Dados do Trabalho

Título

Inflammatory signaling in pancreatic cancer – an IL-6-driven fibroblastic process?

Introdução

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by delayed diagnosis and the lowest five-year survival amongst all cancer sites. PDAC development and progression are principally attributed to chronic inflammation and associated tissue repair mechanisms which contribute to high density tumor formation and chemoresistance. PDAC-associated inflammation is largely owed to high levels of interleukin 6 (IL-6) and its activated pathways including JAK/STAT3. Fibroblast Growth Factor (FGF) signaling pathways are likewise dysregulated in cancer and have been implicated in various malignancies including PDAC.

Objetivo

We sought to explore the association between IL-6-induced inflammatory signaling and FGF signaling activation.

Método

To observe this effect as it pertains to carcinogenesis and cancer progression we used four human cell lines ranging from healthy pancreatic ductal epithelial (HPDE) cells to various grade (G) PDAC cells.

Resultados

Treatment of cancer cells with IL-6 (100 ng/mL) for 24 hours resulted in increased phosphorylation of STAT3 in BxPC-3 (G2) and PANC-1 (G3) cells with no change noted in HPDE and SW1990 (G2, metastatic) cells, respectively.
IL-6 stimulation likewise resulted in markedly increased phosphorylation of the FGF Receptor substrate 2-alpha (FRS2-α) and its downstream component Erk1/2 in BxPC3 cells, indicating activation of FGF signaling through the MAPK/Erk pathway in our low grade PDAC cell model.

Conclusão

In conclusion, the results demonstrate a clear link between IL-6 induced inflammatory signaling and dysregulation of FGF signaling in human pancreatic cancer. Activated STAT3 signaling seems to be involved in this process. Existing cancer therapies aimed at controlling growth factor signaling broadly target vascular endothelial or epithelial growth factor receptors (VEGF/EGFR) with marginal efficacy and adverse side effects in pancreatic cancer. Identifying the pivotal link between inflammatory signaling and dysregulation of Fibroblast Growth Factor signaling will allow for the development of more precisely targeted and effective cancer therapy in PDAC. This may minimize clinically observed exaggerated fibrotic events within the tumor and may hence result in higher vulnerability for established chemotoxic therapies in the tumor cells.