The hypoxic environment in tumor-stromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor/c-Met signaling.
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.
Ide
Takao
T
Department of Surgery, Saga University Faculty of Medicine, Saga, Japan.
Kitajima
Yoshihiko
Y
Miyoshi
Atsushi
A
Ohtsuka
Takao
T
Mitsuno
Mayumi
M
Ohtaka
Kazuma
K
Miyazaki
Kohji
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015687:Cell Hypoxia / Q000502:physiology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met