- Email: [email protected]
Transforming Growth Factor-β Signaling in Skin: Stromal to Epithelial Cross-Talk
See related article on pg 194
Transforming Growth Factor-β Signaling in Skin: Stromal to Epithelial Cross-Talk Alain Mauviel1 In this issue, Denton et al., describe a mouse model of postnatal deletion of the transforming growth factor (TGF)-β receptor type II (TβRII) in skin fibroblasts. Using a tamoxifen-dependent inducible Cre-lox strategy, the authors demonstrate the pivotal role played by TGF-β signaling in fibroblasts during wound healing. Healing of full-thickness wounds after fibroblast-specific deletion of TβRII in the skin was severely impaired and exhibited delayed re-epithelialization. This study emphasizes the importance of fibroblasts in mesenchymal–epithelial interaction in the skin during wound repair. Journal of Investigative Dermatology (2009), 129, 7–9. doi:10.1038/jid.2008.385
TGF-β signaling: an overview
TGF-β transduces its signal via specific cell surface serine/threonine kinase receptors, types I and II (TβRI and TβRII). These receptors exhibit small cysteinerich extracellular regions and intracellular portions consisting mainly of the kinase domains. TGF-β binds TβRII, forming a heterodimeric complex that can recruit and activate TβRI by phosphorylating serine and threonine residues within a region rich in glycine and serine residues (GS domain) preceding the TβRI kinase domain. Signal transduction from TGF-β receptors to the nucleus is mediated predominantly by ligandactivated TβRI-dependent phosphorylation of cytoplasmic mediators of the Smad family (reviewed in Javelaud and Mauviel, 2004; Schiller et al., 2004). TGF-β roles in wound healing: more complex than thought?
TGF-β is a prototypic regulator of extracellular matrix (ECM) deposition, positively regulating the expression of components of the ECM and that of protease inhibitors, including plasminogen activator inhibitor-1 or tissue inhibitor of metalloproteinases, while inhibiting the expression of metalloproteinases in fibroblasts. These combined anabolic
and anticatabolic effects make TGF-β a powerful enhancer of wound healing but also a pathogenic growth factor whose continuing signaling may lead to the development of tissue fibrosis (Verrecchia and Mauviel, 2002, 2004). Denton et al. (2009, this issue) used a tamoxifen-inducible Cre recombinase to delete TβRII in skin fibroblasts in adult mice, generating “TβRII–null fib” mice. Using a full-thickness wound model and ex vivo fibroblast cultures, the authors demonstrate that fibroblast-specific deletion of TβRII profoundly alters wound healing. Wounds in TβRII–null fib mice exhibited an almost complete absence of dermal regeneration, diminished wound contraction and closure, reduced ECM deposition, and delayed re-epithelialization and epidermal differentiation. Ex vivo experiments demonstrated abnormal migratory capacity and impaired myofibroblast differentiation of TβRII-null fibroblasts in response to TGF-β, accompanied by a loss of contractile properties. Numerous studies have documented the ability of exogenous TGF-β to improve wound healing (reviewed in Roberts and Sporn, 1993; Verrecchia and Mauviel, 2007). Yet, Smad3-null mice paradoxically show accelerated
INSERM U697, Hôpital Saint-Louis, Paris, France
1
Correspondence: Dr Alain Mauviel, INSERM U697, Hôpital Saint-Louis, Pavillon Bazin, F-75475 Paris Cedex 10, France. E-mail: [email protected]
© 2009 The Society for Investigative Dermatology
commentary
cutaneous wound healing compared with wild-type mice, characterized by rapid re-epithelialization and reduced local inflammation (Ashcroft et al., 1999). Thus, Smad3 may mediate in vivo signaling that is inhibitory to epithelial wound healing. It is also possible that suppression of Smad3 levels may occur during normal wound healing. This study did not distinguish the relative contributions of each cellular compartment involved in wound healing because no tissuespecific, conditional deletion of Smad3 was performed. Indeed, the specific role played by TGF-β during mesenchymal–epithelial cross-talk has remained rather enigmatic in the context of physiological processes such as wound healing. Remarkably, the work by Denton et al. addresses this issue and demonstrates that abolishing TGF-β signaling postnatally specifically in fibroblasts inhibits healing of excisional skin wounds in adult mice, with markedly attenuated dermal scar formation, defective wound contraction, and reduced epidermal proliferation. Molecular mechanisms affecting skin wound repair: does TGF-β orchestrate all this?
A number of studies have addressed the molecular mechanisms underlying epidermal wound healing. For example, Parks and co-workers showed initially that keratinocyte migration leading to wound closure was dependent on matrix metalloproteinase (MMP) activity induced by keratinocyte contact with the wound bed (Pilcher et al., 1997). Such contacts generate collagen–integrin signaling, resulting in MMP-1 activation in keratinocytes and subsequent degradation of type I collagen, a necessary step for direction ality of keratinocyte migration and efficient wound closure. Using a skin-equivalent model of human keratinocytes and immortalized c-Jun- or JunB-deficient fibroblasts, Szabowski et al. (2000) identified the balance in cJun and JunB expression in fibroblasts as essential for keratinocyte proliferation and differentiation to form www.jidonline.org
7
commentary
a three-dimensionally organized epith- elium. Fibroblast-derived keratinocyte growth factor (KGF) and GM-CSF could be identified as key regulators of the paracrine loop responsible for the finetuned balance of keratinocyte proliferation and differentiation to form an intact epidermis. Remarkably, after conditional deletion of JunB in skin fibroblasts (Florin et al., 2006), excisional wounding resulted in a phenotype similar to that described by Denton et al. in this issue, characterized by delayed wound closure and abnormal dermal collagen reorganization. Also, JunB∆/∆ fibroblasts, unlike TβRII-null fibroblasts, exhibited reduced contractile activity, although with no obvious loss of α-smooth muscle actin. Remarkably, TGF-β is an important regulator of JUN expression, specifically inducing expression of JUNB in fibroblasts and that of both JUNB and cJUN in keratinocytes, with the latter leading to enhanced MMP1 expression (Mauviel et al., 1993, 1996; Verrecchia et al., 2001a,b). How TGF-β signaling in fibroblasts is able to regulate epidermal wound closure remains to be elucidated, yet it may be hypothesized that TGF-β-dependent JUNB expression regulates the expression of soluble factors such as KGF or GM-CSF, or that of
|
TGF-β: many roles in wound healing and skin cancer.
MMP-1 in keratinocytes, all capable of regulating epidermal homeostasis and repair. Another possibility resides in the fact that TGF-β is capable of regulating its own expression via induction of activator protein-1 complexes (Kim et al., 1990; Van Obberghen-Schilling et al., 1988). TβRII deletion in fibroblasts is thus likely to reduce the autocrine expression of TGF-β during wound repair. In turn, this effect may reduce MMP-1 production by adjacent keratinocytes, thereby altering their capacity to migrate and close the wound. Reconciling all the above studies in an integrative approach would 8
provide helpful clues to understanding the mechanisms of skin repair. Fibroblast signaling of adjacent epithelial cells: cross-talk at work
Another level of complexity arises from the fact that fibroblasts are not all equal; conditional inactivation of the TGF-β type II receptor gene in mouse fibroblasts (Tgfbr2fspKO) resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach but not in other tissues (Bhowmick et al., 2004). In another study, tissue-specific conditional knockout of the TGF-β type II receptor gene in mouse mammary fibroblasts led to defective mammary duct development (Cheng et al., 2005). Furthermore, Tgfbr2fspKO mammary fibroblasts transplanted with mammary carcinoma cells promoted growth and invasion in a model of tumorigenesis in mice. It appears, therefore, that TGF-β signaling in fibroblasts is critical for the oncogenic potential and growth of adjacent epithelia in selected tissues (Bhowmick and Moses, 2005; Dennler et al., 2008). Functional differences between fibroblasts in different organs may explain this specificity, which remains to be characterized. The current study by Denton et al. (2009) demonstrates that in skin wound repair, TGF-β signaling in fibroblasts is important not only for ECM production by fibroblasts and for their trans differentiation into myofibroblasts but also for adjacent keratinocytes. Furthermore, the authors identify constitutive activation of extracellular signal–related kinase signaling in TβRII-null fibroblasts as leading to high expression of CTGF, a gene considered to be a typical TGF-β/Smad response gene. This adds a new level of complexity to the understanding of cell signaling, and it exemplifies the difficulties in targeting TGF-β signaling while controlling for the side effects that arise from disruption of cross-talk with other signaling pathways, such as mitogenactivated protein kinases (reviewed in Javelaud and Mauviel, 2005). The precise spatiotemporal role of TGF-βinitiated signals, as well as their effect on other signal transduction cascades and on adjacent tissues, remains to be elucidated. Only with this information
Journal of Investigative Dermatology (2009), Volume 129
can effective therapeutic intervention against TGF-β be envisioned in clinical settings, such as in tissue fibrosis, wound healing, and cancer. CONFLICT OF INTEREST
The author states no conflict of interest.
References
Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE et al. (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1:260–6 Bhowmick NA, Moses HL (2005) Tumor–stroma interactions. Curr Opin Genet Dev 15:97–101 Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S et al. (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303:848–51 Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R, Arteaga et al. (2005) Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene 24:5053–68 Dennler S, Mauviel A, Verrecchia F (2008) TGFbeta and stromal influences over local tumor invasion. In: Jakowlew SB (ed) Transforming Growth Factor-β in Cancer Therapy, vol II. Humana Press: Totowa, NJ, 531–51. Denton CP, Khan K, Hoyles RK, Shiwen X, Leoni P, Chen Y et al. Inducible lineage-specific deletion of TβRII in fibroblasts defines a pivotal regulatory role during adult skin wound healing. J Invest Dermatol 129:194–204 Florin L, Knebel J, Zigrino P, Vonderstrass B, Mauch C, Schorpp-Kistner M et al. (2006) Delayed wound healing and epidermal hyperproliferation in mice lacking JunB in the skin. J Invest Dermatol 126:902–11 Javelaud D, Mauviel A (2004) Mammalian transforming growth factor-betas: Smad signaling and physio-pathological roles. Int J Biochem Cell Biol 36:1161–5 Javelaud D, Mauviel A (2005) Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene 24:5742–50 Kim SJ, Angel P, Lafyatis R, Hattori K, Kim KY, Sporn MB et al. (1990) Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol 10:1492–7 Mauviel A, Chen Y, Dong W, Evans CH, Uitto J (1993) Transcriptional interactions of transforming growth factor-beta (TGF-beta) with pro-inflammatory cytokines. Current Biol 3:822–31 Mauviel A, Chung KY, Agarwal A, Tamai K, Uitto J (1996) Cell-specific induction of distinct oncogenes of the Jun family is responsible for differential regulation of collagenase gene expression by transforming growth factor-beta in fibroblasts and keratinocytes. J Biol Chem 271:10917–23 Pilcher BK, Dumin JA, Sudbeck BD, Krane SM,
commentary
Welgus HG, Parks WC (1997) The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 137:1445–57 Roberts AB, Sporn MB (1993) Physiological actions and clinical applications of transforming growth factor-beta (TGF-beta). Growth Factors 8:1–9 Schiller M, Javelaud D, Mauviel A (2004) TGFbeta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 35:83–92 Szabowski A, Maas-Szabowski N, Andrecht S, Kolbus A, Schorpp-Kistner M, Fusenig NE et al. (2000) c-Jun and JunB antagonistically control cytokine-regulated mesenchymal–epidermal interaction in skin. Cell 103:745–55 Van Obberghen-Schilling E, Roche NS, Flanders KC, Sporn MB, Roberts AB (1988) Transforming growth factor beta 1 positively regulates its own expression in normal and transformed cells.
J Biol Chem 263:7741–6 Verrecchia F, Mauviel A (2002) Transforming growth factor-β signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol 118:211–5 Verrecchia F, Mauviel A (2004) TGF-beta and TNFalpha: antagonistic cytokines controlling type I collagen gene expression. Cell Signal 16:873–80 Verrecchia F, Mauviel A (2007) Transforming growth factor-beta and fibrosis. World J Gastroenterol 13:3056–62 Verrecchia F, Tacheau C, Schorpp-Kistner M, Angel P, Mauviel A (2001a) Induction of the AP-1 members c-Jun and JunB by TGF-beta/Smad suppresses early Smad-driven gene activation. Oncogene 20:2205–11 Verrecchia F, Vindevoghel L, Lechleider RJ, Uitto J, Roberts AB, Mauviel A (2001b) Smad3/AP-1 interactions control transcriptional responses to TGF-beta in a promoter-specific manner. Oncogene 20:3332–40
See related articles on pages 248 and 250
Getting Stronger: The Relationship Between a Newly Identified Virus and Merkel Cell Carcinoma Christopher B. Buck1 and Douglas R. Lowy1 Merkel cell carcinoma (MCC) is an aggressive skin cancer that develops in individuals who are over the age of 50 or immunosuppressed. DNA from a new polyoma virus, MCPyV, was recently shown to be clonally integrated in several MCC cases. In this issue, Becker et al. demonstrate that MCPyV DNA can be isolated from 85% of primary European MCC specimens and their metastases, and Garneski et al. present data indicating that the percentage of Australian MCC cases containing MCPyV may be lower than that of North American cases. These reports support the possibility that MCPyV is etiologically involved in at least some cases of MCC. Journal of Investigative Dermatology (2008), 129, 9–11. doi:10.1038/jid.2008.302
Earlier this year, genetic analysis of Merkel cell carcinomas (MCCs) revealed the existence of a previously unidentified human polyomavirus (Feng et al., 2008). DNA sequences from the virus, designated Merkel cell carcinoma polyoma virus (MCPyV), were detected in 8 of 10 MCC tumor specimens but in only 4 of 25 (16%) control skin samples. In this issue of the Journal of Investigative Dermatology, two letters confirm and significantly extend these findings to
additional cases of MCC (Becker et al., 2008; Garneski et al., 2008). Using PCRbased analysis, Becker et al. found that 45 of 53 (85%) MCC cases from a center in Europe contained MCPyV DNA. Garneski et al. detected MCPyV DNA in 11 of 16 (69%) North American and 5 of 21 (24%) Australian MCC specimens. The frequent detection of MCPyV DNA in European cases of MCC was also recently confirmed by Kassem et al. (2008). The clear confirmation that most
Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland, USA
1
Correspondence: Dr Douglas R. Lowy, Laboratory of Cellular Oncology, National Cancer Institute, Building 37, Room 4106, 9000 Rockville Pike, Bethesda, Maryland 20892-4263, USA. E-mail: [email protected]
MCC tumors carry MCPyV sequences represents an important step in addressing the intriguing hypothesis that the virus is a key etiologic agent behind MCC and perhaps other forms of cancer. Clinical and epidemiological features of MCC
Merkel cells were identified in 1875 as a distinctive, histologically translucent cell type associated with epidermal nerve endings (Halata et al., 2003). At the time of their discovery, it was reasoned that Merkel cells might participate in the sensation of mechanical stimuli. Like melanocyte precursors, the precursors of Merkel cells are thought to migrate during development from the neural crest to their ultimate home in the basal layer of the epidermis and the outer root sheath of hair follicles (Szeder et al., 2003). Although Merkel cells do exhibit a number of neuroendocrine features, such as cytoplasmic neuropeptide–containing granules, the idea that they are directly involved in mechanosensation remains inferential (Boulais and Misery, 2008). Approximately 1,500 new MCC cases are diagnosed in the United States each year (Lemos and Nghiem, 2007). MCC is thus a rare form of skin cancer compared with the more than 1 million cases of nonmelanoma skin cancer and roughly 60,000 cases of melanoma per year in the same population. However, MCC is an aggressive, fast-growing malignancy that ultimately kills about one-third of those diagnosed with the disease. It is also important to note an alarming threefold increase in the incidence of MCC between 1986 and 2001 (Hodgson, 2005). MCC is more common in lighterskinned individuals, is associated with a history of sun exposure, and occurs predominantly on sun-exposed areas, such as the face (especially around the eyes) and extremities (Miller and Rabkin, 1999). Limited mutational screening of cellular genes in MCC identified the presence of two C-to-T transitions, characteristic of UVB-induced mutation, in one MCC cell line (Van Gele et al., 2000). Garneski et al. (2008, this issue) speculate that the smaller percentage of MCPyV in the Australian MCC cases they studied (24% vs. 69% in the North American cases, P = 0.009) might be related to the greater www.jidonline.org
9
Transforming Growth Factor-β Signaling in Skin: Stromal to Epithelial Cross-Talk Alain Mauviel1 In this issue, Denton et al., describe a mouse model of postnatal deletion of the transforming growth factor (TGF)-β receptor type II (TβRII) in skin fibroblasts. Using a tamoxifen-dependent inducible Cre-lox strategy, the authors demonstrate the pivotal role played by TGF-β signaling in fibroblasts during wound healing. Healing of full-thickness wounds after fibroblast-specific deletion of TβRII in the skin was severely impaired and exhibited delayed re-epithelialization. This study emphasizes the importance of fibroblasts in mesenchymal–epithelial interaction in the skin during wound repair. Journal of Investigative Dermatology (2009), 129, 7–9. doi:10.1038/jid.2008.385
TGF-β signaling: an overview
TGF-β transduces its signal via specific cell surface serine/threonine kinase receptors, types I and II (TβRI and TβRII). These receptors exhibit small cysteinerich extracellular regions and intracellular portions consisting mainly of the kinase domains. TGF-β binds TβRII, forming a heterodimeric complex that can recruit and activate TβRI by phosphorylating serine and threonine residues within a region rich in glycine and serine residues (GS domain) preceding the TβRI kinase domain. Signal transduction from TGF-β receptors to the nucleus is mediated predominantly by ligandactivated TβRI-dependent phosphorylation of cytoplasmic mediators of the Smad family (reviewed in Javelaud and Mauviel, 2004; Schiller et al., 2004). TGF-β roles in wound healing: more complex than thought?
TGF-β is a prototypic regulator of extracellular matrix (ECM) deposition, positively regulating the expression of components of the ECM and that of protease inhibitors, including plasminogen activator inhibitor-1 or tissue inhibitor of metalloproteinases, while inhibiting the expression of metalloproteinases in fibroblasts. These combined anabolic
and anticatabolic effects make TGF-β a powerful enhancer of wound healing but also a pathogenic growth factor whose continuing signaling may lead to the development of tissue fibrosis (Verrecchia and Mauviel, 2002, 2004). Denton et al. (2009, this issue) used a tamoxifen-inducible Cre recombinase to delete TβRII in skin fibroblasts in adult mice, generating “TβRII–null fib” mice. Using a full-thickness wound model and ex vivo fibroblast cultures, the authors demonstrate that fibroblast-specific deletion of TβRII profoundly alters wound healing. Wounds in TβRII–null fib mice exhibited an almost complete absence of dermal regeneration, diminished wound contraction and closure, reduced ECM deposition, and delayed re-epithelialization and epidermal differentiation. Ex vivo experiments demonstrated abnormal migratory capacity and impaired myofibroblast differentiation of TβRII-null fibroblasts in response to TGF-β, accompanied by a loss of contractile properties. Numerous studies have documented the ability of exogenous TGF-β to improve wound healing (reviewed in Roberts and Sporn, 1993; Verrecchia and Mauviel, 2007). Yet, Smad3-null mice paradoxically show accelerated
INSERM U697, Hôpital Saint-Louis, Paris, France
1
Correspondence: Dr Alain Mauviel, INSERM U697, Hôpital Saint-Louis, Pavillon Bazin, F-75475 Paris Cedex 10, France. E-mail: [email protected]
© 2009 The Society for Investigative Dermatology
commentary
cutaneous wound healing compared with wild-type mice, characterized by rapid re-epithelialization and reduced local inflammation (Ashcroft et al., 1999). Thus, Smad3 may mediate in vivo signaling that is inhibitory to epithelial wound healing. It is also possible that suppression of Smad3 levels may occur during normal wound healing. This study did not distinguish the relative contributions of each cellular compartment involved in wound healing because no tissuespecific, conditional deletion of Smad3 was performed. Indeed, the specific role played by TGF-β during mesenchymal–epithelial cross-talk has remained rather enigmatic in the context of physiological processes such as wound healing. Remarkably, the work by Denton et al. addresses this issue and demonstrates that abolishing TGF-β signaling postnatally specifically in fibroblasts inhibits healing of excisional skin wounds in adult mice, with markedly attenuated dermal scar formation, defective wound contraction, and reduced epidermal proliferation. Molecular mechanisms affecting skin wound repair: does TGF-β orchestrate all this?
A number of studies have addressed the molecular mechanisms underlying epidermal wound healing. For example, Parks and co-workers showed initially that keratinocyte migration leading to wound closure was dependent on matrix metalloproteinase (MMP) activity induced by keratinocyte contact with the wound bed (Pilcher et al., 1997). Such contacts generate collagen–integrin signaling, resulting in MMP-1 activation in keratinocytes and subsequent degradation of type I collagen, a necessary step for direction ality of keratinocyte migration and efficient wound closure. Using a skin-equivalent model of human keratinocytes and immortalized c-Jun- or JunB-deficient fibroblasts, Szabowski et al. (2000) identified the balance in cJun and JunB expression in fibroblasts as essential for keratinocyte proliferation and differentiation to form www.jidonline.org
7
commentary
a three-dimensionally organized epith- elium. Fibroblast-derived keratinocyte growth factor (KGF) and GM-CSF could be identified as key regulators of the paracrine loop responsible for the finetuned balance of keratinocyte proliferation and differentiation to form an intact epidermis. Remarkably, after conditional deletion of JunB in skin fibroblasts (Florin et al., 2006), excisional wounding resulted in a phenotype similar to that described by Denton et al. in this issue, characterized by delayed wound closure and abnormal dermal collagen reorganization. Also, JunB∆/∆ fibroblasts, unlike TβRII-null fibroblasts, exhibited reduced contractile activity, although with no obvious loss of α-smooth muscle actin. Remarkably, TGF-β is an important regulator of JUN expression, specifically inducing expression of JUNB in fibroblasts and that of both JUNB and cJUN in keratinocytes, with the latter leading to enhanced MMP1 expression (Mauviel et al., 1993, 1996; Verrecchia et al., 2001a,b). How TGF-β signaling in fibroblasts is able to regulate epidermal wound closure remains to be elucidated, yet it may be hypothesized that TGF-β-dependent JUNB expression regulates the expression of soluble factors such as KGF or GM-CSF, or that of
|
TGF-β: many roles in wound healing and skin cancer.
MMP-1 in keratinocytes, all capable of regulating epidermal homeostasis and repair. Another possibility resides in the fact that TGF-β is capable of regulating its own expression via induction of activator protein-1 complexes (Kim et al., 1990; Van Obberghen-Schilling et al., 1988). TβRII deletion in fibroblasts is thus likely to reduce the autocrine expression of TGF-β during wound repair. In turn, this effect may reduce MMP-1 production by adjacent keratinocytes, thereby altering their capacity to migrate and close the wound. Reconciling all the above studies in an integrative approach would 8
provide helpful clues to understanding the mechanisms of skin repair. Fibroblast signaling of adjacent epithelial cells: cross-talk at work
Another level of complexity arises from the fact that fibroblasts are not all equal; conditional inactivation of the TGF-β type II receptor gene in mouse fibroblasts (Tgfbr2fspKO) resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach but not in other tissues (Bhowmick et al., 2004). In another study, tissue-specific conditional knockout of the TGF-β type II receptor gene in mouse mammary fibroblasts led to defective mammary duct development (Cheng et al., 2005). Furthermore, Tgfbr2fspKO mammary fibroblasts transplanted with mammary carcinoma cells promoted growth and invasion in a model of tumorigenesis in mice. It appears, therefore, that TGF-β signaling in fibroblasts is critical for the oncogenic potential and growth of adjacent epithelia in selected tissues (Bhowmick and Moses, 2005; Dennler et al., 2008). Functional differences between fibroblasts in different organs may explain this specificity, which remains to be characterized. The current study by Denton et al. (2009) demonstrates that in skin wound repair, TGF-β signaling in fibroblasts is important not only for ECM production by fibroblasts and for their trans differentiation into myofibroblasts but also for adjacent keratinocytes. Furthermore, the authors identify constitutive activation of extracellular signal–related kinase signaling in TβRII-null fibroblasts as leading to high expression of CTGF, a gene considered to be a typical TGF-β/Smad response gene. This adds a new level of complexity to the understanding of cell signaling, and it exemplifies the difficulties in targeting TGF-β signaling while controlling for the side effects that arise from disruption of cross-talk with other signaling pathways, such as mitogenactivated protein kinases (reviewed in Javelaud and Mauviel, 2005). The precise spatiotemporal role of TGF-βinitiated signals, as well as their effect on other signal transduction cascades and on adjacent tissues, remains to be elucidated. Only with this information
Journal of Investigative Dermatology (2009), Volume 129
can effective therapeutic intervention against TGF-β be envisioned in clinical settings, such as in tissue fibrosis, wound healing, and cancer. CONFLICT OF INTEREST
The author states no conflict of interest.
References
Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE et al. (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1:260–6 Bhowmick NA, Moses HL (2005) Tumor–stroma interactions. Curr Opin Genet Dev 15:97–101 Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S et al. (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303:848–51 Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R, Arteaga et al. (2005) Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene 24:5053–68 Dennler S, Mauviel A, Verrecchia F (2008) TGFbeta and stromal influences over local tumor invasion. In: Jakowlew SB (ed) Transforming Growth Factor-β in Cancer Therapy, vol II. Humana Press: Totowa, NJ, 531–51. Denton CP, Khan K, Hoyles RK, Shiwen X, Leoni P, Chen Y et al. Inducible lineage-specific deletion of TβRII in fibroblasts defines a pivotal regulatory role during adult skin wound healing. J Invest Dermatol 129:194–204 Florin L, Knebel J, Zigrino P, Vonderstrass B, Mauch C, Schorpp-Kistner M et al. (2006) Delayed wound healing and epidermal hyperproliferation in mice lacking JunB in the skin. J Invest Dermatol 126:902–11 Javelaud D, Mauviel A (2004) Mammalian transforming growth factor-betas: Smad signaling and physio-pathological roles. Int J Biochem Cell Biol 36:1161–5 Javelaud D, Mauviel A (2005) Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene 24:5742–50 Kim SJ, Angel P, Lafyatis R, Hattori K, Kim KY, Sporn MB et al. (1990) Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol 10:1492–7 Mauviel A, Chen Y, Dong W, Evans CH, Uitto J (1993) Transcriptional interactions of transforming growth factor-beta (TGF-beta) with pro-inflammatory cytokines. Current Biol 3:822–31 Mauviel A, Chung KY, Agarwal A, Tamai K, Uitto J (1996) Cell-specific induction of distinct oncogenes of the Jun family is responsible for differential regulation of collagenase gene expression by transforming growth factor-beta in fibroblasts and keratinocytes. J Biol Chem 271:10917–23 Pilcher BK, Dumin JA, Sudbeck BD, Krane SM,
commentary
Welgus HG, Parks WC (1997) The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 137:1445–57 Roberts AB, Sporn MB (1993) Physiological actions and clinical applications of transforming growth factor-beta (TGF-beta). Growth Factors 8:1–9 Schiller M, Javelaud D, Mauviel A (2004) TGFbeta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 35:83–92 Szabowski A, Maas-Szabowski N, Andrecht S, Kolbus A, Schorpp-Kistner M, Fusenig NE et al. (2000) c-Jun and JunB antagonistically control cytokine-regulated mesenchymal–epidermal interaction in skin. Cell 103:745–55 Van Obberghen-Schilling E, Roche NS, Flanders KC, Sporn MB, Roberts AB (1988) Transforming growth factor beta 1 positively regulates its own expression in normal and transformed cells.
J Biol Chem 263:7741–6 Verrecchia F, Mauviel A (2002) Transforming growth factor-β signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol 118:211–5 Verrecchia F, Mauviel A (2004) TGF-beta and TNFalpha: antagonistic cytokines controlling type I collagen gene expression. Cell Signal 16:873–80 Verrecchia F, Mauviel A (2007) Transforming growth factor-beta and fibrosis. World J Gastroenterol 13:3056–62 Verrecchia F, Tacheau C, Schorpp-Kistner M, Angel P, Mauviel A (2001a) Induction of the AP-1 members c-Jun and JunB by TGF-beta/Smad suppresses early Smad-driven gene activation. Oncogene 20:2205–11 Verrecchia F, Vindevoghel L, Lechleider RJ, Uitto J, Roberts AB, Mauviel A (2001b) Smad3/AP-1 interactions control transcriptional responses to TGF-beta in a promoter-specific manner. Oncogene 20:3332–40
See related articles on pages 248 and 250
Getting Stronger: The Relationship Between a Newly Identified Virus and Merkel Cell Carcinoma Christopher B. Buck1 and Douglas R. Lowy1 Merkel cell carcinoma (MCC) is an aggressive skin cancer that develops in individuals who are over the age of 50 or immunosuppressed. DNA from a new polyoma virus, MCPyV, was recently shown to be clonally integrated in several MCC cases. In this issue, Becker et al. demonstrate that MCPyV DNA can be isolated from 85% of primary European MCC specimens and their metastases, and Garneski et al. present data indicating that the percentage of Australian MCC cases containing MCPyV may be lower than that of North American cases. These reports support the possibility that MCPyV is etiologically involved in at least some cases of MCC. Journal of Investigative Dermatology (2008), 129, 9–11. doi:10.1038/jid.2008.302
Earlier this year, genetic analysis of Merkel cell carcinomas (MCCs) revealed the existence of a previously unidentified human polyomavirus (Feng et al., 2008). DNA sequences from the virus, designated Merkel cell carcinoma polyoma virus (MCPyV), were detected in 8 of 10 MCC tumor specimens but in only 4 of 25 (16%) control skin samples. In this issue of the Journal of Investigative Dermatology, two letters confirm and significantly extend these findings to
additional cases of MCC (Becker et al., 2008; Garneski et al., 2008). Using PCRbased analysis, Becker et al. found that 45 of 53 (85%) MCC cases from a center in Europe contained MCPyV DNA. Garneski et al. detected MCPyV DNA in 11 of 16 (69%) North American and 5 of 21 (24%) Australian MCC specimens. The frequent detection of MCPyV DNA in European cases of MCC was also recently confirmed by Kassem et al. (2008). The clear confirmation that most
Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland, USA
1
Correspondence: Dr Douglas R. Lowy, Laboratory of Cellular Oncology, National Cancer Institute, Building 37, Room 4106, 9000 Rockville Pike, Bethesda, Maryland 20892-4263, USA. E-mail: [email protected]
MCC tumors carry MCPyV sequences represents an important step in addressing the intriguing hypothesis that the virus is a key etiologic agent behind MCC and perhaps other forms of cancer. Clinical and epidemiological features of MCC
Merkel cells were identified in 1875 as a distinctive, histologically translucent cell type associated with epidermal nerve endings (Halata et al., 2003). At the time of their discovery, it was reasoned that Merkel cells might participate in the sensation of mechanical stimuli. Like melanocyte precursors, the precursors of Merkel cells are thought to migrate during development from the neural crest to their ultimate home in the basal layer of the epidermis and the outer root sheath of hair follicles (Szeder et al., 2003). Although Merkel cells do exhibit a number of neuroendocrine features, such as cytoplasmic neuropeptide–containing granules, the idea that they are directly involved in mechanosensation remains inferential (Boulais and Misery, 2008). Approximately 1,500 new MCC cases are diagnosed in the United States each year (Lemos and Nghiem, 2007). MCC is thus a rare form of skin cancer compared with the more than 1 million cases of nonmelanoma skin cancer and roughly 60,000 cases of melanoma per year in the same population. However, MCC is an aggressive, fast-growing malignancy that ultimately kills about one-third of those diagnosed with the disease. It is also important to note an alarming threefold increase in the incidence of MCC between 1986 and 2001 (Hodgson, 2005). MCC is more common in lighterskinned individuals, is associated with a history of sun exposure, and occurs predominantly on sun-exposed areas, such as the face (especially around the eyes) and extremities (Miller and Rabkin, 1999). Limited mutational screening of cellular genes in MCC identified the presence of two C-to-T transitions, characteristic of UVB-induced mutation, in one MCC cell line (Van Gele et al., 2000). Garneski et al. (2008, this issue) speculate that the smaller percentage of MCPyV in the Australian MCC cases they studied (24% vs. 69% in the North American cases, P = 0.009) might be related to the greater www.jidonline.org
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