The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment

Abstract

Tumor-associated inflammation is a consequence and a driver of tumorigenesis. Three papers in this issue of Cancer Cell demonstrate the importance of tumor-elicited inflammation in the development and progression of pancreatic ductal adenocarcinoma and esophageal squamous carcinoma. Disruption of tissue homeostasis culminates in activation of STAT3, generating a pro-tumorigenic inflammatory microenvironment.

Figure 1

A) Fukuda et al. suggest that KRas activation drives epithelial cell expression of cytokines, such as IL-6 and IL-11, which in turn activate STAT3 in an autocrine fashion. STAT3-induced MMP7 is required for tumor progression but not for tumor initiation, which depends on other STAT3 targets. B) Lesina et al. suggest that epithelial cells harboring active KRas recruit immune cells, particularly myeloid cells, which produce IL-6 and soluble IL-6R and activate STAT3 in epithelial cells via IL-6 trans-signaling in a paracrine manner. STAT3 induces anti-apoptotic and pro-proliferative genes, fueling tumor initiation, promotion and progression. C) Stairs et al. show that loss of p120-catenin in epithelial cells alters local tissue homeostasis, generating a pro-tumorigenic microenvironment through recruitment of iMCs and other immune cells. Recruitment of these cells is presumably mediated by cytokines and chemokines produced by mutant epithelial cells, eventually causing activation of Akt, NF-κB and STAT3 in neoplastic cells.