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


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.

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  1. Bogden, AE, Moreau, JP & Eden, PA (1997) Proliferative response of human and animal tumours to surgical wounding of normal tissues: onset, duration and inhibition. Br J Cancer 75: 1021–1027

  2. Eagles, G, Warn, A, Ball, RY, Baillie-Johnson, H, Arakaki, N, Daikuhara, Y & Warn, RM (1996) Hepatocyte growth factor/scatter factor is present in most pleural effusion fluids from cancer patients. Br J Cancer 73: 377–381

  3. Giordano, S, Zhen, Z, Medico, E, Gaudino, G, Galimi, F & Comoglio, PM (1993) Transfer of motogenic and invasive response to scatter factor/hepatocyte growth factor by transfection of human MET protooncogene. Proc Natl Acad Sci USA 90: 649–653

  4. Jeffers, M, Rong, S & Woude, GF (1996) 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 16: 1115–1125

  5. Kenworthy, P, Dowrick, P, Baillie-Johnson, H, McCann, B, Tsubouchi, H, Arakaki, N, Daikuhara, Y & Warn, RM (1992) The presence of scatter factor in patients with metastatic spread to the pleura. Br J Cancer 66: 243–247

  6. Kimura, F, Miyazaki, M, Suwa, T, Kakizaki, S, Itoh, H, Kaiho, T, Ambiru, S, Shimizu, H & Togawa, A (1996) Increased levels of human hepatocyte growth factor in serum and peritoneal fluid after partial hepatectomy. Am J Gastroenterol 91: 116–121

  7. Kodama, M, Kodama, T, Nishi, Y & Totani, R (1992) Does surgical stress cause tumor metastasis? Anticancer Res 12: 1603–1616

  8. Matsumoto, K & Nakamura, T (1997) Hepatocyte growth factor (HGF) as a tissue organizer for organogenesis and regeneration. Biochem Biophys Res Commun 239: 639–644

  9. Matsumoto, K, Okazaki, H & Nakamura, T (1992) Up-regulation of hepatocyte growth factor gene expression by interleukin-1 in human skin fibroblasts. Biochem Biophys Res Commun 188: 235–243

  10. Matsumoto, K, Date, K, Shimura, H & Nakamura, T (1996) 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

  11. Miyazawa, K, Tsubouchi, H, Naka, D, Takahashi, K, Okigaki, M, Arakaki, N, Nakayama, H, Hirono, S, Sakiyama, O, Gohda, E, Daikuhara, Y & Kitamura, N (1989) Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun 163: 967–973

  12. Nakamura, T, Nawa, K & Ichihara, A (1984) Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun 122: 1450–1459

  13. Nakamura, T, Nishizawa, T, Hagiya, M, Seki, T, Shimonishi, M, Sugimura, A, Tashiro, K & Shimizu, S (1989) Molecular cloning and expression of human hepatocyte growth factor. Nature 342: 440–443

  14. Nakamura, T, Matsumoto, K, Kiritoshi, A, Tano, Y & Nakamura, T (1997) 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 57: 3305–3313

  15. Noji, S, Tashiro, K, Koyama, E, Nohno, T, Ohyama, K, Taniguchi, S & Nakamura, T (1990) 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 173: 42–47

  16. Nomoto, S, Nakao, A, Kasai, Y, Harada, A, Nonami, T & Takagi, H (1996) Detection of ras gene mutations in perioperative peripheral blood with pancreatic adenocarcinoma. Jpn J Cancer Res 87: 793–797

  17. Ohmichi, H, Matsumoto, K & Nakamura, T (1996) In vivo mitogenic action of hepatocyte growth factor on bronchial epithelial cells: pulmotrophic role of HGF in lung regeneration. Am J Physiol 270: L1031–L1039

  18. Sakon, M, Kita, Y, Yoshida, T, Umeshita, K, Gotoh, M, Kanai, T, Kawasaki, T, Kambayashi, J & Monden, M (1996) Plasma hepatocyte growth factor levels are increased in systemic inflammatory response syndrome. Surg Today 26: 236–241

  19. Siegfried, JM, Weissfeld, LA, Singh-Kaw, P, Weyant, RJ, Testa, JR & Landreneau, RJ (1997) Association of immunoreactive hepatocyte growth factor with poor survival in resectable non-small cell lung cancer. Cancer Res 57: 433–439

  20. Sieuwerts, AM, Klijn, JG & Foekens, JA (1997) 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 15: 53–62

  21. Sonnenberg, E, Meyer, D, Weidner, KM & Birchmeier, C (1993) Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase can mediate a signal exchange between mesenchymal and epithelia during mouse development. J Cell Biol 123: 223–235

  22. Tomiya, T, Tani, M, Yamada, S, Hayashi, S, Umeda, N & Fujiwara, K (1992) Serum hepatocyte growth factor levels in hepatectomized and nonhepatectomized surgical patients. Gastroenterology 103: 1621–1624

  23. Uchiyama, A, Essner, R, Doi, F, Nguyen, T, Ramming, KP, Nakamura, T, Morton, DL & Hoon, DSB (1996) Interleukin 4 inhibits hepatocyte growth factor-induced invasion and migration of colon carcinomas. J Cell Biochem 62: 443–453

  24. Ueda, T, Takeyama, Y, Toyokawa, A, Kishida, S, Yamamoto, M & Saitoh, Y (1996) Significant elevation of serum human hepatocyte growth factor levels in patients with acute pancreatitis. Pancreas 12: 76–83

  25. Weidner, KM, Behrens, J, Vandekerckhove, J & Birchmeier, W (1990) Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol 111: 2097–2108

  26. Yanagita, K, Nagaike, M, Ishibashi, H, Niho, Y, Matsumoto, K & Nakamura, T (1992) Lung may have an endocrine function producing hepatocyte growth factor in response to injury of distant organs. Biochem Biophys Res Commun 182: 801–809

  27. Yanagita, K, Matsumoto, K, Sekiguchi, K, Ishibashi, H, Niho, Y & Nakamura, T (1993) Hepatocyte growth factor may act as a pulmotrophic factor on lung regeneration after acute lung injury. J Biol Chem 268: 21212–21217

  28. Zarnegar, R & Michalopoulos, GK (1995) The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol 129: 1177–1180

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Correspondence to:A Uchiyama

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Uchiyama, A., Morisaki, T., Beppu, K. et al. Hepatocyte growth factor and invasion-stimulatory activity are induced in pleural fluid by surgery in lung cancer patients. Br J Cancer 81, 721–726 (1999). https://doi.org/10.1038/sj.bjc.6690754

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  • hepatocyte growth factor
  • lung surgery
  • cancer invasion

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