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Annals of Surgical Oncology

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01-09-2007 | Hepatic and Pancreatic Tumors

The Hypoxic Environment in Tumor-Stromal Cells Accelerates Pancreatic Cancer Progression via the Activation of Paracrine Hepatocyte Growth Factor/c-Met Signaling

Authors: Takao Ide, Yoshihiko Kitajima, Atsushi Miyoshi, Takao Ohtsuka, Mayumi Mitsuno, Kazuma Ohtaka, Kohji Miyazaki

Published in: Annals of Surgical Oncology | Issue 9/2007

Abstract

Background

Pancreatic cancer is one of the representative solid tumors, in which the hypoxic microenvironment plays a crucial role in malignant progression. We previously demonstrated that tumor-stromal interaction under hypoxia enhances the invasiveness of pancreatic cancer cells through hepatocyte growth factor (HGF)/c-Met signaling.

Methods

We investigated the immunohistochemical expression of hypoxia inducible factor-1α (HIF-1α) c-Met, and HGF in both cancer and stromal cells using 41 pancreatic cancer tissue specimens, and tried to identify any correlations with the clinical features and survival.

Results

Positive staining for HIF-1α was observed in both pancreatic cancer and the surrounding stromal cells in more than 30% of the cases, and it significantly correlated with lymph node metastasis (P < .05). A significant correlation was observed between the expression of HIF-1α and HGF in stromal cells (P < .05). In addition, the c-Met expression in cancer cells was found to significantly correlate with the HGF expression in not only cancer but also stromal cells. The disease-free survival rates of the patients with HIF-1α in cancer, stromal, c-Met in cancer, and an HGF expression in stromal cells was significantly worse than those without such expressions (P < .05).

Conclusions

These data suggest that the HGF/c-Met signaling via HIF-1α ?may therefore negatively affect the prognosis in patients with pancreatic cancer, and targeting tumor stroma under hypoxia might thus be potentially useful as a novel therapy for this cancer.

Warshaw AL, Fernandez-del Castillo C. Pancreatic carcinoma. N Engl J Med 1992; 326:455–65PubMedCrossRef

Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 2001; 18:243–59PubMedCrossRef

Semenza GL. HIF-1 and tumor progression: pathophysiology and therapeutics. Tredds Mol Biol 2002; 8:S62–67

Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev 2003; 3:721–32CrossRef

Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-1α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292:468–72PubMed

Maxwell PH, Dachs GU, Gleadle JM, et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 1997; 94:8104–9PubMedCrossRef

Koong AC, Mehta VK, Le QT, et al. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 2000; 48:919–22PubMedCrossRef

Durand RE, Raleigh JA. Identification of nonproliferating but viable hypoxic tumor cells in vivo. Cancer Res 1998; 58:3547–50PubMed

DiMagno EP, Reber HA, Tempero MA. AGA Technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. Gastroenterology 1999; 117:1464–84PubMedCrossRef

10.

Kloppel G, Lingenthal G, von Bulow M, Kern HF. Histological and fine structural features of pancreatic ductal adenocarcinomas in relation to growth and prognosis: studies in xenografted tumours and clinico-histopathological correlation in a series of 75 cases. Histopathology 1985; 9:841–56PubMedCrossRef

11.

Dvorak HF. Tumors: wounds that do not heal: similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315:1650–9PubMedCrossRef

12.

Di Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR. Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res 1995; 55:1129–38PubMed

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; 122:1450–9PubMedCrossRef

14.

Nakamura T, Nishizawa T, Hagiya M, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342:440–3PubMedCrossRef

15.

Montesano R, Matsumoto K, Nakamura T, Orci L. Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell 1991; 67:901–8PubMedCrossRef

16.

Ramirez R, Hsu D, Patel A, Fenton C, Dinauer C, Tuttle RM, Francis GL. Over-expression of hapatocyte growth factor/scatter factor (HGF/SF) and the HGF/SF receptor (cMET) are associated with a high risk of metastasis and recurrence for children and young adults with thyroid carcinoma. Clin Endocrinol 2000; 53:635–44CrossRef

17.

Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E. Expression of hepatocyte growth factor and its receptor c-met protooncogene in hepatocellular carcinoma. Hepatology 1997; 25:862–6PubMedCrossRef

18.

Ide T, Kitajima Y, Miyoshi A, et al. Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer through the hapatocyte growth factor/c-Met pathway. Int J Cancer 2006; 119:2750–9PubMedCrossRef

19.

Sakamoto Y, Kitajima Y, Edakuni G, Sasatomi E, Mori M, Kitahara K, Miyazaki K. Expression of Trk tyrosine kinase receptor is a biologic marker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma. Oncol Rep 2001; 8:477–84PubMed

20.

Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93:266–76PubMedCrossRef

21.

Rice GC, Hoy C, Schimke RT. Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cells. Proc Natl Acad Sci USA 1986; 83:5978–82PubMedCrossRef

22.

Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. Concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 1953; 26:638–48PubMedCrossRef

23.

Shibaji T, Nagao M, Ikeda N, et al. Prognostic significance of HIF-1α ?overexpression in human pancreatic cancer. Anticancer Res 2003; 23:4721–8PubMed

24.

Sethi T, Rintoul RC, Moore SM, et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 1999; 5:662–8PubMedCrossRef

25.

Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003; 4:915–25PubMedCrossRef

26.

Qian LW, Mizumoto K, Maehara N, et al. Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production. Cancer Lett 2003; 190:105–12PubMedCrossRef

27.

Nilsson I, Shibuya M, Wennstrom S. Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res 2004; 299:476–85PubMedCrossRef

28.

Katsuta M, Miyashita M, Makino H, et al. Correlation of hypoxia inducible factor-1α with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer. Exp Mol Pathol 2005; 78:123–30PubMedCrossRef

29.

Okada K, Osaki M, Araki K, Ishiguro K, Ito H, Ohgi S. Expression of hypoxia-inducible factor (HIF-1 alpha), VEGF-C and VEGF-D in non-invasive and invasive breast ductal carcinomas. Anticancer Res 2005; 25:3003–9PubMed

30.

Tsukinoki K, Yasuda M, Mori Y, et al. Hepatocyte growth factor and c-Met immunoreactivity are associated with metastasis in high grade salivary gland carcinoma. Oncol Rep 2004; 12:1017–21PubMed

31.

Semenza GL. Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol 2000; 59:47–53PubMedCrossRef

32.

Tacchini L, Dansi P, Matteucci E, Desiderio MA. Hepatocyte growth factor signaling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis 2001; 22:1363–71PubMedCrossRef

33.

Okano J, Shiota G, Matsumoto K, et al. Hepatocyte growth factor exerts a proliferative effect on oval cells through the PI3K/AKT signaling pathway. Biochem Biophysic Res Com 2003; 309:298–304CrossRef

34.

Winbanks CE, Grimwood L, Gasser A, Darby IA, Hewitson TD, Becker GJ. Role of the phosphatidylinositol 3-kinase and mTOR pathways in the regulation of renal fibroblast function and differentiation. Int J Biochem Cell Biol 2007; 39:206–19PubMedCrossRef

35.

Giacco F, Perruolo G, D’Agostino E, et al. Thrombin-activated platelets induce proliferation of human skin fibroblasts by stimulating autocrine production of insulin-like growth factor-1. FASEB J 2006; 20:2402–4PubMedCrossRef

Title: The Hypoxic Environment in Tumor-Stromal Cells Accelerates Pancreatic Cancer Progression via the Activation of Paracrine Hepatocyte Growth Factor/c-Met Signaling
Authors: Takao Ide
Yoshihiko Kitajima
Atsushi Miyoshi
Takao Ohtsuka
Mayumi Mitsuno
Kazuma Ohtaka
Kohji Miyazaki
Publication date: 01-09-2007
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 9/2007
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-007-9435-3

At a glance: The STEP trials

Springer Medicine

The Hypoxic Environment in Tumor-Stromal Cells Accelerates Pancreatic Cancer Progression via the Activation of Paracrine Hepatocyte Growth Factor/c-Met Signaling

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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