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10.1245/s10434-007-9435-3
Annals of Surgical Oncology 14:2600-2607 (2007)
© 2007 Society of Surgical Oncology
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Original Article

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

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

Department of Surgery, Saga University Faculty of Medicine, Saga, Japan

Correspondence: Address correspondence and reprint requests to: Kohji Miyazaki; E-mail: miyazak2{at}cc.saga-u.ac.jp

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-1{alpha} (HIF-1{alpha}) 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-1{alpha} 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-1{alpha} 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-1{alpha} 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-1{alpha} ?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.

Key Words: Pancreatic cancer • Hypoxia • Tumor-stromal interaction • Hepatocyte growth factor • c-Met




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