Interleukin 1α Sustains the Expression of Inflammatory Factors in Human Pancreatic Cancer Microenvironment by Targeting Cancer-Associated Fibroblasts

Abstract

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic, with an extensive interaction between the stroma and tumor cells. The aim of this study was to delineate the cross talk between PDAC and cancer-associated fibroblasts (CAFs), with a focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effects of the cross talk between PDAC and CAF cell lines on the creation and sustenance of the inflammatory tumor microenvironment in pancreatic cancer. The coculture of PDAC and CAF cell lines enhanced the levels of inflammatory factors including IL-1α, IL-6, CXCL8, VEGF-A, CCL20, and COX-2. CAFs were superior to tumor cells regarding the production of most inflammatory factors, and tumor cell-associated IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. Furthermore, we found a correlation between IL-1α and CXCL8 expression levels in PDAC tissues and correlation between IL-1α expression and the clinical outcome of the patients. This confirmed an important role for the IL-1 signaling cascade in the creation and sustenance of a tumor favorable microenvironment. Neutralization of the IL-1α signaling efficiently diminished the cross talk-induced production of inflammatory factors. These data suggest that the cross talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one essential factor in the formation of the inflammatory tumor environment, and we propose that neutralization of the IL-1α signaling might be a potential therapy for this cancer.

Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression

“…Finally, recent studies demonstrate a critical function for IL-1α in the initiation of the proinflammatory phenotype in the pancreas (26,(28)(29)(30). It is tempting to speculate that upon oncogene activation, SIN3B, through a cell-autonomous upregulation of IL-1α, drives SASP production and promotes a proinflammatory tumor microenvironment.…”

“…Likewise, immune infiltration (CD45-, CD68-, and F4/80-positive cells) was limited and highly localized in Sin3B-deficient animals compared with controls ( Figure 4, B and D), when analyzed before 24 weeks of age. Inflammation in evolving PanINs is associated with a positive feedback loop of cytokine secretion involving pancreatic cells, immune cells, and cancerassociated fibroblasts (CAF) (25,26). Neoplastic cells mediate this process by secreting inflammatory cytokines, including IL-1α and IL-6, which are induced upon oncogenic KRAS expression through activation of the ERK1/2, STAT3, and NF-κB pathways (27).…”

“…In contrast with the tumor-suppressing impact of senescence-associated cell-cycle arrest, in vitro studies suggest that the SASP may promote a protumorigenic microenvironment (18)(19)(20)(21). This notion is particularly relevant to PDAC, as its progression is intimately linked to inflammation (1, [22][23][24][25][26]. The cellular factors that contribute to the oncogene-driven inflammation in pancreatic cells remain for the most part unknown, but recent studies have implicated IL-1α expression as an inducer of constitutive NF-κB activation and subsequent inflammation (27)(28)(29)(30).…”

“…SASP triggers senescence in neighboring cells and mobilizes immune cells, but can also induce inflammation and thus promote cancer progression (18,42,43). This phenomenon is particularly relevant in pancreatic cancer, where inflammation is a well-established factor in tumor progression (23,26). Based on our recent discovery that SIN3B is required for oncogene-induced senescence in mouse embryonic fibroblasts (34), we investigated whether Sin3B deletion affects the senescence process in pancreatic lesions.…”

Membrane IL1α Inhibits the Development of Hepatocellular Carcinoma via Promoting T- and NK-cell Activation

“…On the contrary, in smooth muscle cells, intracellular IL1a was shown to stimulate cell proliferation (17). Besides, in pancreatic ductal adenocarcinoma, tumor-associated IL1a was identified as the initiator of tumor growth by promoting the production of inflammatory factors (18). Overexpression of IL1a propiece in tumor cells induced malignant transformation and increased tumor invasiveness to visceral organs (19).…”