Fig. 7.

Increased TGF-β signaling and immunosuppression in mutp53 CRC patients. a Strong epithelial immunostaining of p53 is correlated with strong non-epithelial immunostaining of FOXP3 in a representative human CRC case carrying mutp53 and compared with a WT p53 case. b FOXP3 staining abundance and intensity was calculated for all specimens as described in the Methods section. c,d A general inflammatory gene set (c) and hallmark TGF-β signaling gene set (d) produced by a GSEA analysis of mRNA expression levels of the GOF p53 mutants group of CRC tumors compared with the rest of the missense p53 mutants group (other mut). Specific genes significantly upregulated in the GOF group are displayed in red while inflammatory genes downregulated in the GOF group are in blue. NES normalized enrichment score, FDR false discovery rate. GOF mutants refers to the following p53 positions: R245, R248, R175, R273, and R282. e The proposed molecular model by which mutp53 facilitates the tumor microenvironment. Colon tumor cell acquires a mutation in TP53 yielding an increased release of exosomes containing miR-1246. Such exosomes are received by neighboring macrophages that undergo a phenotypic shift resulting with enhanced secretion of anti-inflammatoy cytokines (which also recruit immunosuppressive T-regulatory cells) and epithelial−mesenchymal transition (EMT) promoting factors contributing to tumorigenesis and eventually to poor prognosis. Error bars represent standard errors