Radiation to Stromal Fibroblasts Increases Invasiveness of Pancreatic Cancer Cells through Tumor-Stromal Interactions

Abstract

Radiotherapy represents a major treatment option for patients with pancreatic cancer, but recent evidence suggests that radiation can promote invasion and metastasis of cancer cells. Interactions between cancer cells and surrounding stromal cells may play an important role in aggressive tumor progression. In the present study, we investigated the invasive phenotype of pancreatic cancer cells in response to coculture with irradiated fibroblasts. Using in vitro invasion assay, we demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of pancreatic cancer cells and, surprisingly, the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. The hepatocyte growth factor (HGF) secretion from fibroblasts remained unchanged after irradiation, whereas exposure of pancreatic cancer cells to supernatant from irradiated fibroblasts resulted in increased phosphorylation of c-Met (HGF receptor) and mitogen-activated protein kinase activity, possibly or partially via increased expression of c-Met. We also demonstrated that scattering of pancreatic cancer cells was accelerated by the supernatant from irradiated fibroblasts. The enhanced invasiveness of pancreatic cancer cells induced by coculture with irradiated fibroblasts was completely blocked by NK4, a specific antagonist of HGF. These data suggest that invasive potential of certain pancreatic cancer cells is enhanced by soluble mediator(s) released from irradiated fibroblasts possibly through up-regulation of c-Met expression/phosphorylation and mitogen-activated protein kinase activity in pancreatic cancer cells. Our present findings further support the potential use of NK4 during radiotherapy for patients with pancreatic cancer.

In vitro irradiation of basement membrane enhances the invasiveness of breast cancer cells

“…Sublethal in vitro irradiation of rat 9L glioma cells resulted in the formation of a greater number of tumour satellites after injection of these irradiated cells into the striatum of rat brain. The ability of radiation to increase the expression of some MMPs and the invasiveness of cancer cells have also been reported for pancreatic cancer cells (Qian et al, 2002;Ohuchida et al, 2004), melanoma cells (Kaliski et al, 2005), rectal carcinoma cells (Speake et al, 2005), colon carcinoma cells and osteosarcoma cells (Wang et al, 2000).…”

The Multifunctional Growth Factor Midkine Promotes Proliferation and Migration in Pancreatic Cancer

“…Elevated expression and secretion of MK by the tumor might affect the surrounding stromal cells that express MK receptors in a paracrine mechanism and thereby contribute to the formation of the latter. Because it was shown that the stromal compartment in PDAC negatively affects radiation therapy (33,34) and creates a milieu for chemotherapy resistance (35,36), a fundamental issue in PDAC treatment, the role of MK in tumor stroma interplay and its effects on chemotherapy resistance requires further investigation.…”

Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas

“…Cells were maintained as described previously. 25 We used quantitative real-time reverse transcription-PCR (qRT-PCR) to determine CLDN4 mRNA in formalin-fixed paraffin-embedded tissues of intraductal papillary mucinous neoplasms. In all, 80 formalin-fixed paraffin-embedded tissue samples of intraductal papillary mucinous neoplasms and 8 formalin-fixed paraffin-embedded tissue samples of pancreatic ductal adenocarcinomas obtained from patients undergoing pancreatic resection at our department (Kyushu University Hospital, Fukuoka, Japan) from 1987 to 2008 were selected for the present study based on the availability of sufficient quantities of neoplastic cells.…”