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Invasion of the trophoblasts
Cell, Vol. 71, 355-357,
October
30, 1992, Copyright
0 1992 by Cell Press
Invasion of the Trophoblasts Sidney Strickland and William G. Richards Department of Pharmacology and Program in Genetics State University of New York Stony Brook, New York 11794-8851 What is our life? a play of passion, Our mirth the music of division, Our mothers’ wombs attiring houses be Where we are dressed for this short comedy. -Sir
Walter
Raleigh
(1612)
Mammalian embryonic development and growth require implantation into the uterus. In mammals that form a hemochorial placenta(e.g., humans, mice), embryonictrophoblast cells enable the embryo to invade through the uterine epithelium and deep into the stroma. The penetrative nature of hemochorial placentation so mimics that seen with highly invasive tumors that the normal trophoblast has been called pseudomalignant. Thus, in normal pregnancies the uterus must act to limit implantation; the uncontrolled invasion of the trophoblast, as in choriocarcinoma, results in one of the most metastatic tumors known. Recent work using both naturally occurring and experimentally generated mouse mutations has shed new light on implantation and its regulation. Present knowledge can be considered from the perspective of the two interacting tissues: the trophoblast and the uterus. The Trophoblast In mice and humans, trophoblast cells must cross the basement membranes of the uterine epithelium and vasculature to effect successful implantation. It has long been suspected that proteolytic enzymes play a role in this process. For example, the production of the protease urokinase-type plasminogen activator (U-PA) by mouse trophoblast cells temporally coincides with the embryo’s invasive phase and is localized to regions of invasion (Strickland et al., 1976; Sappino et al., 1989). Human trophoblast cells also express U-PA receptor (Mini et al., 1992), which can bind active U-PA and localize proteolysis to the leading edge of migrating cells (Estreicher et al., Roldan et al., 1990). In addition, mouse embryos homozygous for the mutation rY73have reduced levels of PA and do not implant (Axelrod, 1985). Metalloproteinases, such as stromelysin and the 92 kd type IV collagenase, are also produced by trophoblast cells. The 92 kd collagenase is necessary for the matrixdegrading activity of mouse trophoblast cells in an in vitro invasion assay, suggesting it could perform a similar function during uterine implantation (Behrendtsen et al., 1992). The expression of metalloproteinases and tissue inhibitor of metalloproteinases (TIMP) in the peri-implantation embryo provides further evidence for the role of proteases in implantation (Brenner, 1989). Now a new thread has been woven into this tapestry of proteases in implantation. Herz et al. (1992) demonstrate that embryos lacking a functional LDL receptor-related
Minireview
protein (LRP) gene are phenotypically normal until the blastocyst stage but do not implant into the uterus. LRP is a protein with many activities: it functions as a clearance receptor for chylomicron remnants and can also mediate internalization of various protease-inhibitor complexes, e.g., PA-inhibitor complexes (Nykjaer et al., 1992; Orth et al., 1992) and a2-macroglobulin-protease complexes (Strickland et al., 1990; Kristensen et al., 1990). This latter activity is probably most germane to the effect observed in implantation. Invasion through the uterine epithelium is presumably promoted by proteases bound to the trophoblast cell surface or present in the extracellular environment. Eventually, these proteases would be complexed with inhibitors produced either by the uterus or the embryo itself, thereby decreasing the invasive ability of the trophoblast. In the model proposed by Herz et al., LRP mediates internalization of receptor-protease-inhibitor complexes, allowing free protease receptor to recycle to the cell surface where it can again bind active enzyme. Alternatively, endocytosis of the complexes might trigger synthesis of new receptor. In either circumstance, a deficiency in LRP would compromise invasion, since the protease receptors would remain on the cell surface occupied with inhibited enzymes. A number of embryo resorption sites were observed in the uterus of LRP mutant mice (Herz et al., 1992), suggesting that LRP null embryos may be capable of initiating implantation but are not capable of completing the process. Given LRP’s potential to effect clearance of multiple protease-inhibitor complexes, it could function to keep the cell endowed with its full armament of proteolytic activity. A defect in LRP would thus block implantation owing to its convergent position in proteolytic pathways, whereas individual proteases might be dispensable. Null mutations in genes for proteases and their cognate receptors and inhibitors will test many facets of this model. The Uterus The uterus must delicately balance its status, such that it becomes receptive to invasion of the embryo but is still able to control and eventually stop this process. Mammals exert control over trophoblast invasion to varying degrees.
Table
1. Control
of Implantation Embryo
Initiation
Protease
Uterus production
Protease receptor production LRP production Termination
Differentiation of cytotrophoblast Decreased protease production Increased protease inhibitor production
The table is limited
to those
aspects
Response to ovarian hormones LIF production CSF-1
production
Decidual
response
TGFP activation Increased inhibitor described
protease production
in the text.
Cell 356
For example, ungulates such as the pig form an epitheliochorial placenta in which uterine penetration does not occur. However, if a pig embryo is transferred to an ectopic site, it vigorously invades the tissue, suggesting that the uterus is specifically resistant. Analysis of uterine flushings from pregnant sows reveals high levels of a PA inhibitor(Mullinset al., 1980). Thus, inhibition of the PA-plasmin system may prevent trophoblast invasion in epitheliochorial placentation. Uterine receptivity can also be influenced by ovariectomizing a mouse after mating, which prevents the embryo from implanting at a normal time (day 4.5 postcoitus). The delay can be reversed by an injection of estrogen, showing that ovarian hormones influence the initiation of implantation. Uterine expression of the cytokine leukemia inhibitory factor (LIF) (Hilton, 1992; Smith et al., 1992) transiently increases at day 4 of mouse pregnancy, just prior to implantation. A similar burst of expression is observed at an equivalent time in pseudopregnant mice, indicating that this induction is independent of the embryo. When implantation is experimentally delayed, transient LIF expression is not seen until estrogen is injected (Bhatt et al., 1991) indicative of a function early in implantation. This hypothesis has been confirmed, since the uteri of mice homozygous for a nonfunctional LIF gene do not permit implantation (Stewart et al., 1992). Embryo transfer experiments demonstrate that it is the absence of maternal LIF, rather than absence of embryonic LIF, that results in failure to implant. In assessing implantation of LIF null embryos into LIF null mothers, partial rescue could be accomplished by treating the females with exogenous LIF, whereas treatment of the embryo in vitro had no effect. These experiments suggest that maternal LIF acts during the initiation of implantation, perhaps by inducing a change in the uterine epithelium that favors blastocyst attachment or invasion. Evidence for another cytokine functioning in implantation has come from the study of osteopefroric (oplop) mutant mice. These mice have a frameshift mutation in the gene encoding colony-stimulating factor 1 (CSF-l), which causes premature translational termination. The oplop deficiency results in a failure of embryos to implant within mutant uteri, and this effect is maternal in origin (Pollard et al., 1991). However, the defect can be partially rescued when oplop females are mated with either wild-type or op/+ males, indicating that either seminal or embryonic factors can partially compensate for the lack of maternal CSF-1. Once initiated, invasion must be tightly regulated. To this end, the uterine decidual response delimits the boundaries of invasion. One of the molecules thought to regulate implantation is transforming growth factor f3 (TGFf3) (Lala and Graham, 1990). TGFf3s are produced in the uterine decidua and the developing embryo at a time consistent with a function in this process (Manova et al., 1992). TGFf31 can induce differentiation of human cytotrophoblast cells into noninvasive syncytiotrophoblasts (Graham et al., 1992) and could restrict implantation via this mechanism. Since TIMP and PA inhibitor 1 expression is induced by TGFP in some invasive cell types (Laiho and Keski-Cja,
1989) this growth factor may also act to control invasion by regulating expression of proteases and their inhibitors in the uterus and embryo. An interesting aspect of this regulatory pathway is that latent TGFf3 can be activated by plasmin (Flaumenhaft et al., 1992). Therefore, decidual cells might limit invasion by loading latent TGFf3 into the extracellular matrix. As a trophoblast cell invades, plasmin generated via cell surface U-PA could trigger activation of latent TGFP, consequently increasing inhibitor expression and helping to terminate the invasion process. Thus, the proteases potentially responsible for invasion may also engender the restriction of implantation, creating an elegant selfregulated process analogous to those found in other complex biological systems. Relevance of Implantation to Tumor invasion and Metastasis Release of the unfertilized egg from the ovary, transport of the embryo through the oviduct and uterus, and implantation of the embryo bear similarity to tumor cell metastasis. To metastasize, a tumor cell must escape from its tissue of origin, intravasate into the blood stream, and then escape from the vasculature and invade a secondary tissue. It is therefore likely that the enzymatic and cellular machinery necessary for these processes is related. In fact, the degradation of basement membranes during metastasis is in part regulated by proteolysis, often by the same proteases implicated in implantation (reviewed in Testa and Quigley, 1990; Liotta et al., 1991). The report by Herz et al. (1992) raises the question of whether LRP plays a role in tumor invasion and metastasis by regulating the proteolytic balance of tumor cells. In a situation in which LRP is limiting, an increase in LRP production might enhance the proteolytic potential of the cell surface, resulting in a more invasive phenotype. LRPmediated control of proteolysis could also be regulated via the 39 kd LRP receptor-associated protein (RAP) (Herz et al., 1991; Williams et al., 1992). This protein has a high affinity for LRP and is able to inhibit ligand binding. Therefore, increases in RAP expression could decrease the internalization of protease-inhibitor complexes, thereby reducing the ability of a cell to traverse basement membranes. Finally, the biology of the decidual response deserves careful attention. If TGFf3 is shown to be instrumental in blocking progression of the trophoblast, it would promote the potential of this growth factor as a general inhibitor of metastasis. Since invasion and metastasis are the major causes of cancer morbidity and mortality, any molecule such as RAP or TGFb that might limit spread of tumor cells could be of great therapeutic value. References Axelrod, H. R. (1985). Dev. Biol. 108, 185-190. Behrendtsen, O., Alexander, C. M., and Werb, 2. (1992). Development 114, 447-456.
Bhatt, H., Brunet, L. J., and
Stewart,
C. L. (1991).
Proc.
Natl. Acad.
Sci. USA 88. 11408-11412.
Brenner, C. A., Adler, R. R.. Rappolee, D. A., Pedersen, R. A., and Werb, 2. (1989). Genes Dev. 3, 848-859.
Minireview 357
Estretcher, A., Mtihlhauser, J., Carpentier, J.-D. (1990). J. Cell Biol. 177, 783-792. Ftaumenhaft, R., Abe, M., Mignatti, Biol. 778. 901-909.
J.-L., Orci, L., and Vassaffi,
P., and Rifkin,
Graham, C. H., Lysiak, J. J., McCrae, Biol. Reprod. 46, 561-572.
D. 8. (1992). J. Cell
K. R., and Lala, P. K. (1992).
Herz, J., Goldstein, J. L., Strickland, D. K., Ho, Y. K., and Brown, (1991). J. Biol. Chem. 266, 21232-21238. Hew
J., Ctouthier,
Hilton,
D. E., and Hammer,
D. J. (1992).
Trends
R. E. (1992).
Biochem.
M. S.
Cell 77, this issue.
Sci. 77, 72-76.
Kristensen, T., Moestrup, S. K., Gliemann, J., Bendtsen, L., Sand, O., and SottrupJensen, L. (1990). FEBS Lett. 276, 151-155. Laiho,
M.. and Keski-Oja,
Lala. P. K., and Graham, 379. Liotta, L. A., Steeg, 64, 327-336.
J. (1989).
Cancer
C. H. (1990).
Res. 49, 2533-2553.
Cancer
Metastasis
P. S., and Stetler-Stevenson,
Manova, K., Paynton, 36. 141-152.
B. V., and Bachvarova,
Mullins, 872.
F. W., and Roberts,
D. E., Bazer,
Nykjaer, A., Petersen, Holtet, T. L., Etzerodt, P. A., and Gliemann,
Rev. 9,369-
W. G. (1991).
R. F. (1992). R. M. (1980).
Cell
Mech. Dev. Cell 20, 865-
C. M., Mailer, B., Jensen, P. H., Moestrup, S. K., M., Thegersen, H. C., Munch, M., Andreasen, J. (1992). J. Biol. Chem. 267, 14543-14546.
Orth, K., Madison, E. L., Gething, M.-J., Sambrook, J. F., and Herz, J. (1992). Proc. Natl. Acad. Sci. USA 89, 7422-7426. Pollard, J. W., Hunt, J. S., WiktorJedrzejczak, (1991). Dev. Biol. 748, 273-283. Roldan, A. L., Cubellis, L. R., Dane, K., Appella, Sappino, A.-P., Huarte, Biol. 709, 2471-2479.
W., and Stanley,
E. R.
M. V., Masucci, M. T., Behrendt, N., Lund, E., and Blasi, F. (1990). EMBO J. 9,467-474. J.. Belin. D., and Vassalli,
Smith, A. G., Nichols, J., Robertson, Dev. Biol. 757, 339-351. Stewart, C. L., Kaspar, P., Brunet, F., and Abbondanzo, S. J. (1992).
J.-D. (1989).
J. Cell
M., and Rathjen,
P. D. (1992).
L. J., Bhatt, H., Gadi, Nature 359, 76-79.
I., Kontgen,
Strickland, D. K., Ashcom, J. D., Williams, S., Burgess, W. H., Migliorini, M., and Argraves, W. S. (1990). J. Biol. Chem. 265, 17401-17404. Strickland, Testa, 367.
S., Reich,
E., and Sherman,
J. E., and Ouigley,
J. P. (1990).
M. I. (1976). Cancer
Williams, S. E., Ashcom, J. D., Argraves, (1992). J. Biol. Chem. 267, 9035-9040.
Cell 9, 231-240.
Metastasis
Rev. 9,353-
W. S., and Strickland,
D. K.
Zini, J.-M., Murray, S. C., Graham, C. H., Lala, P. K., Karikb, K., Barnathan, E. S., Mazar, A., Herkin, J., Cines, D. B., and McCrae, K. R. (1992). Blood 79, 2917-2929.
October
30, 1992, Copyright
0 1992 by Cell Press
Invasion of the Trophoblasts Sidney Strickland and William G. Richards Department of Pharmacology and Program in Genetics State University of New York Stony Brook, New York 11794-8851 What is our life? a play of passion, Our mirth the music of division, Our mothers’ wombs attiring houses be Where we are dressed for this short comedy. -Sir
Walter
Raleigh
(1612)
Mammalian embryonic development and growth require implantation into the uterus. In mammals that form a hemochorial placenta(e.g., humans, mice), embryonictrophoblast cells enable the embryo to invade through the uterine epithelium and deep into the stroma. The penetrative nature of hemochorial placentation so mimics that seen with highly invasive tumors that the normal trophoblast has been called pseudomalignant. Thus, in normal pregnancies the uterus must act to limit implantation; the uncontrolled invasion of the trophoblast, as in choriocarcinoma, results in one of the most metastatic tumors known. Recent work using both naturally occurring and experimentally generated mouse mutations has shed new light on implantation and its regulation. Present knowledge can be considered from the perspective of the two interacting tissues: the trophoblast and the uterus. The Trophoblast In mice and humans, trophoblast cells must cross the basement membranes of the uterine epithelium and vasculature to effect successful implantation. It has long been suspected that proteolytic enzymes play a role in this process. For example, the production of the protease urokinase-type plasminogen activator (U-PA) by mouse trophoblast cells temporally coincides with the embryo’s invasive phase and is localized to regions of invasion (Strickland et al., 1976; Sappino et al., 1989). Human trophoblast cells also express U-PA receptor (Mini et al., 1992), which can bind active U-PA and localize proteolysis to the leading edge of migrating cells (Estreicher et al., Roldan et al., 1990). In addition, mouse embryos homozygous for the mutation rY73have reduced levels of PA and do not implant (Axelrod, 1985). Metalloproteinases, such as stromelysin and the 92 kd type IV collagenase, are also produced by trophoblast cells. The 92 kd collagenase is necessary for the matrixdegrading activity of mouse trophoblast cells in an in vitro invasion assay, suggesting it could perform a similar function during uterine implantation (Behrendtsen et al., 1992). The expression of metalloproteinases and tissue inhibitor of metalloproteinases (TIMP) in the peri-implantation embryo provides further evidence for the role of proteases in implantation (Brenner, 1989). Now a new thread has been woven into this tapestry of proteases in implantation. Herz et al. (1992) demonstrate that embryos lacking a functional LDL receptor-related
Minireview
protein (LRP) gene are phenotypically normal until the blastocyst stage but do not implant into the uterus. LRP is a protein with many activities: it functions as a clearance receptor for chylomicron remnants and can also mediate internalization of various protease-inhibitor complexes, e.g., PA-inhibitor complexes (Nykjaer et al., 1992; Orth et al., 1992) and a2-macroglobulin-protease complexes (Strickland et al., 1990; Kristensen et al., 1990). This latter activity is probably most germane to the effect observed in implantation. Invasion through the uterine epithelium is presumably promoted by proteases bound to the trophoblast cell surface or present in the extracellular environment. Eventually, these proteases would be complexed with inhibitors produced either by the uterus or the embryo itself, thereby decreasing the invasive ability of the trophoblast. In the model proposed by Herz et al., LRP mediates internalization of receptor-protease-inhibitor complexes, allowing free protease receptor to recycle to the cell surface where it can again bind active enzyme. Alternatively, endocytosis of the complexes might trigger synthesis of new receptor. In either circumstance, a deficiency in LRP would compromise invasion, since the protease receptors would remain on the cell surface occupied with inhibited enzymes. A number of embryo resorption sites were observed in the uterus of LRP mutant mice (Herz et al., 1992), suggesting that LRP null embryos may be capable of initiating implantation but are not capable of completing the process. Given LRP’s potential to effect clearance of multiple protease-inhibitor complexes, it could function to keep the cell endowed with its full armament of proteolytic activity. A defect in LRP would thus block implantation owing to its convergent position in proteolytic pathways, whereas individual proteases might be dispensable. Null mutations in genes for proteases and their cognate receptors and inhibitors will test many facets of this model. The Uterus The uterus must delicately balance its status, such that it becomes receptive to invasion of the embryo but is still able to control and eventually stop this process. Mammals exert control over trophoblast invasion to varying degrees.
Table
1. Control
of Implantation Embryo
Initiation
Protease
Uterus production
Protease receptor production LRP production Termination
Differentiation of cytotrophoblast Decreased protease production Increased protease inhibitor production
The table is limited
to those
aspects
Response to ovarian hormones LIF production CSF-1
production
Decidual
response
TGFP activation Increased inhibitor described
protease production
in the text.
Cell 356
For example, ungulates such as the pig form an epitheliochorial placenta in which uterine penetration does not occur. However, if a pig embryo is transferred to an ectopic site, it vigorously invades the tissue, suggesting that the uterus is specifically resistant. Analysis of uterine flushings from pregnant sows reveals high levels of a PA inhibitor(Mullinset al., 1980). Thus, inhibition of the PA-plasmin system may prevent trophoblast invasion in epitheliochorial placentation. Uterine receptivity can also be influenced by ovariectomizing a mouse after mating, which prevents the embryo from implanting at a normal time (day 4.5 postcoitus). The delay can be reversed by an injection of estrogen, showing that ovarian hormones influence the initiation of implantation. Uterine expression of the cytokine leukemia inhibitory factor (LIF) (Hilton, 1992; Smith et al., 1992) transiently increases at day 4 of mouse pregnancy, just prior to implantation. A similar burst of expression is observed at an equivalent time in pseudopregnant mice, indicating that this induction is independent of the embryo. When implantation is experimentally delayed, transient LIF expression is not seen until estrogen is injected (Bhatt et al., 1991) indicative of a function early in implantation. This hypothesis has been confirmed, since the uteri of mice homozygous for a nonfunctional LIF gene do not permit implantation (Stewart et al., 1992). Embryo transfer experiments demonstrate that it is the absence of maternal LIF, rather than absence of embryonic LIF, that results in failure to implant. In assessing implantation of LIF null embryos into LIF null mothers, partial rescue could be accomplished by treating the females with exogenous LIF, whereas treatment of the embryo in vitro had no effect. These experiments suggest that maternal LIF acts during the initiation of implantation, perhaps by inducing a change in the uterine epithelium that favors blastocyst attachment or invasion. Evidence for another cytokine functioning in implantation has come from the study of osteopefroric (oplop) mutant mice. These mice have a frameshift mutation in the gene encoding colony-stimulating factor 1 (CSF-l), which causes premature translational termination. The oplop deficiency results in a failure of embryos to implant within mutant uteri, and this effect is maternal in origin (Pollard et al., 1991). However, the defect can be partially rescued when oplop females are mated with either wild-type or op/+ males, indicating that either seminal or embryonic factors can partially compensate for the lack of maternal CSF-1. Once initiated, invasion must be tightly regulated. To this end, the uterine decidual response delimits the boundaries of invasion. One of the molecules thought to regulate implantation is transforming growth factor f3 (TGFf3) (Lala and Graham, 1990). TGFf3s are produced in the uterine decidua and the developing embryo at a time consistent with a function in this process (Manova et al., 1992). TGFf31 can induce differentiation of human cytotrophoblast cells into noninvasive syncytiotrophoblasts (Graham et al., 1992) and could restrict implantation via this mechanism. Since TIMP and PA inhibitor 1 expression is induced by TGFP in some invasive cell types (Laiho and Keski-Cja,
1989) this growth factor may also act to control invasion by regulating expression of proteases and their inhibitors in the uterus and embryo. An interesting aspect of this regulatory pathway is that latent TGFf3 can be activated by plasmin (Flaumenhaft et al., 1992). Therefore, decidual cells might limit invasion by loading latent TGFf3 into the extracellular matrix. As a trophoblast cell invades, plasmin generated via cell surface U-PA could trigger activation of latent TGFP, consequently increasing inhibitor expression and helping to terminate the invasion process. Thus, the proteases potentially responsible for invasion may also engender the restriction of implantation, creating an elegant selfregulated process analogous to those found in other complex biological systems. Relevance of Implantation to Tumor invasion and Metastasis Release of the unfertilized egg from the ovary, transport of the embryo through the oviduct and uterus, and implantation of the embryo bear similarity to tumor cell metastasis. To metastasize, a tumor cell must escape from its tissue of origin, intravasate into the blood stream, and then escape from the vasculature and invade a secondary tissue. It is therefore likely that the enzymatic and cellular machinery necessary for these processes is related. In fact, the degradation of basement membranes during metastasis is in part regulated by proteolysis, often by the same proteases implicated in implantation (reviewed in Testa and Quigley, 1990; Liotta et al., 1991). The report by Herz et al. (1992) raises the question of whether LRP plays a role in tumor invasion and metastasis by regulating the proteolytic balance of tumor cells. In a situation in which LRP is limiting, an increase in LRP production might enhance the proteolytic potential of the cell surface, resulting in a more invasive phenotype. LRPmediated control of proteolysis could also be regulated via the 39 kd LRP receptor-associated protein (RAP) (Herz et al., 1991; Williams et al., 1992). This protein has a high affinity for LRP and is able to inhibit ligand binding. Therefore, increases in RAP expression could decrease the internalization of protease-inhibitor complexes, thereby reducing the ability of a cell to traverse basement membranes. Finally, the biology of the decidual response deserves careful attention. If TGFf3 is shown to be instrumental in blocking progression of the trophoblast, it would promote the potential of this growth factor as a general inhibitor of metastasis. Since invasion and metastasis are the major causes of cancer morbidity and mortality, any molecule such as RAP or TGFb that might limit spread of tumor cells could be of great therapeutic value. References Axelrod, H. R. (1985). Dev. Biol. 108, 185-190. Behrendtsen, O., Alexander, C. M., and Werb, 2. (1992). Development 114, 447-456.
Bhatt, H., Brunet, L. J., and
Stewart,
C. L. (1991).
Proc.
Natl. Acad.
Sci. USA 88. 11408-11412.
Brenner, C. A., Adler, R. R.. Rappolee, D. A., Pedersen, R. A., and Werb, 2. (1989). Genes Dev. 3, 848-859.
Minireview 357
Estretcher, A., Mtihlhauser, J., Carpentier, J.-D. (1990). J. Cell Biol. 177, 783-792. Ftaumenhaft, R., Abe, M., Mignatti, Biol. 778. 901-909.
J.-L., Orci, L., and Vassaffi,
P., and Rifkin,
Graham, C. H., Lysiak, J. J., McCrae, Biol. Reprod. 46, 561-572.
D. 8. (1992). J. Cell
K. R., and Lala, P. K. (1992).
Herz, J., Goldstein, J. L., Strickland, D. K., Ho, Y. K., and Brown, (1991). J. Biol. Chem. 266, 21232-21238. Hew
J., Ctouthier,
Hilton,
D. E., and Hammer,
D. J. (1992).
Trends
R. E. (1992).
Biochem.
M. S.
Cell 77, this issue.
Sci. 77, 72-76.
Kristensen, T., Moestrup, S. K., Gliemann, J., Bendtsen, L., Sand, O., and SottrupJensen, L. (1990). FEBS Lett. 276, 151-155. Laiho,
M.. and Keski-Oja,
Lala. P. K., and Graham, 379. Liotta, L. A., Steeg, 64, 327-336.
J. (1989).
Cancer
C. H. (1990).
Res. 49, 2533-2553.
Cancer
Metastasis
P. S., and Stetler-Stevenson,
Manova, K., Paynton, 36. 141-152.
B. V., and Bachvarova,
Mullins, 872.
F. W., and Roberts,
D. E., Bazer,
Nykjaer, A., Petersen, Holtet, T. L., Etzerodt, P. A., and Gliemann,
Rev. 9,369-
W. G. (1991).
R. F. (1992). R. M. (1980).
Cell
Mech. Dev. Cell 20, 865-
C. M., Mailer, B., Jensen, P. H., Moestrup, S. K., M., Thegersen, H. C., Munch, M., Andreasen, J. (1992). J. Biol. Chem. 267, 14543-14546.
Orth, K., Madison, E. L., Gething, M.-J., Sambrook, J. F., and Herz, J. (1992). Proc. Natl. Acad. Sci. USA 89, 7422-7426. Pollard, J. W., Hunt, J. S., WiktorJedrzejczak, (1991). Dev. Biol. 748, 273-283. Roldan, A. L., Cubellis, L. R., Dane, K., Appella, Sappino, A.-P., Huarte, Biol. 709, 2471-2479.
W., and Stanley,
E. R.
M. V., Masucci, M. T., Behrendt, N., Lund, E., and Blasi, F. (1990). EMBO J. 9,467-474. J.. Belin. D., and Vassalli,
Smith, A. G., Nichols, J., Robertson, Dev. Biol. 757, 339-351. Stewart, C. L., Kaspar, P., Brunet, F., and Abbondanzo, S. J. (1992).
J.-D. (1989).
J. Cell
M., and Rathjen,
P. D. (1992).
L. J., Bhatt, H., Gadi, Nature 359, 76-79.
I., Kontgen,
Strickland, D. K., Ashcom, J. D., Williams, S., Burgess, W. H., Migliorini, M., and Argraves, W. S. (1990). J. Biol. Chem. 265, 17401-17404. Strickland, Testa, 367.
S., Reich,
E., and Sherman,
J. E., and Ouigley,
J. P. (1990).
M. I. (1976). Cancer
Williams, S. E., Ashcom, J. D., Argraves, (1992). J. Biol. Chem. 267, 9035-9040.
Cell 9, 231-240.
Metastasis
Rev. 9,353-
W. S., and Strickland,
D. K.
Zini, J.-M., Murray, S. C., Graham, C. H., Lala, P. K., Karikb, K., Barnathan, E. S., Mazar, A., Herkin, J., Cines, D. B., and McCrae, K. R. (1992). Blood 79, 2917-2929.