Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs), the expression of insulin-like growth factor-1 (IGF1) and IGF1 receptor (IGF1R) was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9) was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2) and hypoxia (1% O2). IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC.

Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells

“…IGF1 is a cancer progression-related gene that is associated with the growth, metastasis and chemoresistance of various cancers (23)(24)(25)(26)(27). In the present study, we confirmed that TAMs significantly expressed higher IGF1 levels than M0 cells as (Fig.…”

“…This pathway can enhance the proliferation and development of cells by initiating the anti-apoptotic PI3K/Akt/mTOR and the mitogenic Ras/Raf/Mek/Erk pathways (21,22). The IGF1 pathway is associated with the growth, metastasis and clinical outcome of various cancers, including prostate cancer, gastric cancer, lung cancer and breast cancer (23)(24)(25)(26)(27). For example, CAFs can increase the invasion ability of pancreatic cancer cells via paracrine IGF1/ IGF1R signaling, particularly under hypoxia (27), and IGF1R is highly expressed in chronic lymphocytic leukemia cells, whereas the inhibition of IGF1R can enhance the death of CLL cells (28).…”

The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer

“…Meanwhile, tumor cells stabilize HIF-1α in CAFs by increasing ROS production to increase glycolysis, leading to the formation of a “pseudohypoxic” environment for CAFs 97 . In addition, Hirakawa et al 98 demonstrated that the motility of PCCs cocultured with CAFs was greater under hypoxic conditions than under normoxic conditions, partly via paracrine IGF1/IGF1R signaling.…”

Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer

“…In addition to Shh, stromal (myo-) fibroblasts can also become activated under tumor hypoxia. Indeed, PDACs are hypovascularized and thus hypoxic tumors [ 34 ]. In PDAC, cancer-associated fibroblasts produce IGF-1 under hypoxic conditions and promote tumor cell migration via IGF-1R signaling under hypoxia in vitro [ 34 ].…”