDa) of the NC1 domain of type XVIII collagen, which is liberated by proteolytic cleavage of the whole NC1 domain, has been termed endostatin by Judah Folkman’s group (O’Reilly et al., 1997). The structure of endostatin was verified by cloning of its gene (Dhanabal et al., 1999a). The C‐terminal subdomain of the NC1 domain of type XV collagen, after cleavage from the whole molecules, is named restin (Ramchandran et al., 1999), or endostatin‐like (Sasaki et al., 2000), because it presents a 60% sequence homology with endostatin. Both endostatin and restin have analogous folding of the protein chains and a similar crystal structure (Sasaki et al., 2000; Hohenester and Engel, 2002); however, endostatin presents a zinc‐binding site and a basic sequence comprising 11 arginine residues (Ricard‐Blum et al., 2004). Restin does not contain these two structural features.

B. Biological Properties of Endostatin Endostatin binds integrins a5b1, avb5, and avb3 (Rehn et al., 2001; Sudhakar et al., 2003), to heparin and heparan sulfate proteoglycans, such as glypican (Karumanchi et al., 2001). The binding to heparan sulfate occurs on two arginine residues of the basic sequence of endostatin and requires the presence of divalent cations (Ricard‐Blum et al., 2004). One of the primary roles of endostatin is to decrease angiogenesis (O’Reilly et al., 1997; Marneros and Olsen, 2001; Ortega and Zerb, 2002) by promoting apoptosis of the endothelial cells (Dhanabal et al., 1999b) and by competitively preventing the binding of the growth factors FGF‐2 and vascular endothelial growth factor (VEGF) to the cells. Their binding to the heparan sulfate chains of glypicans, which serve as a reservoir for these factors, inhibits their eVects (Dhanabal et al., 1999b; Taddei et al., 1999; Yamaguchi et al., 1999; You et al., 1999). Soluble endostatin induces the regression of tumors. It inhibits proliferation and migration of endothelial cells (Ortega and Werb, 2000; Rehn et al., 2001; Marneros and Olsen, 2001; Hanai et al., 2002). It inhibits tumor angiogenesis (O’Reilly et al., 1997; Boehm et al., 1997; Bergers et al., 1999; Blezinger et al., 1999; Dhanabal et al., 1999b; Yoon

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et al., 1999; Boehle et al., 2001; Kisker et al., 2001; Sorensen et al., 2002). It exerts morphogenetic eVects on the eye, and its absence results in ocular abnormalities (Li et al., 2000). Systemic administration of recombinant mouse endostatin suppressed the growth of Lewis lung carcinoma metastases, as well as the growth of primary tumors growing in syngeneic mice. The antiangiogenic and antitumor activity of endostatin has subsequently been demonstrated in a variety of diVerent tumors (e.g., renal or mammary carcinomas), which prompted the initiation of human clinical trials including gene transfer approaches (Joki et al., 200l; Read et al., 200l; Sauter et al., 2000).

C. Biological Properties of Restin The restin or endostatin‐like monomer formed from collagen XV (Ramchandran et al., 1999) corresponds to the NC1 domain of this collagen. It binds to nidogen‐2, fibulin‐1, or fibulin‐2, and to perlecan. Recombinant restin shows a weak binding aYnity for laminin‐1, and the laminin l–entactin/nidogen‐l complex. Further structural and functional characterization of the NC1 domain of type XV collagen demonstrated that it also contains a trimerization domain, a hinge region that is less sensitive to proteolysis than in collagen XVIII, and an endostatin‐like domain at the C‐terminus (Sasaki et al., 2000). The crystal structure of the endostatin‐like collagen XV fragment shows a very similar overall fold compared to the crystal structure of endostatin but contains no heparin‐binding site. Restin inhibits tumor growth and the migration of endothelial cells. Its trimer represses the angiogenesis induced by FGF‐2 or by VEGF in the chick chorio‐allantoic membrane model (Sasaki et al., 2000). The in vitro and in vivo antiangiogenic activities of restin have been demonstrated using recombinant protein. The recombinant type XV collagen NC1 domain has no promigratory activity on endothelial cells, as it fails to inhibit human endothelial cell tube formation on Matrigel was observed (Kuo et al., 2001).

D. Generation and Role of Endostatin and Restin Several diVerent immunoreactive NC1 fragments of collagens XV and XVIII have been extracted from tissues, and circulating forms have been isolated from human blood, indicating that these fragments exist as physiological cleavage products (Sasaki et al., 1998; John et al., 1999). Endostatin originally was purified from conditioned medium of a murine

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hemangioendothelioma cell line (EOMA) as a 20‐kDa fragment that binds to heparin (O’Reilly et al., 1997). Several distinct proteolytic pathways have been described in the generation of endostatin in various tissues. The proteases cathepsin L, MMP‐7, and pancreatic elastase are capable of eVecting the cleavage of endostatin from type XVIII collagen (Ferreras et al., 2000; Lin et al., 2001; Ortega and Werb, 2002). In vitro studies with the EOMA cell line have shown that the NC1 hinge domain contains cleavage sites for MMPs and cathepsin L. MMPs generate fragments of 30 kDa, containing the endostatin domain, whereas cathepsin L directly and specifically releases the 20‐kDa endostatin domain (Felbor et al., 2000). Other in vitro studies confirmed these results and showed that generation of endostatin is also mediated by elastase, after a first processing of NC1 by MMPs (Ferreras et al., 2000; Lin et al., 2001). In corneal epithelial cells, MMP‐7 generates a 28‐kDa NC1 (collagen XVIII) fragment (Lin et al., 2001). The interaction of type XVIII collagen with basement membranes indicates a local regulatory role of endostatin in vessel growth. Circulating endostatin may participate in regulating angiogenesis, as its concentration in serum (100–300 ng/mL) is similar to the concentrations that eYciently inhibit endothelial cell proliferation in vitro (Sasaki et al., 2000). It is of interest to note that patients with Knobloch syndrome (see p. 212) do not show increased frequency of vascular abnormalities (Marneros and Olsen, 2001). Similarly, COL 18A1 endostatin‐deficient mice display no major vascular abnormalities. These data indicate that endostatin does not appear to be a rate‐limiting regulator of vessel growth. Kim et al. (2000) and Lee et al. (2002) reported that endostatin is a protease inhibitor. The catalytic activity of MMP‐2 was shown to be inhibited: this is an important finding, as MMPs are produced by endothelial cells and proteolytically degrade the perivascular extracellular matrix during sprouting angiogenesis. Thus, locally generated endostatin at sites of induced angiogenesis may directly inhibit MMP activity. Recent data have shown a direct interaction of endostatin with the catalytic domain of MMP‐2 (Lee et al., 2002). The studies by O’Reilly et al. (1997) showed that the apoptosis rate of tumor cells in endostatin‐treated tumor‐bearing mice was significantly higher than in untreated mice. It was concluded that this high rate of apoptosis in endostatin‐treated tumors reflected the inhibition of angiogenesis. In subsequent studies, Dhanabal et al. (1999b) demonstrated that endostatin could induce apoptosis in endothelial cells in a process that is dependent on tyrosine phosphorylation of the adaptor protein Shb (Dixelius et al., 2000). A direct interaction between endostatin and the VEGF receptor 2 has been described by Kim et al. (2002). This eVect interferes with the binding of VEGF to its receptors, VEGF‐R2 and VEGF‐R1.

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IV. EFFECTS OF THE MATRIKINES FORMED FROM LAMININ AND FROM OTHER PROTEINS, AND PROTEOGLYCANS OF THE BASEMENT MEMBRANE A. Laminin Matrikines The long sequences of the many chains of laminin furnish a large repertory of putative peptides capable of exerting biological eVects, the knowledge of which is still fragmentary compared to that of the fragments of collagens. Several studies with laminin were carried out by Hynda Kleinman’s group (Kleinman et al., 1989; Nomizu et al., 1993; Kuratomi et al., 1999). In their initial studies, the researchers used isolated peptides corresponding to sequences of the laminin‐1 chains and, more recently, the screening of the biological eVects exerted by overlapping synthetic peptides that permitted the detection of many active sites located on all polypeptide chains. The first laminin‐derived peptide to be characterized had the sequence SIKVAV, corresponding to a site of the a1 chain that promoted mouse tumor growth and metastases, particularly when coinjected with Matrigel (Sweeney et al., 1991). It was found that the stimulation of tumor growth and of metastatic propensity of this peptide was stereochemically specific: when it was made of L‐amino acids, it was activating, and when it was made of D‐amino acids, it exerted an inhibitory eVect (Alminana et al., 2004). The same peptide stimulated angiogenic activity in mice and in mouse tumors (Kibbey et al., 1992; Grant et al., 1992). The eVects of SIKVAV were documented by the finding that this peptide stimulated the synthesis by polymorphonuclear leukocytes of factors inducing the proliferation of human umbilical vein endothelial cells in vitro (Kibbey et al., 1994). The same peptide was found to promote the diVerentiation of primary neurons and of a variety of neural cell lines (Kibbey et al., 1995). Another peptide, YIGSR, corresponding to a sequence contained in the laminin b1 chain, was shown to decrease tumor growth and metastases in nude mice, particularly when it was injected intravenously with Matrigel. Its action was explained by its binding to the 67‐kDa laminin receptor, which was considered to be the receptor for the malignancy‐stimulating eVect of the whole laminin‐1 (Nomizu et al., 1993; Yamamura et al., 1933; Zhao et al., 1994b). In addition, this peptide induces the apoptosis of cancer cells (Kim et al., 1994). Another peptide from the laminin‐1 a1 chain, designated AG‐73, having the sequence LQVQLSIR, was found to enhance in vitro adhesion, migration, invasion, and gelatinase production and in vivo lung colonization and metastases to the liver of the B16‐F10 murine melanoma cells (Song et al. 1997). The screening of 405 overlapping synthetic peptides with sequences

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identical to those of laminin a1 and b1 chains resulted in the selection of 13 peptides that stimulated endothelial cell adhesion and tube formation on Matrigel (Malinda et al., 1999). The screening of 208 overlapping synthetic peptides covering the short arm and the long arm of the laminin a1 chain permitted the selection of 19 peptides showing B16‐F10 cell adhesion activity and four peptides that promoted metastases (Kuratomi et al., 1999). In addition, the screening of 545 overlapping synthetic peptides corresponding to most of the amino acid sequences of laminin‐1 (a1, b1, and g1 chains) furnished 23 peptides active on cell attachment and neurite outgrowth (Powell et al. 2000). Using the same screening technique, Nomizu et al. (2001) demonstrated that the domain IV of laminin a2 contains four adhesion sequences for HT‐1080 human fibrosarcoma cells, whereas that of the a3 and a5 chains each contain two adhesion sequences (Nomizu et al., 2001). Laminins play a role in angiogenesis and in the dissemination of cancers (Patarroyo et al., 2002). Cancer cells often attack the laminins of basement membranes during the process of invasion, and liberate peptides (Pyke et al., 1994, 1995; Ma¨ a¨ tta¨ et al., 2001). The laminin a1 chain is overexpressed in colonic cancer cells, and these chains seem responsible for the activation of the growth of the tumor (De Arcangelis et al., 2001). The laminin a2 chain increases the adhesion of melanoma cells (Jenq et al., 1994; Han et al., 1999). The screening of 559 overlapping synthetic peptides corresponding to laminin chains a1, b1, and g1 identified 20 angiogenic sites. The two most potent sites are located on the a1 chain (RQVFQVAYIIIKA) and the g1 chain (peptide C16, KAFDITYVRLKF), which is angiogenic in vivo (Ponce et al., 2001, 2003). The latter sequence, when scrambled into DFKLFAVTIKYR, exerts an inhibiting eVect on angiogenesis. The same peptide C16 promotes the migration of B16‐F10 mouse melanoma cells, their secretion of MMP‐9, and the formation of pulmonary metastases in vivo (Kuratomi et al., 2002). In chapter 10, we underlined the importance of the contacts between the LG globular domains of the various laminins and cells, which adhere on it through diverse membrane molecules. Depending on its degree of proteolysis, laminin‐5 may act as a factor of motility for cells (when cleaved by plasmin), and in other instances (when cleaved oV by MMP‐14) as an adhesive factor (Goldfinger et al., 1998; Koshikawa et al., 2000). The cleavage of laminin‐5 by MMP‐2 or by MMP‐14 furnishes a fragment of the g2 chain that increases the mobility of the cells (Gianelli et al., 1997, 1999; Koshikawa et al., 2000). Fragments of the LG2 domain of laminin interfere with the binding of this protein on the N‐linked HNK‐carbohydrate expressed in postnatal cerebellar neurons (Hall et al., 1995). The LG4–LG5 sequence of the a3 chain of laminin‐5 stimulates epithelial cell migration (Tsubota et al., 2000). Twenty peptides from the LG domain of the a4 chain have been shown to compete with the binding of heparin to

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laminin 8/9 (Okazaki et al., 2002). Another study of 113 overlapping synthetic peptides corresponding to sequences of the C‐terminal domain of laminin a1 chain found that three sequences, SIYITRF, IAFQRN, and LQVQLSIR, highly conserved among diVerent species, promote tumor cell attachment activities (Nomizu et al., 1995; Hibino et al., 2004). Three sequences from the mouse LG4 module promote fibroblast attachment, whereas another one inhibits this adhesion (Suzuki et al., 2003). Some studies have thrown some light on the plasma membrane molecules that are responsible for these bindings. The a3 chain LG domain binds to heparin and to syndecan‐2 and syndecan‐4 (Utani et al., 2001).

B. Protein SPARC Matrikines Protein SPARC is degraded into peptides, which inhibit endothelial cell proliferation (Ricard‐Blum, 2003). Another peptide liberated from SPARC, termed 2.3 (residues 113–130), contains a copper‐binding site and stimulates the proliferation of endothelial cells and angiogenesis (Yan and Sage, 1999; Brekken and Sage, 2001).

C. Proteoglycan Matrikines The C‐terminus of the perlecan core protein inhibits endothelial cell migration, collagen‐induced endothelial tube morphogenesis, and blood vessel growth in the chorioallantoic membrane and in Matrigel plug assays. It blocks endothelial cell adhesion to fibronectin and to type I collagen without directly binding to either protein. It acts at nanomolar concentration, and it exerts an antiangiogenic eVect. It was termed endorepellin (Mongiat et al., 2003; Bix et al., 2004; Bix and Iozzo, 2005). Its liberation by enzymatic proteolysis was demonstrated in vivo (Gonzalez et al., 2004). Some nonprotein matrikines are formed by degradation of the basement membrane proteoglycans. Hyaluronidase separates oligosaccharides containing 4–25 dissacharide units that exert an angiogenic eVect (West et al., 1985; Rooney et al., 1995; Noble, 2002).

V. CONCLUSION In this chapter we described several new biological functions shared by at least three collagen molecules, type IV, type XV, and type XVIII, and their NC1 domains. In addition, other noncollagen proteins, such as laminin,

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SPARC, and the protein core of some proteoglycans exhibit similar functions. It is of interest to note that the NC1 domains of type IV collagen all exert antitumoral or antiangiogenic eVects, whereas laminin matrikines exert protumoral eVects. As immobilized substrates, fragments of the NC1 domains can induce migration and proliferation, depending on the cell type; however, soluble forms act in the opposite way, inhibiting proliferation and migration and, in some cases, inducing apoptosis. In terms of invasive processes such as neutrophil transmigration, angiogenesis, or tumor invasion—processes that depend on protease activity—partial degradation of the matrix may reveal some cryptic sites, exposing NC1‐immobilized domains, and leading to binding to cell surface integrins, thus activating diVerent intracellular pathways. One of these processes is exemplified by the inhibitory eVect of the a3(IV) peptides on neutrophil activation, which occurs in vitro and most likely occurs in vivo. Continued proteolytic activity on the extracellular matrix may release high local amounts of soluble fragments, capable of inhibiting proliferation of migrating cells, leading to stabilization of new vessels, or may induce regression of neovascularization. References Ackley, B. D., Crew, J. R., Elamaa, H., Pihlajaniemi, T., Kuo, C. J., and Kramer, J. N. (2001). The NC‐1/endostatin domain of Caenorhabditis elegans type XVIII collagen aVects cell migration and axon guidance. J. Cell Biol. 152, 1219–1232. Alminana, N., Grau‐Oliete, M. R., Reig, F., and Rivera‐Fillat, M. P. (2004). In vitro eVects of SIKVAV retro and retro‐enantio analogues on tumor metastatic events. Peptides 25, 251–259. Bergers, G., Jahaverian, K., Lo, K., Folkman, J., and Hanahan, D. (1999). EVects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284, 808–812. Bix, G., Fu, J., Gonzalez, E. M., Macro, L., Barker, A., Campbell, S., Zutter, M. M., Santoro, S. A., Kim, J. K., Hook, M., Reed, C. C., and Iozzo, R. V. (2004). Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through a2b1 integrin. J. Cell Biol. 166, 97–109. Bix, G., and Iozzo, R. V. (2005). Matrix revolutions: ‘‘tails’’ of basement‐membrane components with angiostatic functions. Trends Cell Biol. 15, 52–60. Blezinger, P., Wang, J., Gondo, M., Quezada, A., Mehrens, D., French, M., Singhal, A., Sullivan, S., Rolland, A., Ralston, R., and Min, W. (1999). Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene. Nat. Biotechnol. 17, 343–348. Boehle, A. S., Kurdow, R., Schultze, M., Kliche, U., Sipos, B., Soondrum, K., Ebrahimnejad, A., Dorhmann, P., KalthoV, H., Henne‐Bruns, D., and Neumaier, M. (2001). Human endostatin inhibits growth of human non small‐cell lung cancer in a murine xenotransplant model. Int. J. Cancer 94, 420–428. Boehm, T., Folkman, J., Browder, D., and O’Reilly, M. R. (1997). Angiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390, 404–407. Borel, J. P., Bellon, G., Garnotel, R., and Monboisse, J. C. (1992). Adhesion and activation of human neutrophils on basement membrane molecules. Kidney Intern. 43, 26–29.

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Brekken, R. A., and Sage, E. H. (2001). SPARC, a matricellular protein: At the crossroads of cell‐matrix communication. Matrix Biol. 19, 816–827. Brooks, P. C., Stro¨ mblad, S., Sanders, L. C., Von Schalscha, T. L., Aimes, R. T., Staetler‐ Stevenson, W. G., Quigley, J. P., and Cheresh, D. A. (1996). Localisation of matrix metalloproteinase MMP‐2 to the surface of invasive cells by interaction with integrin aVb3. Cell 85, 683–693. Chelberg, M. K., Tsilibary, E. C., Hauser, A. R., and McCarthy, J. B. (1989). Type IV collagen‐ mediated melanoma cell adhesion and migration: Involvement of multiple distinct domains of the collagen molecule. Cancer Res. 49, 4796–4802. Chelberg, M. K., McCarthy, J. B., Skubitz, A. P. N., Furcht, L. T., and Tsilibary, E. C. (1990). Characterization of a synthetic peptide from type IV collagen that promotes melanoma cell adhesion, spreading and motility. J. Cell Biol. 11, 262–270. Colorado, P. C., Torre, A., Kamphaus, G., Maeshima, Y., Hopfer, H., Takahashi, K., Volk, R., Zamborsky, E. D., Herman, S., Sarkar, P. K., Ericksen, M. B., Dhanabal, M., Simons, M., Post, M., Kufe, D. W., Weichselbaum, R. R., Sukhatme, V. P., and Kalluri, P. (2000). Anti‐ angiogenic cues from vascular basement membrane collagen. Cancer Res. 60, 2520–2526. Davis, T. P., Gillespie, T. J., and Porreca, F. (1989). Peptide fragments derived from the b chain of hemoglobin (hemorphins) are centrally active in vivo. Peptides 10, 747–751. Davis, G. E., Bayless, K. J., Davis, M. J., and Meininger, G. A. (2000). Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. Am. J. Pathol. 156, 1489–1498. De Arcangelis, A., Lefebvre, O., Mechine‐Neuville, A., Arnold, C., Klein, A., Re´ my, L., Kedinger, M., and Simon‐Assman, P. (2001). Overexpression of laminin a1 chain in colonic cancer cells induces an increase in tumor growth. Int. J. Cancer. 94, 44–53. Dhanabal, M., Volk, R, Ramchandran, R., Simons, M., and Sukhatme, V. P. (1999a). Cloning, expression and in vitro activity of human endostatin. Biochem. Biophys. Res. Commun. 258, 345–352. Dhanabal, M., Ramchandran, R., Waterman, M. J. F., Lu, H., Knebelmann, B., Segal, M., and Sukhatme, V. P. (1999b). Endostatin induces endothelial cell apoptosis. J. Biol. Chem. 274, 11721–11726. Dixelius, J., Larsson, H., Sasaki, T., Holmqvist, K., Lu, L., Engstrom, A., Timpl, R., Welsh, M., and Claesson‐Welsh, L. (2000). Endostatin‐induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood 95, 3403–3411. Dumin, J. A., Dickeson, S. K., Stricker, T. P., Bhattacharyya‐Pakrasi, M., Roby, J. D., Santoro, S. A., and Parks, W. C. (2001). Pro‐collagenase‐1 (matrix metalloproteinase‐1) binds the a2b1 integrin upon release from keratinocytes migrating on type I collagen. J. Biol. Chem. 276, 29368–29374. Fawzi, A., Robinet, A., Monboisse, J. C., Ziaie, Z., Kefalides, N. A., and Bellon, G. (2000). A peptide of the a3(IV) chain of type IV collagen modulates stimulated neutrophil function via activation of cAMP‐dependant protein kinase and Ser/Thr protein phosphatase. Cell Signal. 12, 327–335. Felbor, U., Dreier, L., Bryant, R. A., Ploegh, H. L., Olsen, B. R., and Mothes, W. (2000). Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J. 19, 1187–1194. Ferreras, M., Felbor, U., Lenhard, T., Olsen, B. R., and Delaisse, J‐M. (2000). Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett. 486, 247–251. Fields, C. G., Mickelson, D. J., Drake, S. L., McCarthy, J. B., and Fields, G. B. (1993). Melanoma cell adhesion and spreading on a synthetic 124‐residues triple‐helical ‘‘mini‐ collagen.’’ J. Biol. Chem. 268, 14153–14160.

13. Novel Biological Properties of Peptides

403

Floquet, N., Pasco, S., Ramont, L., Derreumaux, P., Laronze, J. Y., Nuzillard, J. M., Maquart, F. X., Alix, A. J., and Monboisse, J. C. (2004). The antitumor properties of the a3(IV)‐ (185–203) peptide from the NC1 domain of type IV collagen (tumstatin) are conformation‐ dependent. J. Biol. Chem. 279, 2091–2100. Gianelli, G., Falk‐Marzillier, J., Schiraldi, O., Stetler‐Stevenson, W. G., and Quaranta, V. (1997). Induction of cell migration by matrix metalloproteinase‐2 clivage of laminin‐5. Science 277, 225–228. Gianelli, G., Pozzi, A., Stetler‐Stevenson, W. G., Gardner, H. A., and Quaranta, V. (1999). Expression of matrix metalloproteinase‐2 cleaved laminin‐5 in breast remodelling stimulated by sex‐steroids. Amer. J. Path. 154, 1193–1201. Goldfinger, L. E., Stack, M. S., and Jones, J. C. R. (1998). Processing of laminin‐5 and its functional consequences: Role of plasmin and tissue‐type plasminogen activator. J. Cell Biol. 141, 255–265. Gonzalez, E. M., Reed, C. C., Bix, G., Fu, J., Zhang, Y., Gopalakrishnan, B., Greenspan, D. S., and Iozzo, R. V. (2004). BMP‐1/tolloid‐like metalloproteases process endorepellin, the angiostatic C‐terminal fragment of perlecan. J. Biol. Chem. In press. Grant, D. S., Kinsella, J. L., Fridman, R., Auerbach, R., Piasecki, B. A., Yamada, Y., Zain, M., and Kleinman, H. K. (1992). Interaction of endothelial cells with a laminin A chain peptide (SIKVAV) in vitro and induction of angiogenic behavior in vivo. J. Cell Physiol. 153, 614–625. Hall, H., Vorherr, T., and Schacher, M. (1995). Characterization of a 21 amino acid peptide sequence of the laminin domain that is involved in HNK‐1 carbohydrate binding and cell adhesion. Glycobiology 5, 435–441. Hamano, Y., Zeisberg, M., Sugimoto, H., Lively, J. C., Maeshima, Y., Yang, C., Hynes, R. O., Werb, Z., Sudhakar, A., and Kalluri, R. (2003). Physiological levels of tumstatin, a fragment of collagen IV a3 chain are generated by MMP‐9 proteolysis and suppress angiogenesis via avb3 integrin. Cancer Cell 3, 589–601. Han, J., Ohno, N., Pasco, S., Monboisse, J. C., Borel, J. P., and Kefalides, N. A. (1997). A cell binding domain from the a3 chain of type IV collagen inhibits proliferation of melanoma cells. J. Biol. Chem. 272, 20395–20401. Han, J., Jenq, W., and Kefalides, N. A. (1999). Integrin a2b1 recognizes laminin‐2 and induces C‐erb B2 tyrosine phosphorylation in metastatic human melanoma cells. Connect. Tissue Res. 40, 283–293. Hanai, J.‐L., Dhanabai, M., Karumanchi, S. A., Albanese, C., Waterman, M., Chan, B., Ramchandran, R., Pestell, R., and Sukhatme, V. P. (2002). Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1. J. Biol. Chem. 277, 16464–16469. Haralabopoulos, G. C., Grant, D. S., Kleinman, H. K., Lelkes, P. I., Papaioannou, S. P., and Maragoudakis, M. E. (1994). Inhibitors of basement membrane synthesis prevent endothelial cell alignment in matrigel in vitro and angiogenesis in vivo. Lab. Invest. 71, 575–582. He, G. A., Luo, J. X., Zhang, T. Y., Wang, F. Y., and Li, R. F. (2003). Canstatin‐N fragment inhibits in vitro endothelial cell proliferation and suppresses in vivo tumor growth. Biochem. Biophys. Res. Commun. 312, 801–805. He, G. A., Luo, J. X., Zhang, T. Y., Hu, Z. S., and Wang, F. Y. (2004). The C‐terminal domain of canstatin suppresses in vivo tumor growth associated with proliferation of endothelial cells. Biochem. Biophys. Res. Commun. 318, 354–360. Hibino, S., Shibuya, M., Engbring, J. A., Mochizuki, M., Nomizu, M., and Kleinman, H. K. (2004). Identification of an active site on the laminin a5 chain globular domain that binds to CD44 and inhibits malignancy. Cancer Res. 64, 4810–4816. Hodgson, L., Henderson, A. J., and Dong, C. (2003). Melanoma cell migration to type IV collagen requires activation of NF‐kB. Oncogene 22, 98–108.

404

Kefalides and Borel

Hohenester, E., and Engel, J. (2002). Domain structure and organization in extracellular matrix proteins. Matrix Biol. 21, 115–128. Hornebeck, W., Emonard, H., Monboisse, J. C., and Bellon, G. (2002). Matrix‐directed regulation of pericellular proteolysis and tumor progression. Sem. Cancer Biol. 12, 231–241. Hornebeck, W., and Maquart, F. X. (2003). Proteolyzed matrix as a template for the regulation of tumor progression. Biomed. Pharmacoth. 57, 223–230. Jenq, W., Wu, S. J., and Kefalides, N. A. (1994). Expression of the a2‐subunit of laminin correlates with increased cell adhesion and metastatic propensity. DiVerentiation 58, 29–36. John, H., Preissner, K. T., Forssmann, W. G., and Standker, L. (1999). Novel glycosylated forms of human plasma endostatin and endostatin‐related fragments of collagen XV. Biochemistry 38, 10217–10224. Joki, T., Machluf, M., Atala, A., Zhu, J., Seyfried, N. T., Dunn, I. F., Abe, T., Carroll, R. S., and Black, P. M. (2001). Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. Nat Biotechnol. 19, 35–39. Kalluri, R., Cantley, L. G., Kerjaschki, D., and Neilson, E. G. (2000). Reactive oxygen species expose cryptic epitopes associated with autoimmune Goodpasture syndrome. J. Biol. Chem. 275, 20027–20032. Kamphaus, G. D., Colorado, P. C., Panka, D. J., Hopfer, H., Ramchandran, R., Torre, A., Maeshima, Y., Mier, J. W., Sukhatme, V. P., and Kalluri, R. (2000). Canstatin, a novel matrix‐derived inhibitor of angiogenesis and tumor growth. J. Biol. Chem. 275, 1209–1215. Karihaloo, A., Karumanchi, S. A., Barasch, J., Jha, V., Nickel, C. H., Yang, J., Grisaru, S., Bush, K. T., Nigam, S., Rosenblum, N. D., Sukhatme, V. P., and Cantley, L. G. (2001). Endostatin regulates branching morphogenesis of renal epithelial cells and ureteric bud. Proc. Natl. Acad. Sci. USA 98, 12509–12514. Karumanchi, S. A., Jha, V., Ramchandran, R., Karihaloo, A., Tsiokas, L., Chan, B., Dhanabal, M., Hanai, J. I., Venkataraman, G., Shriver, Z., Keiser, N., Kalluri, R., Zeng, H., Mukhopadhyay, D., Chen, R. L., Lander, A. D., Hagihara, K., Yamaguchi, Y., Sasisekharan, R., Cantley, L., and Sukhatme, V. P. (2001). Cell surface Glypicans are low‐ aYnity endostatin receptors. Mol. Cell 7, 811–822. Kefalides, N. A., Ohno, N., Wilson, C. B., Fillit, H., Zabriski, J., and Rosenbloom, J. (1993). Identification of antigenic epitopes in type IV collagen by use of synthetic peptides. Kidney Int. 43, 94–100. Kern, A., Eble, J., Golbik, R., and Ku¨ hn, K. (1993). Interaction of type IV collagen with the isolated integrins a1b1 and a2b1. Eur. J. Biochem. 215, 151–159. Kibbey, M. C., Grant, D. S., and Kleinman, H. K. (1992). Role of the SIKVAV site of laminin in promotion of angiogenesis and tumor growth: An in vivo Matrigel model. J. Natl. Cancer Inst. 84, 1633–1638. Kibbey, M. C., Corcoran, M. L., Wahl, L. M., and Kleinman, H. K. (1994). Laminin SIKVAV peptide‐induced angiogenesis in vivo is potentiated by neutrophils. J. Cell Physiol. 160, 185–193. Kibbey, M. C., Johnson, B., Petryshyn, R., Jucker, M., and Kleinman, H. K. (1995). A 110‐kD nuclear shuttling protein, nucleolin, binds to the neurite‐promoting IKVAV site of laminin‐1. J. Neurosci. Res. 42, 314–322. Kim, W. H., Schnaper, H. W., Nomizu, M., Yamada, Y., and Kleinman, H. K. (1994). Apoptosis in human fibrosarcoma cells is induced by a multimeric synthetic Tyr‐Ile‐Gly‐ Ser‐Arg (YIGSR)‐containing polypeptide from laminin. Cancer Res. 54, 5005–5010. Kim, Y. M., Jang, J. W., Lee, O. H., Yeon, J., Choi, E. Y., Kim, K. W., Lee, S. T., and Kwon, Y. G. (2000). Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase. Cancer Res. 60, 5410–5413.

13. Novel Biological Properties of Peptides

405

Kim, Y. M., Hwang, S., Kim, Y. M., Pyun, B. J., Kim, K. W., Lee, S. T., and Kwon, Y. G. (2002). Endostatin blocks VEGF‐mediated signaling via direct interaction with KDR/ Flk‐1. J. Biol. Chem. 277, 27872–27879. Kisker, O., Becker, C. M., Prox, D., Fannon, M., D’Amato, R., Flynn, E., Fogler, W. E., Sim, B. K., Allred, E. N., Pirie‐Shepherd, S. R., and Folkman, J. (2001). Continuous administration of endostatin by intraperitoneally implanted osmotic pumps improves the eYcacy and potency of therapy in a mouse xenograft tumor model. Cancer Res. 61, 7669–7674. Kleinman, H. K., Graf, J., Iwamoto, Y., Saski, M., Schasteen, C. S., Yamada, Y., Martin, G. R., and Robey, F. A. (1989). Identification of a second active site in laminin for promotion of cell adhesion and migration and inhibition of in vivo melanoma lung colonization. Arch. Biochem. Biophys. 272, 39–45. Knutson, J. R., Iida, J, Fields, G. B., and McCarthy, J. B. (1996). CD 44/chondroitin sulfate proteoglycan and a2b1 integrin mediate human melanoma cell migration on type IV collagen of basement membrane. Mol. Cell Biol. 7, 383–396. Koliakos, G. G., Kouzi‐Koliakos, K., Furcht, L. T., Reger, L. A., and Tsilibary, E. C. (1989). The binding of heparin to type IV collagen: Domain specificity with identification of peptide sequences from the a1(IV) and a2(IV) chains which specifically bind heparin. J. Biol. Chem. 264, 2313–2323. Koshikawa, N., Gianelli, G., Cirulli, V., Miyazaki, K., and Quaranta, V. (2000). Role of cell surface metalloproteinase MT1‐MMP in epithelial cell migration over laminin‐5. J. Cell Biol. 148, 255–265. Kuo, C. J., Lamontagne, K. R., Jr., Garcia‐Cardena, G, Ackley, B. D., Kalman, D., Park, S., ChristoVerson, R., Kamihara, J., Ding, Y. H., Lo, K. M., Gillies, S., Folkman, J., Mulligan, R. C., and Javaherian, K. (2001). Oligomerization‐dependent regulation of motility and morphogenesis by the collagen XVIII NC1/endostatin domain. J. Cell Biol. 152, 1233–1246. Kuratomi, Y., Nomizu, M., Nielsen, P. K., Tanaka, K., Song, S. Y., Kleinman, H. K., and Yamada, Y. (1999). Identification of metastasis‐promoting sequences in the mouse laminin a1 chain. Exp. Cell Res. 249, 386–395. Kuratomi, Y., Nomizu, M., Tanaka, K., Ponce, M. L., Komiyama, S., Kleinman, H. K., and Yamada, Y. (2002). Laminin g1 chain peptide, C‐16 (KAFDITYVRLKF), promotes migration, MMP‐9 secretion, and pulmonary metastasis of B16‐F10 mouse melanoma cells. Br. J. Cancer. 86, 1169–1173. Lauer, J. L., Gendron, C. M., and Fields, G. B. (1998). EVect of ligand conformation on melanoma cell a3b1 integrin‐mediated signal transduction events: Implications for a collagen structural modulation mechanism of tumor cell invasion. Biochemistry 37, 5279–5287. Lauer‐Fields, J. L., Malkar, N. B., Richet, G., Dauz, K., and Fields, G. B. (2003). Melanoma cell CD 44 interaction with the a1(IV) 1236–1277 region from basement membrane collagen is modulated by ligand glycosylation. J. Biol. Chem. 278, 14321–14330. Lee, S. J., Jang, J. W., Kim, Y. M., Lee, H. I., Jeon, J. Y., Kwon, Y. G., and Lee, S. T. (2002). Endostatin binds to the catalytic domain of matrix metalloproteinase‐2. FEBS Lett. 519, 147–152. Li, D., Clark, C. C., and Myers, J. C. (2000). Basement membrane zone type XV human collagen is a disulfide‐bonded chondroitin sulfate proteoglycan in human tissues and cultured cells. J. Biol. Chem. 275, 22339–22347. Lin, H. C., Chang, J‐H., Jain, S., Gabison, E. E., Kure, T., and Kato, T. (2001). Matrilysin cleavage of corneal collagen type XVIII NC1 domain and generation of a 28‐kDa fragment. Invest. Ophthalmol. Vis. Sci. 42, 2517–2524.

406

Kefalides and Borel

Ma¨ a¨ tta¨ , M., Virtanen, I., Burgeson, R., and Autio‐Harmainen, H. (2001). Comparative analysis of the distribution of laminin chains in the basement membranes in some malignant epithelial tumors: The a1 chain of laminin shows a selected expression pattern in human carcinomas. J. Histochem. Cytochem. 49, 711–725. Maeshima, Y., Colorado, P. C., and Kalluri, R. (2000a). Two RGD‐independent avb3 integrin binding sites on tumstatin regulate anti‐tumor properties. J. Biol. Chem. 275, 23745–23750. Maeshima, Y., Colorado, P. C., Torre, A., Holthaus, K. A., Grunkmeyer, J. A., Ericksen, M. B., Hopfer, H., Xiao, Y., Stillman, I. E., and Kalluri, R. (2000b). Distinct antitumor properties of a type IV collagen domain derived from basement membrane. J. Biol. Chem. 275, 21340–21348. Maeshima, Y., Manfredi, M., Reimer, C., Holthaus, K. A., Hopfer, H., Chandamuri, B. R., Kharbanda, S., and Kalluri, R. (2001a). Identification of the antiangiogenic site within vascular basement membrane‐derived tumstatin. J. Biol. Chem. 276, 15240–15248. Maeshima, Y., Yerramalla, U. L., Dhanabal, M., Holthaus, K. A., Barbashov, S., Kharbanda, S., Reimer, C., Manfredi, M., Dickerson, W. M., and Kalluri, R. (2001b). Extra cellular matrix‐derived peptide binds to avb3 integrin and inhibits angiogenesis. J. Biol. Chem. 276, 31959–31968. Maeshima, Y., Sudhakar, A., Lively, J. C., Ueki, K., Kharbanda, S., Khan, C. R., Sonnenberg, N., Hynes, R. O., and Kalluri, R. (2002). Tumstatin, an endothelial cell‐specific inhibitor of protein synthesis. Science 295, 140–143. Malinda, K. M., Nomizu, M., Chung, M., Delgado, M., Kuratomi, Y., Yamada, Y., Kleinman, H. K., and Ponce, M. L. (1999). Identification of laminin a1 and b1 chain peptides active for endothelial cell adhesion, tube formation, and aortic sprouting. FASEB J. 13, 53–62. Maquart, F. X., Sime´ on, A., Pasco, S., and Monboisse, J. C. (1999). Regulation of cell activity by the extracellular matrix: The concept of matrikines. J. Soc. Biol. 193, 423–428. Maquoi, E., Frankenne, F., Noe¨ l, A., Krell, H. W., Grams, F., and Foidart, J. M. (2000). Type IV collagen induces matrix metalloproteinase‐2 activation in HT 1080 fibrosarcoma cells. Exp. Cell Res. 261, 348–359. Maragoudakis, M. E., Missirlis, E., Karakiulakis, G. D., Sarmonica, M., Bastakis, M., and Tsopanoglou, N. (1993). Basement membrane biosynthesis as a target for developping inhibitors of angiogenesis with antitumor properties. Kidney Int. 43, 147–150. Marneros, A. G., and Olsen, B. R. (2001). The role of collagen‐derived proteolytic fragments in angiogenesis. Matrix Biol. 20, 337–345. Martinella‐Catusse, C., Polette, M., Noe¨ l, A., Gilles, C., Dehan, P., Munaut, C., Colige, A., Volders, L., Monboisse, J. C., Foidart, J. M., and Birembaut, P. (2001). Down‐regulation of MT1‐MMP expression by the a3 chain of type IV collagen inhibits bronchial tumor cell line invasion. Lab. Invest. 81, 167–191. Miles, A. J., Skubitz, A. P. N., Furcht, L. T., and Fields, G. B. (1994). Promotion of cell adhesion by single‐stranded and triple‐helical peptide models of basement membrane collagen a1(IV). J. Biol. Chem. 269, 30939–30945. Miles, A. J., Knutson, J. R., Skubitz, A. P., Furcht, L. T., McCarthy, J. B., and Fields, G. B. (1995). A peptide model from basement membrane collagen a1(IV) 531–543 binds to the a3b1 integrin. J. Biol. Chem. 270, 29047–29050. Monboisse, J. C., Bellon, G., Dufer, J., Randoux, A., and Borel, J. P. (1987). Collagen activates superoxide anion production by human polymorphonuclear neutrophils. Biochem. J. 246, 599–603. Monboisse, J. C., Bellon, G., Randoux, A., Dufer, J., and Borel, J. P. (1990). Adhesion of human neutrophils to and activation by type I collagen involving a b2 integrin. Biochem. J. 270, 459–462.

13. Novel Biological Properties of Peptides

407

Monboisse, J. C., Bellon, G., Perreau, C., Garnotel, R., and Borel, J. P. (1991a). Bovine lens capsule basement membrane collagen exerts a negative priming on polymorphonuclear neutrophils. FEBS Lett. 294, 129–132. Monboisse, J. C., Garnotel, R., Randoux, A., Dufer, J., and Borel, J. P. (1991b). Adhesion of human neutrophils to and activation by type‐I collagen, involving a b2 integrin. J. Leuk. Biol. 50, 373–380. Monboisse, J. C., Garnotel, R., Bellon, G., Ohno, N., Perreau, C., Borel, J. P., and Kefalides, N. A. (1994). The a3 chain of type IV collagen prevents activation of human polymorphonuclear leukocytes. J. Biol. Chem. 269, 25475–25482. Monboisse, J. C., Bellon, G., Garnotel, R., Fawzi, A., Ohno, N., Kefalides, N. A., and Borel, J. P. (1998). The interaction of human neutrophils with type IV collagen involves an inhibitory signal transduction pathway. In ‘‘Angiogenesis: Models, modulators and clinical applications’’ (Maragoudakis M. E., ed.), pp. 203–211. Plenum, New York. Mongiat, M., Sweeney, S. M., San Antonio, J. D., Fu, J., and Iozzo, R. V. (2003). Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan. J. Biol. Chem. 278, 4238–4249. Nakano, K. Y., Iyama, K. I., Mori, T., Yoshioka, M., Hirakoa, T., Sado, I., and Ninomiya, Y. (2001). Loss of alveolar basement membrane type IV collagen a3, a4 and a5 chains in bronchioalveolar carcinoma of the lung. J. Pathol. 194, 420–427. Netzer, K. O., Suzuki, K., Itoh, Y., Hudson, B. G., and Khalifah, R. G. (1998). Comparative analysis of the noncollagenous NC1 domain of type IV collagen: Identification of structural features important for assembly, function and pathogenesis. Protein Sci. 7, 1340–1351. Noble, P. W. (2002). Hyaluronan and its catabolic products in tissue injury and repair. Matrix Biol. 21, 25–29. Nomizu, M., Yamamura, K., Kleinman, H. K., and Yamada, Y. (1993). Multimeric forms of Tyr‐Ile‐Gly‐Ser‐Arg (YIGSR) peptide enhance the inhibition of tumor growth and metastasis. Cancer Res. 53, 3459–3461. Nomizu, M., Kim, W. H., Yamamura, K., Utani, A., Song, S. Y., Otaka, A., Roller, P. P., Kleinman, H. K., and Yamada, Y. (1995). Identification of cell binding sites in the laminin a1 chain carboxyl‐terminal globular domain by systematic screening of synthetic peptides. J. Biol. Chem. 270, 20583–20590. Nomizu, M., Yokoyama, F., Suzuki, N., Okazaki, I., Nishi, N., Ponce, M. L., Kleinman, H. K., Yamamoto, Y., Nakagawa, S., and Mayumi, T. (2001). Identification of homologous biologically active sites on the N‐terminal domain of laminin a chains. Biochemistry 40, 15310–15317. Ntayi, C., Lorimier, S., Berthier‐Vergnes, O., Hornebeck, W., and Bernard, P. (2001). Cumulative influence of matrix metalloproteinase‐1 and ‐2 in the migration of melanoma cells within three‐dimensional type I collagen lattices. Exp. Cell Res. 270, 110–118. Nyberg, F., Sanderson, K., and Glamsta, E. L. (1997). The hemorphins: A new class of opioid peptides derived from the blood protein hemoglobin. Biopolymers 43, 147–156. Okazaki, I., Suzuki, N., Nishi, N., Utani, A., Matsuura, H., Shinkai, H., Yamashita, H., and Nomizu, M. (2002). Identification of biologically active sequences in the laminin a domain. J. Biol. Chem. 277, 37070–37078. O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., and Folkman, J. (1997). Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285. Ortega, N., and Werb, Z. (2002). New functional roles for‐non‐collagenous domains of basement membrane collagens. J. Cell Sci. 115, 4201–4214.

408

Kefalides and Borel

Panka, D. J., and Mier, J. W. (2003). Canstatin inhibits Akt activation and induces Fas‐ dependent apoptosis in endothelial cells. J. Biol. Chem. 278, 37632–37636. Pasco, S., Han, J., Gillery, P., Bellon, G., Maquart, F. X., Borel, J. P., Kefalides, N. A., and Monboisse, J. C. (2000a). A specific sequence of the noncollagenous domain of the a3(IV) chain of type IV collagen inhibits expression and activation of matrix metalloproteinase by tumor cells. Cancer Res. 60, 467–473. Pasco, S., Monboisse, J. C., and KieVer, N. (2000b). The a3(IV) 185–203 peptide from non‐ collagenous domain of type IV collagen interacts with a novel binding site on the b3 subunit of integrin aVb3 and stimulates focal adhesion kinase and phosphatidylinositol 3‐ kinase phosphorylation. J. Biol. Chem. 275, 32999–33007. Pasco, S., Ramont, L., Maquart, F. X., and Monboisse, J. C. (2003). EVets biologiques de peptides des collage`nes I et IV. J. Soc. Biol. Paris 197, 31–39. Pasco, S., Ramont, L., Maquart, F. X., and Monboisse, J. C. (2004a). Control of melanoma progression by various matrikines from basement membrane macromolecules. Oncol/ Haematol. 41, 221–233. Pasco, S., Ramont, L., Venteo, L., Pluot, M., Maquart, F. X., and Monboisse, J. C. (2004b). In vivo expression of tumstatin domains by tumor cells inhibits their invasive properties in a mouse melanoma model. Exp. Cell Res. 301, 251–265. Patarroyo, M., Tryggvason, K., and Virtanen, I. (2002). Laminin isoforms in tumor invasion, angiogenesis and metastasis. Cancer Biol. 12, 197–207. Petitclerc, E., Boutaud, A., Prestyako, A., Xu, J., Sado, Y., Ninomiya, Y., Sarras, M. P., Jr., Hudson, B., and Brooks, P. C. (2000). New functions for non‐collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo. J. Biol. Chem. 275, 8051–8061. Polette, M., Thiblet, J., Ploton, D., Buisson, A. C., Monboisse, J. C., Tournier, J. M., and Birembaut, P. (1997). Distribution of a1(IV) and a3(IV) chains of type IV collagen in lung tumors. J. Pathol. 182, 185–191. Ponce, M. L., Nomizu, M., and Kleinman, H. K. (2001). An angiogenic laminin site and its antagonist bind through the avb3 and a5b1 integrins. FASEB J. 8, 1389–1397. Ponce, M. L., Hibino, S., Lebioda, A. M., Mochizuki, M., Nomizu, M., and Kleinman, H. K. (2003). Identification of a potent peptide antagonist to an active laminin‐1 sequence that blocks angiogenesis and tumor growth. Cancer Res. 63, 5060–5064. Powell, S. K., Rao, J., Roque, E., Nomizu, M., Kuratomi, Y., Yamada, Y., and Kleinman, H. K. (2000). Neural cell response to multiple novel sites on laminin‐1. J. Neurosci. Res. 61, 302–312. Pyke, C., Romer, J., Kallunki, P., Lund, L. R., Ralfkia¨ r, E., Dano¨ , K., and Tryggvason, K. (1994). The g2 chain of kalinin/laminin‐5 is preferentially expressed in invading malignant cells in human cancers. Am. J. Pathol. 145, 782–791. Pyke, C., Salo, S., Ralfkia¨ r, E., Dano¨ , K., and Tryggvason, K. (1995). Laminin‐5 is a marker of invading cells in some human carcinomas and is expressed with the receptor for urokinase plasminogen activator in budding cancer in colon adenocarcinomas. Cancer Res. 55, 4132–4139. Ramchandran, R., Dhanabal, M., Volk, R., Waterman, M. J. F., Segal, M., Lu, H., Knebelmann, B., and Sukhatme, V. P. (1999). Antiangiogenic activity of restin, NC1 domain of human collagen XV: Comparison to endostatin. Biochem. Biophys. Res. Commun. 255, 735–739. Read, T. A., Sorensen, D. R., Mahesparan, R., Enger, P. O., Timpl, R., Olsen, B. R., Hjelstuen, M. H., Haraldseth, O., and Bjerkvig, R. (2001). Local endostatin treatment of gliomas administered by microencapsulated producer cells. Nat. Biotechnol. 19, 29–34.

13. Novel Biological Properties of Peptides

409

Rehn, M., Veikkola, T., Kukk‐Valdre, E., Nakamura, H., Ilmonen, M., Lombardo, C. R., Pihlajaniemi, T., Alitalo, K., and Vuori, K. (2001). Interaction of endostatin with integrins implicated in angiogenesis. Proc. Natl. Acad. Sci. USA 98, 1024–1029. Reynolds, L. E., Wyder, L., Lively, J. C., Taverna, D., Robinson, S. D., Huang, X., Sheppard, D., Hynes, R. O., and Hodivala‐Dilke, K. M. (2002). Enhanced pathological angiogenesis in mice lacking b3 integrin or b3 and b5 integrins. Nat. Med. 8, 27–34. Ricard‐Blum, S. (2003). Implication des matricryptines issues des collage`nes non fibrillaires, de MMP‐2 et de SPARC dans le controˆ le de l’angioge´ ne`se. J. Soc. Biol. 197, 41–44. Ricard‐Blum, S., Feraud, O., Lortat‐Jacob, H., Rencurosi, A., Fukai, N., Dkhissi, F., Vittet, D., Imberty, A., Olsen, B. R., and Van der Rest, M. (2004). Characterization of endostatin binding to heparin and heparan sulfate by surface plasmon resonance and molecular modeling: Role of divalent cations. J. Biol. Chem. 279, 2927–2936. Rooney, P., Kumar, S., Ponting, J., and Wang, M. (1995). The role of hyaluronan in tumor vascularization. Int. J. Cancer 60, 632–636. Sarras, M. P., Jr., Zhang, X., HuV, J. K., Accavitti, M. A., St John, P. L., and Abrahamson, D. R. (1993). Extracellular matrix (mesoglea) of Hydra vulgaris III. Formation and function during morphogenesis of hydra cells aggregates. Dev. Biol. 157, 383–398. Sasaki, T., Fukai, N., Mann, K., Gohring, W., Olsen, B. R., and Timpl, R. (1998). Structure, function and tissue forms of the C‐terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin. EMBO J. 17, 4249–4256. Sasaki, T., Larsson, H., Tisi, D., Claesson‐Welsch, L., Hohenester, E., and Timpl, R. (2000). Endostatins derived from collagens XV and XVIII diVer in structural and binding properties, tissue distribution and anti‐angiogenic activity. J. Mol. Biol. 301, 1179–1190. Sauter, B. V., Martinet, O., Zhang, W. J., Mandeli, J., and Woo, S. L. (2000). Adenovirus‐ mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases. Proc. Natl. Acad. Sci. USA 97, 4802–4807. Savarese, D. M., Russell, J. T., Fatatis, A., and Liotta, L. (1992). Type IV collagen stimulates an increase in intracellular calcium. Potential role in tumor cell motility. J. Biol. Chem. 267, 21928–21935. Setty, S., Kim, Y., Fields, G. B., Clegg, D. O., Wayner, E. A., and Tsilibary, E. C. (1998). Interactions of type IV collagen and its domains with human mesangial cells. J. Biol. Chem. 273, 12244–12449. Shahan, T. A., Ziaie, Z., Pasco, S., Fawzi, A., Bellon, G., Monboisse, J. C., and Kefalides, N. A. (1999a). Identification of CD 47/integrin associated protein and aVb3 as two receptors for the a3(IV) chain of type IV collagen on tumor cells. Cancer Res. 59, 4584–4590. Shahan, T. A., Ohno, N, Pasco, S., Borel, J. P., Monboisse, J. C., and Kefalides, N. A. (1999b). Inhibition of tumor cell proliferation by type IV collagen requires increased levels of cAMP. Connect. Tissue Res. 40, 221–232. Shahan, T. A., Fawzi, A., Bellon, G., Monboisse, J. C., and Kefalides, N. A. (2000). Regulation of tumor cell chemotaxis by type IV collagen is mediated by a Ca2þ‐dependent mechanism requiring CD 47 and the integrin aVb3. J. Biol. Chem. 275, 4796–4802. Shahan, T. A., Grant, D. S., Tootell, M., Ziaie, Z., Ohno, N., Mousa, S., Mohamad, S., Delisser, H., and Kefalides, N. A. (2004). Oncothanin, a Peptide from the a3 chain of type IV collagen modifies endothelial cell function and inhibits angiogenesis. Connect. Tissue. Res. 45, 151–163. Song, S. Y., Nomizu, M., Yamada, Y., and Kleinman, H. K. (1997). Liver metastasis formation by laminin‐1 peptide (LQVQLSIR)‐adhesion selected B16‐F10 melanoma cells. Int. J. Cancer. 71, 436–441.

410

Kefalides and Borel

Sorensen, D. R., Read, T. A., Porwol, T., Olsen, B. R., Timpl, R., Sasaki, T., Iversen, P. O., Benestad, H. B., Sim, B. K., and Bjerkvig, R. (2002). Endostatin reduces vascularization, blood flow and growth in a rat gliosarcoma. Neuro‐Oncol. 4, 1–8. Starkey, J. R., Hosick, H. L., Stanford, D. R., and Liggitt, H. D. (1984). Interaction of metastatic tumor cells with bovine lens capsule basement membrane. Cancer Res. 44, 1585–1594. Sudhakar, A., Sugimoto, H., Yang, C., Lively, J. C., Zeisberg, M., and Kalluri, R. (2003). Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by avb3 and a5b1 integrins. Proc. Natl. Acad. Sci. USA 100, 4766–4771. Suzuki, N., Nakatsuka, H., Mochizuki, M., Nishi, N., Kadoya, Y., Utani, A., Oishi, S., Fujii, N., Kleinman, H. K., and Nomizu, M. (2003). Biological activities of homologous loop regions in the laminin a chain G domains. J. Biol. Chem. 278, 45697–45705. Sweeney, T. M., Kibbey, M. C., Zain, M., Fridman, R., and Kleinman, H. K. (1991). Basement membrane and the SIKVAV laminin‐derived peptide promote tumor growth and metastases. Cancer Metastasis Rev. 10, 245–254. Taddei, L., Chiarugi, P., Brogelli, L., Cirri, P., Magnelli, L., Raugel, G., Ziche, M., Granger, H. J., Chiarugi, V., and Ramponi, G. (1999). Inhibitory eVect of full‐length human endostatin on in vitro angiogenesis. Biochem. Biophys. Res. Commun. 263, 340–345. Tsilibary, E. C., Reger, L. A., Vogel, A. M., Koliakos, G. G., Anderson, S. S., Charonis, A. S., Alegre, J. N., and Furcht, L. T. (1990). Identification of a multifunctional, cell‐binding peptide sequence from the a1 (NC1) of type IV collagen. J. Cell Biol. 111, 1583–1591. Tsubota, Y., Mizushima, H., Hirosaki, T., Higashi, S., Yasumitsu, H., and Miyazaki, K. (2000). Isolation and activity of proteolytic fragment of laminin‐5 a3 chain. Biochem. Biophys. Res. Communic. 278, 614–620. Utani, A., Nomizu, M., Matsuura, H., Kato, K., Kobayashi, T., Takeda, U., Aota, S., Nielsen, P. K., and Shinkai, H. (2001). A unique sequence of the laminin a3 G domain binds to heparin and promotes cell adhesion through syndecan‐2 and ‐4. J. Biol. Chem. 276, 28779–28788. Vandenberg, P., Kern, A., Ries, A., Luckenbill‐Edds, L., Mann, K., and Ku¨ hn, K. (1991). Characterization of a type IV collagen major cell binding site with aYnity to a1b1 and a2b1 integrin. J. Cell Biol. 113, 1475–1483. Van der Schaft, D. W. J., Dings, R. P. M., De Lussanet, Q. J., Van Eijk, A. W., Nap, A. W., Beets‐Tan, R. G. H., Steege, B‐T., WagstaV, J., Mayo, K. H., and GriYoen, A. W. (2002). The designer anti‐angiogenic peptide anginex targets tumor endothelial cells and inhibits tumor growth in animal models. FASEB J. 16, 1991–1993. West, D. C., Hampson, I. N., Arnold, F., and Kumar, S. R. (1985). Angiogenesis induced by degradation products of hyaluronic acid. Science 228, 1324–1326. Xu, J., Rodriguez, D., Petitclerc, E., Kim, J. J., Hangai, M., Yuen, S. M., Davis, G. E., and Brooks, P. (2001). Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J. Cell Biol. 154, 1069–1079. Yamaguchi, N., Anad‐Apte, B., Lee, M., Sasaki, T., Fukai, N., Shapiro, R., Que, I., Lowik, C., Timpl, R., and Olsen, B. R. (1999). Endostatin inhibits VEGF‐induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J. 18, 4414–4423. Yamamura, K., Kibbey, M. C., Jun, S. H., and Kleinman, H. K. (1993). EVect of Matrigel and laminin peptide YIGSR on tumor growth and metastasis. Semin. Cancer Biol. 4, 259–265. Yan, Q., and Sage, E. H. (1999). SPARC, a matricellular glycoprotein with important biological functions. J. Histochem, Cytochem. 47, 1495–1506. Yoon, S. S., Eto, H., Lin, C. M., Nahamura, H., Pawlik, T. M., Song, S. U., and Tanabe, K. K. (1999). Mouse endostatin inhibits the formation of lung and liver metastases. Cancer Res. 59, 6251–6256.

13. Novel Biological Properties of Peptides

411

You, W. K., So, S. H., Lee, H., Park, S. Y., Yoon, M. R., Chang, S. I., Kim, H. K., Joe, Y. A., Hong, Y. K., and Chung, S. I. (1999). Purification and characterization of recombinant murine endostatin in E. coli. Exp. Mol. Med. 31, 197–202. Zhang, X., Hudson, B. G., and Sarras, M. P., Jr. (1994). Hydra cell aggregate development is blocked by selective fragments of fibronectin and type IV collagen. Dev. Biol. 164, 10–23. Zhao, Q., Sannier, F., Garreau, I., Guillochon, D., and Piot, J. M. (1994a). Inhibition and inhibition kinetics of angiotensin converting enzyme activity by hemorphins, isolated from a peptic bovine hemoglobin hydrolysate. Biochem. Biophys. Res. Commun. 204, 216–223. Zhao, M., Kleinman, H. K., and MokotoV, M. (1994b). Synthetic laminin‐like peptides and pseudopeptides as potential antimetastatic agents. J. Med. Chem. 37, 3383–3388. Zhao, Q., Garreau, I., Sannier, F., and Piot, J. M. (1997). Opioid peptides derived from hemoglobin: Hemorphins. Biopolymers 43, 75–98.