<p>P53 Mutant p53^N236S Regulates Cancer-Associated Fibroblasts Properties Through Stat3 Pathway</p>

Abstract

Background: Cancer-associated fibroblasts (CAFs) play important roles in cancer development and progression. Recent studies show that p53 plays a cell non-autonomous tumorsuppressive role to restrict tumor growth in CAFs. However, the role of p53 mutant in CAFs remains obscure. Methods: In this study, the contribution of p53 mutant p53 N236S (p53S) to CAFs activation was examined using mouse embryonic fibroblasts (MEFs) from wild-type (WT), p53 deficient (p53-/-) and p53 S/S mice. The role of p53S in MEFs in inducing prostate cancer cell growth and metastasis was studied by utilizing xenograft models and transwell assays. The effects of p53S on the properties of CAFs were assessed by measuring CAFs-specific factors expression and functional collagen contraction assay. Moreover, Microarray data were analyzed by GSEA and Stat3 signaling was inhibited to further determine p53S's role in the CAFs activation. Results: We found that p53 S/S MEF accelerated cancer cells growth and metastasis compared with WT and p53-/-MEF. We also found that p53S induced significantly increasing collagen contraction in fibroblasts and overexpression of CAFs-specific factors, such as αsmooth muscle actin (α-SMA), FGF10 and CXCL12. p53S regulated these CAF-specific properties through Stat3 activation. Conclusion: Our results illustrate that p53S plays an important role in CAFs activation by the Stat3 pathway. The study indicates that cancer cells and fibroblasts interaction promotes prostate cancer cell growth, migration and invasion due to p53S expression in fibroblasts.

The Role of Cancer-Associated Fibroblasts in Tumor Progression

“…Unfortunately, the expression of CAF markers is extremely heterogeneous and varies strongly between different CAF subpopulations as described below ( Table 1 ). For example, some common CAF markers that have been identified include alpha smooth muscle actin (α-SMA), vimentin, fibroblast activation protein (FAP), fibroblast-specific protein 1 (FSP1), and platelet-derived growth factor receptor alpha/beta (PDGFR-α/β) [ 31 , 32 , 33 , 34 ].…”

“…YAP1 was upregulated in prostate cancer tissue, and FAP and α-SMA expression were significantly elevated in stromal and epithelial cells with high YAP1 expression levels, demonstrating the association between YAP1 and CAF development. Another study found that p53S induced overexpression of CAF-specific factors, such as α-SMA and vimentin, through the Stat3 pathway, resulting in accelerated prostate cancer cell development, migration, and invasion [ 33 ].…”

STAT3 and p53: Dual Target for Cancer Therapy

“…In addition to wtp53, mtp53 also plays an important role in the activation of STAT3 signaling; mtp53 was also found to regulate cancer-associated fibroblast-specific factors such as α-SMA, FGF10, and CXCL12 through the STAT3 pathway [ 110 ]. LOF p53 contributes to JAK2-STAT3 signaling and promotes pancreatic tumor growth and stroma modification [ 29 ].…”

Cancer Associated Fibroblasts Derived from Pancreatic Adenocarcinoma and Their Role in Cell Migration

“…Several studies have detected a p53 alteration in CAFs that modify their functioning and enhance the malignant features of their respective cancers (47). This non-autonomous effect is initiated via regulation of cancerpromoting genes and secreted proteins (35,48), also in line with a different study, which revealed a direct link between cancer cells and CAFs in chemotherapy response of lung cancers based on p53 dependence (49).…”