Abstract
Mutations in the p53 tumor suppressor protein are highly frequent in tumors and often endow cells with tumorigenic capacities. We sought to examine a possible role for mutant p53 in the cross-talk between cancer cells and their surrounding stroma, which is a crucial factor affecting tumor outcome. Here we present a novel model which enables individual monitoring of the response of cancer cells and stromal cells (fibroblasts) to co-culturing. We found that fibroblasts elicit the interferon beta (IFNβ) pathway when in contact with cancer cells, thereby inhibiting their migration. Mutant p53 in the tumor was able to alleviate this response via SOCS1 mediated inhibition of STAT1 phosphorylation. IFNβ on the other hand, reduced mutant p53 RNA levels by restricting its RNA stabilizer, WIG1. These data underscore mutant p53 oncogenic properties in the context of the tumor microenvironment and suggest that mutant p53 positive cancer patients might benefit from IFNβ treatment.
Highlights
The tumor microenvironment has gone well into the mainstream of cancer research, manifested by a constant flow of publications and by a growing interest coming from anti-cancer drug companies
As we planned to investigate the effect of mutant p53, we chose to work with lung cancer cells (H1299) which are null for p53 expression and introduced them with two p53 ‘hotsopt’ mutations residing within the DNA binding domain, namely R175H and R248Q (H1299175 and H1299248 respectively, Figure 1A and B)
The cells were labeled with a red fluorescent protein, while lung Cancer Associated Fibroblasts (CAFs) (HK3-T) were labeled with a green fluorescent protein (GFP)
Summary
The tumor microenvironment has gone well into the mainstream of cancer research, manifested by a constant flow of publications and by a growing interest coming from anti-cancer drug companies. It was even professed as a novel ‘hallmark’ of cancer [1,2,3]. Cancer Associated Fibroblasts (CAFs) - a sub population of stromal cells residing adjacently to the tumor, are considered pro-tumorigenic, and in some cancers serve as prognostic markers for the course of the disease [4]. Mutant p53 expressed in stromal cells surrounding prostate tumors, enhances tumor growth and facilitates metastasis [13]. Mutant p53 was reported to cooperate with E2F to induce the expression of ID4, which in turn leads to augmented angiogenesis [16]
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