Phosphatidylinositol 3-Kinase

Abstract

Even though a strong association between inflammation and cancer has been widely accepted, the underlying precise molecular mechanisms are still largely unknown. A complex signaling network between tumor and stromal cells is responsible for the infiltration of inflammatory cells into the cancer micro-environment. Tumor stromal cells such as pancreatic stellate cells (PSCs) and immune cells create a microenvironment that protects cancer cells through a complex interaction, ultimately facilitating their local proliferation and their migration to different sites. Furthermore, PSCs have multiple functions related to local immunity, angiogenesis, inflammation and fibrosis. Recently, many studies have shown that members of the phosphoinositol-3-phosphate kinase (PI3K) family are activated in tumor cells, PSCs and tumor infiltrating inflammatory cells to promote cancer growth. Pro-inflammatory cytokines and chemokines secreted by immune cells and fibroblasts within the tumor environment can activate the PI3K pathway both in cancer and inflammatory cells. In this review, we focus on the central role of the PI3K pathway in regulating the cross-talk between immune/stromal cells and cancer cells. Understanding the role of the PI3K pathway in the development of chronic pancreatitis and cancer is crucial for the discovery of novel and efficacious treatment options.

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“…Tumor stromal cells such as pancreatic stellate cells (PSCs) and immune cells create a microenvironment that protects cancer cells through a complex interaction, ultimately facilitating their local proliferation and their migration to different sites [ 54 ]. Activated PSCs play a pivotal role in the development of pancreatic fibrosis, thanks to the ability of actively proliferating, migrating, and producing ECM components, such as type I collagen, and expressing cytokines and chemokines [ 55 ].…”

“…Activated PSCs play a pivotal role in the development of pancreatic fibrosis, thanks to the ability of actively proliferating, migrating, and producing ECM components, such as type I collagen, and expressing cytokines and chemokines [ 55 ]. Activation of PSCs is regulated by different key mediators of stimulatory and inhibitory signals (i.e., peroxisome proliferator-activated receptor-c, Rho/Rho kinase, NF-κB), mitogen-activated protein kinases, PI3K, Sma- and Mad-related proteins, and reactive oxygen species, the targeting of which could be of interest for developing anti-fibrosis therapy in the future [ 54 , 55 , 56 ]. It is very important to demonstrate that pharmacological inhibition of PI3Kγ could also affect PSCs.…”