Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Oct;81(4):721–726. doi: 10.1038/sj.bjc.6690754

Hepatocyte growth factor and invasion-stimulatory activity are induced in pleural fluid by surgery in lung cancer patients

A Uchiyama 1, T Morisaki 1, K Beppu 1, M Kojima 1, Y Matsunari 1, A Nakatsuka 1, K Mizumoto 1, K Matsumoto 2, T Nakamura 2, M Tanaka 1
PMCID: PMC2362901  PMID: 10574262

Abstract

Hepatocyte growth factor (HGF) is a stromal cell-derived cytokine that can stimulate matrix invasion by carcinoma cells. We analysed the concentrations of HGF and invasion-stimulatory activity in pleural fluid after lung surgery. The concentration of HGF in pleural fluids was measured by enzyme-linked immunosorbent assay in seven patients who underwent pulmonary resection for primary or metastatic lung cancer. The effect of the pleural fluid on cancer cell invasion across reconstituted basement membrane (Matrigel) was assessed with a Boyden chamber assay using a lung adenocarcinoma cell line, A549. HGF levels in the pleural fluid after lung surgery ranged from 6.0 to 23.0 ng ml−1 (average: 10.2 ± 4.3 ng ml−1). The matrix invasion of lung carcinoma cells in the presence of the pleural fluid was significantly higher than that in the presence of culture medium alone or sera from normal subjects (P < 0.01). The invasion-stimulatory activity of the pleural fluid was strongly inhibited by HGF-neutralizing antibody. Positive correlation was found between the HGF level and invasion-stimulatory activity in the pleural fluids and normal sera (P = 0.0073). This is the first report demonstrating that the lung surgery induces a considerable amount of HGF, which is closely correlated with the invasion-stimulatory activity of the pleural fluid. © 1999 Cancer Research Campaign

Keywords: hepatocyte growth factor, lung surgery, cancer invasion

Full Text

The Full Text of this article is available as a PDF (78.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bogden A. E., Moreau J. P., Eden P. A. Proliferative response of human and animal tumours to surgical wounding of normal tissues: onset, duration and inhibition. Br J Cancer. 1997;75(7):1021–1027. doi: 10.1038/bjc.1997.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Eagles G., Warn A., Ball R. Y., Baillie-Johnson H., Arakaki N., Daikuhara Y., Warn R. M. Hepatocyte growth factor/scatter factor is present in most pleural effusion fluids from cancer patients. Br J Cancer. 1996 Feb;73(3):377–381. doi: 10.1038/bjc.1996.64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Giordano S., Zhen Z., Medico E., Gaudino G., Galimi F., Comoglio P. M. Transfer of motogenic and invasive response to scatter factor/hepatocyte growth factor by transfection of human MET protooncogene. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):649–653. doi: 10.1073/pnas.90.2.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Jeffers M., Rong S., Vande Woude G. F. Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-met signalling in human cells concomitant with induction of the urokinase proteolysis network. Mol Cell Biol. 1996 Mar;16(3):1115–1125. doi: 10.1128/mcb.16.3.1115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Kenworthy P., Dowrick P., Baillie-Johnson H., McCann B., Tsubouchi H., Arakaki N., Daikuhara Y., Warn R. M. The presence of scatter factor in patients with metastatic spread to the pleura. Br J Cancer. 1992 Aug;66(2):243–247. doi: 10.1038/bjc.1992.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kimura F., Miyazaki M., Suwa T., Kakizaki S., Itoh H., Kaiho T., Ambiru S., Shimizu H., Togawa A. Increased levels of human hepatocyte growth factor in serum and peritoneal fluid after partial hepatectomy. Am J Gastroenterol. 1996 Jan;91(1):116–121. [PubMed] [Google Scholar]
  7. Kodama M., Kodama T., Nishi Y., Totani R. Does surgical stress cause tumor metastasis? Anticancer Res. 1992 Sep-Oct;12(5):1603–1616. [PubMed] [Google Scholar]
  8. Matsumoto K., Date K., Shimura H., 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. 1996 Jul;87(7):702–710. doi: 10.1111/j.1349-7006.1996.tb00281.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Matsumoto K., Nakamura T. Hepatocyte growth factor (HGF) as a tissue organizer for organogenesis and regeneration. Biochem Biophys Res Commun. 1997 Oct 29;239(3):639–644. doi: 10.1006/bbrc.1997.7517. [DOI] [PubMed] [Google Scholar]
  10. Matsumoto K., Okazaki H., Nakamura T. Up-regulation of hepatocyte growth factor gene expression by interleukin-1 in human skin fibroblasts. Biochem Biophys Res Commun. 1992 Oct 15;188(1):235–243. doi: 10.1016/0006-291x(92)92375-8. [DOI] [PubMed] [Google Scholar]
  11. Miyazawa K., Tsubouchi H., Naka D., Takahashi K., Okigaki M., Arakaki N., Nakayama H., Hirono S., Sakiyama O., Takahashi K. Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun. 1989 Sep 15;163(2):967–973. doi: 10.1016/0006-291x(89)92316-4. [DOI] [PubMed] [Google Scholar]
  12. Nakamura T., Matsumoto K., Kiritoshi A., Tano Y., Nakamura T. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions. Cancer Res. 1997 Aug 1;57(15):3305–3313. [PubMed] [Google Scholar]
  13. Nakamura T., Nawa K., Ichihara A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun. 1984 Aug 16;122(3):1450–1459. doi: 10.1016/0006-291x(84)91253-1. [DOI] [PubMed] [Google Scholar]
  14. Nakamura T., Nishizawa T., Hagiya M., Seki T., Shimonishi M., Sugimura A., Tashiro K., Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989 Nov 23;342(6248):440–443. doi: 10.1038/342440a0. [DOI] [PubMed] [Google Scholar]
  15. Noji S., Tashiro K., Koyama E., Nohno T., Ohyama K., Taniguchi S., Nakamura T. Expression of hepatocyte growth factor gene in endothelial and Kupffer cells of damaged rat livers, as revealed by in situ hybridization. Biochem Biophys Res Commun. 1990 Nov 30;173(1):42–47. doi: 10.1016/s0006-291x(05)81018-6. [DOI] [PubMed] [Google Scholar]
  16. Nomoto S., Nakao A., Kasai Y., Harada A., Nonami T., Takagi H. Detection of ras gene mutations in perioperative peripheral blood with pancreatic adenocarcinoma. Jpn J Cancer Res. 1996 Aug;87(8):793–797. doi: 10.1111/j.1349-7006.1996.tb02102.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ohmichi H., Matsumoto K., Nakamura T. In vivo mitogenic action of HGF on lung epithelial cells: pulmotrophic role in lung regeneration. Am J Physiol. 1996 Jun;270(6 Pt 1):L1031–L1039. doi: 10.1152/ajplung.1996.270.6.L1031. [DOI] [PubMed] [Google Scholar]
  18. Sakon M., Kita Y., Yoshida T., Umeshita K., Gotoh M., Kanai T., Kawasaki T., Kambayashi J., Monden M. Plasma hepatocyte growth factor levels are increased in systemic inflammatory response syndrome. Surg Today. 1996;26(4):236–241. doi: 10.1007/BF00311581. [DOI] [PubMed] [Google Scholar]
  19. Siegfried J. M., Weissfeld L. A., Singh-Kaw P., Weyant R. J., Testa J. R., Landreneau R. J. Association of immunoreactive hepatocyte growth factor with poor survival in resectable non-small cell lung cancer. Cancer Res. 1997 Feb 1;57(3):433–439. [PubMed] [Google Scholar]
  20. Sieuwerts A. M., Klijn J. G., Foekens J. A. Assessment of the invasive potential of human gynecological tumor cell lines with the in vitro Boyden chamber assay: influences of the ability of cells to migrate through the filter membrane. Clin Exp Metastasis. 1997 Jan;15(1):53–62. doi: 10.1023/a:1018436407280. [DOI] [PubMed] [Google Scholar]
  21. Sonnenberg E., Meyer D., Weidner K. M., Birchmeier C. Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol. 1993 Oct;123(1):223–235. doi: 10.1083/jcb.123.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Tomiya T., Tani M., Yamada S., Hayashi S., Umeda N., Fujiwara K. Serum hepatocyte growth factor levels in hepatectomized and nonhepatectomized surgical patients. Gastroenterology. 1992 Nov;103(5):1621–1624. doi: 10.1016/0016-5085(92)91186-8. [DOI] [PubMed] [Google Scholar]
  23. Uchiyama A., Essner R., Doi F., Nguyen T., Ramming K. P., Nakamura T., Morton D. L., Hoon D. S. Interleukin 4 inhibits hepatocyte growth factor-induced invasion and migration of colon carcinomas. J Cell Biochem. 1996 Sep 15;62(4):443–453. doi: 10.1002/(SICI)1097-4644(19960915)62:4%3C443::AID-JCB2%3E3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  24. Ueda T., Takeyama Y., Toyokawa A., Kishida S., Yamamoto M., Saitoh Y. Significant elevation of serum human hepatocyte growth factor levels in patients with acute pancreatitis. Pancreas. 1996 Jan;12(1):76–83. doi: 10.1097/00006676-199601000-00010. [DOI] [PubMed] [Google Scholar]
  25. Weidner K. M., Behrens J., Vandekerckhove J., Birchmeier W. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol. 1990 Nov;111(5 Pt 1):2097–2108. doi: 10.1083/jcb.111.5.2097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Yanagita K., Matsumoto K., Sekiguchi K., Ishibashi H., Niho Y., Nakamura T. Hepatocyte growth factor may act as a pulmotrophic factor on lung regeneration after acute lung injury. J Biol Chem. 1993 Oct 5;268(28):21212–21217. [PubMed] [Google Scholar]
  27. Yanagita K., Nagaike M., Ishibashi H., Niho Y., Matsumoto K., Nakamura T. Lung may have an endocrine function producing hepatocyte growth factor in response to injury of distal organs. Biochem Biophys Res Commun. 1992 Jan 31;182(2):802–809. doi: 10.1016/0006-291x(92)91803-x. [DOI] [PubMed] [Google Scholar]
  28. Zarnegar R., Michalopoulos G. K. The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol. 1995 Jun;129(5):1177–1180. doi: 10.1083/jcb.129.5.1177. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES