The hypoxic environment in tumor-stromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor/c-Met signaling

Ann Surg Oncol. 2007 Sep;14(9):2600-7. doi: 10.1245/s10434-007-9435-3. Epub 2007 May 30.


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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Hypoxia / physiology
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Pancreatectomy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / surgery
  • Proportional Hazards Models
  • Proto-Oncogene Proteins c-met
  • Signal Transduction
  • Stromal Cells / cytology
  • Stromal Cells / metabolism*


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met