Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1997 Feb;88(2):152–159. doi: 10.1111/j.1349-7006.1997.tb00360.x

Transforming Growth Factor‐β and Hepatocyte Growth Factor Produced by Gastric Fibroblasts Stimulate the Invasiveness of Scirrhous Gastric Cancer Cells

Tohru Inoue 1,✉, Yong‐Suk Chung 1, Masakazu Yashiro 1, Shigehiko Nishimura 1, Tadayoshi Hasuma 2, Shuzo Otani 2, Michio Sowa 1
PMCID: PMC5921364  PMID: 9119743

Abstract

Scirrhous gastric carcinoma is characterized by cancer cells that infiltrate rapidly in the stroma with extensive growth of fibroblasts. In the present study, we examined the effect of gastric fibroblasts on the invasiveness of a Scirrhous gastric cancer cell line, OCUM‐2D, using an invasion assay. Gastric fibroblast‐derived conditioned medium (CM) significantly stimulated the invasiveness of OCUM‐2D cells, as did transforming growth factor‐β (TGF‐β) and hepatocyte growth factor (HGF). The stimulating activity of gastric fibroblast‐derived CM was inhibited significantly by anti‐TGF‐β neutralizing antibody or anti‐HGF neutralizing antibody. TGF‐β and HGF were detected in the gastric fibroblast‐derived CM, and TGF‐β receptor and C‐met (HGF receptor) were expressed on OCUM‐2D cells. Thus, TGF‐β and HGF produced by gastric fibroblasts appear to affect the invasiveness of scirrhous gastric cancer cells. TGF‐β was also detected in the conditioned medium derived from OCUM‐2D cells, though HGF was not. TGF‐β appears to affect the invasiveness of OCUM‐2D cells in both paracrine and autocrine fashions.

Keywords: Scirrhous gastric carcinoma, Fibroblast, Invasion, Transforming growth factor‐β, Hepatocyte growth factor

Full Text

The Full Text of this article is available as a PDF (477.3 KB).

REFERENCES

  • 1. ) Kiyasu , Y. , Kaneshima , S. and Koga , S.Morphogenesis of peritoneal metastasis in human gastric cancer . Cancer Res. , 41 , 1236 – 1239 ( 1981. ). [PubMed] [Google Scholar]
  • 2. ) Yashiro , M. , Chung , Y. S. , Nishimura , S. , Inoue , T. and Sowa , M.Peritoneal metastatic model for human scirrhous gastric carcinoma in nude mice . Clin. Exp. Metastasis , 14 , 43 – 54 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Yashiro , M. , Chung , Y. S. , Nishimura , S. , Inoue , T. and Sowa , M.Establishment of two new scirrhous gastric cancer cell lines: analysis of factors associated with disseminated metastasis . Br. J, Cancer , 72 , 1200 – 1210 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Tahara , E.Growth factors and oncogenes in human gastrointestinal carcinomas . J. Cancer Res. Clin. OncoL , 116 , 121 – 131 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Shimura , H. , Date , K. , Matsumoto , K. , Nakamura , T. and Tanaka , M.Induction of invasive growth in a gallbladder cancer cell line by hepatocyte growth factor in vitro . Jpn. J, Cancer Res. , 86 , 662 – 669 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Gohji , K. , Nakajima , M. , Fabra , A. , Bucana , C. D. , von Eschenbach , A. C. , Tsuruo , T. and Fidler , I. J.Regulation of gelatinase production in metastatic renal cell carcinoma by organ‐specific fibloblasts . Jpn. J. Cancer Res. , 85 , 152 – 160 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) van den Hooff , A.Stromal involvement in malignant growth . Adv. Cancer Res. , 50 , 159 – 196 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Morikawa , K. , Walker , S. M. , Nakajima , M. , Pathak , S. , Jessup , J. M. and Fidler , I. J.Influence of the organ environment on the growth, selection, and metastasis of human colon carcinoma cells in nude mice . Cancer Res. , 48 , 6863 – 6871 ( 1988. ). [PubMed] [Google Scholar]
  • 9. ) Nakajima , M. and Chop , A. M.Tumor invasion and extracellular matrix degradative enzymes: regulation of activity by organ factors . Sem. Cancer Biol , 2 , 115 – 127 ( 1991. ). [PubMed] [Google Scholar]
  • 10. ) Fabra , A. , Nakajima , M. , Bucana , C. D. and Fidler , I. J.Modulation of the invasive phenotype of human colon carcinoma cells by organ specific fibroblasts of nude mice . Differentiation , 52 , 101 – 110 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Matsumoto , K. , Date , K. , Shimura , H. and Nakamura , T.Acquisition of invasive phenotype in gallbladder cancer cells via mutual interaction of stromal fibroblasts and cancer cells as mediated by hepatocyte growth factor . Jpn. J. Cancer Res. , 87 , 702 – 710 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Yashiro , M. , Chung , Y.‐S. and Sowa , M.Role of orthotopic fibroblasts in the development of scirrhous gastric carcinoma . Jpn. J. Cancer Res. , 85 , 883 – 886 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Albini , A. , Iwamoto , Y. , Kleinman , H. K. , Martin , G. R. , Aaronson , S. A. , Kozlowski , J. M. and McEvan , R. N.A rapid in vitro assay for quantitating the invasive potential of tumor cells . Cancer Res. , 47 , 3239 – 3245 ( 1987. ). [PubMed] [Google Scholar]
  • 14. ) Laemmli , U. K.Cleavage of structural proteins during the assembly of the head of bacteriophage T4 . Nature , 227 , 680 – 687 ( 1970. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Welch , D. R. , Fabra , A. and Nakajima , M.Transforming growth factor beta stimulates mammary adenocarcinoma cell invasion and metastatic potential . Proc. Natl. Acad. Sci. USA , 87 , 7678 – 7682 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Ueki , N. , Ohkawa , T. , Yokoyama , Y. , Maeda , J. , Kawai , Y. , Ikeda , T. , Amuro , Y. , Hada , T. and Higashio , K.Potentiation of metastatic capacity by transforming growth factor‐β gene transfection . Jpn. J. Cancer Res. , 84 , 589 – 593 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Mooradian , D. L. , McCarthy , J. B. , Komanduri , K. V. and Furcht , L. T.Effects of transforming growth factor‐β 1 on human pulmonary adenocarcinoma cell adhesion, motility, and invasion in vitro . J. Natl Cancer Inst , 84 , 523 – 527 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Merzak , A. , McCrea , S. , Koocheckpour , S. and Pilkington , G. J.Control of human glioma cell growth, migration and invasion in vitro by transforming growth factor β.Br . J. Cancer , 70 , 199 – 203 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Mahara , K. , Kato , J. , Terui , T. , Takimoto , R. , Horirnoto , M. , Murakami , T. , Mogi , Y. , Watanabe , N. , Kongo , Y. and Niitsu , Y.Transforming growth factor β1 secreted from scirrhous gastric cancer cells is associated with excess collagen deposition in the tissue . Br. J. Cancer , 69 , 177 – 783 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. ) Guirguits , R. , Marguies , L , Taraboletti , G. , Schiffmann , E. and Liotta , L.Cytokine‐induced pseudopodal protrusion is coupled to tumor cell migration . Nature , 329 , 261 – 263 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Liotta , L. A. , Rao , C. N. and Barsky , S. H.Tumor invasion and the extracellular matrix . Lab. Invest. , 49 , 636 – 649 ( 1983. ). [PubMed] [Google Scholar]
  • 22. ) Saksela , O. , Moscatelli , D. and Rifkin , D. B.The opposing effects of basic fibroblast growth factor and transforming growth factor beta on the regulation of plasminogen activator activity in capillary endothelial cells . J. Cell Biol , 105 , 957 – 963 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. ) Weidner , K. M. , Arakaki , N. , Vandekereckhove , J. , Weingart , S. , Hartmann , G. , Rieder , H. , Fonatsch , C. , Tsubouchi , H. , Hishida , T. , Daikuhara , Y. and Birchmeier , W.Evidence for the identity of human scatter factor and human hepatocyte growth factor . Proc. Natl. Acad. Sci. USA , 88 , 7001 – 7005 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Rosen , E. M. , Knesel , J. , Goldberg , I. D. , Jin , L. , Bhargava , M. , Joseph , A. , Zitnik , R. , Wines , J. , Kelley , M. and Rockwell , S.Scatter factor modulates the metastatic phenotype of the EMT6 mouse mammary tumor . Int. J. Cancer , 57 , 706 – 714 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Rong , S. , Segal , S. , Anver , M. , Resau , J. H. and Vande Woude , G. F.Invasiveness and metastasis of NIH 3T3 cells induced by Met‐hepatocyte growth factor/scatter factor autocrine stimulation . Proc, Natl. Acad. Sci. USA , 91 , 4731 – 4735 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Nakamura , T. , Nishizawa , T. , Hagiya , M. , Seki , T. , Shimonishi , M. , Sugiura , A. , Tashiro , K. and Shimizu , S.Molecular cloning and expression of human hepatocyte growth factor . Nature , 342 , 440 – 443 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Takahashi , M. , Ota , S. , Shimada , T. , Hamada , E. , Kawabe , T. , Okudaira , T. , Matsumura , M. , Kaneko , N. , Terano , A. , Nakamura , T. and Omata , M.Hepatocyte growth factor is the most potent endogenous stimulant of rabbit gastric epithelial cell proliferation and migration in primary culture . J. Clin. Invest. , 95 , 1994 – 2003 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. ) Bottaro , D. P. , Rubin , J. S. , Faletto , D. L. , Chan , A. M.‐L. , Kmiecik , T. E. , van de Woude , G. F. and Aaronson , S. A.Identification of the hepatocyte growth factor receptor as the c‐met proto‐oncogene product . Science , 251 , 802 – 804 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Nardini , L. , Vigna , E. , Narsimhan , R. , Guadino , G. , Zarnegar , R. , Michalopoulos , G. and Comoglio , P. M.Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto‐oncogene c‐MET . Oncogene , 6 , 501 – 504 ( 1991. ). [PubMed] [Google Scholar]
  • 30. ) Kuniyasu , H. , Yasui , W. , Kitadai , Y. , Yokozaki , H. , Ito , H. and Tahara , E.Frequent amplification of the c‐met gene in scirrhous type gastric cancer . Biochem. Biophys. Res. Commun. , 189 , 227 – 232 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Tahara , E. , Kuniyasu , H. , Yasui , W. and Yokozaki , H.Abnormal expression of growth factors and their receptors in stomach cancer . Gann Monogr. Cancer Res. , 42 , 163 – 173 ( 1994. ). [Google Scholar]
  • 32. ) Lyons , R. M. , Keski‐Oja , J. and Moses , H. L.Proteolytic activation of latent transforming growth factor β from flbroblast conditioned medium . J. Cell Biol , 106 , 1659 – 1665 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. ) Horimoto , M. , Kato , T. , Takimoto , R. , Terui , T. , Mogi , Y. and Niitsu , Y.Identification of a transforming growth factor‐β l activator derived from a human gastric cancer cell line . Br. J. Cancer , 72 , 676 – 682 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. ) Miyazono , K. and Heldin , C.‐H.Role for carbohydrate structures in TGF‐β 1 latency . Nature , 338 , 158 – 160 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) Odekon , L. E. , Blasi , F , and Rifkin , D. B.Requirement for receptor‐bound urokinase in plasmin‐dependent cellular conversion of latent TGF‐beta to TGF‐beta . J. Cell. Physiol. , 158 , 398 – 407 ( 1994. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES