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The role of fibroblast APC mutation in carcinogenesis is not clear. Apc+/− colon fibroblasts have been previously characterized: however, little is known about their behavior at very early‐stage of colon carcinogenesis. We cultured colon mucosa fibroblasts (PCF, Apc+/−) of Pirc rats (F344/NTac‐Apcam1137) at an early stage of tumorigenesis, in absence of preneoplastic lesions, and of age‐matched wt (WCF): DNA damage levels, inflammatory phenotype and the expression of known markers of CAFs were analyzed. The latter were also assessed by microarray analysis on colon normal mucosa of Pirc and wt animals. PCF exhibited higher proliferative rates (P <.001) and delayed replicative senescence onset (P <.05) compared to WCF, along with a lower level of oxidative DNA damage (P <.05). Furthermore, a constitutively higher expression of COX‐2 and sensitivity to inflammatory stimuli was found in PCF compared to WCF (P <.05), accompanied by higher invasive capability (P <.05) and presence of cytoplasmic chromatin foci (cytoplasmic chromatin foci, P <.05). However, they neither expressed CAFs markers (α‐SMA, IL‐6) nor responded to CAFs activating stimuli (TGF‐β). Accordingly, CAFs markers and activating stimuli resulted down‐regulated in Pirc normal mucosa compared to wt, whereas DNA damage response and tolerance pathways were overexpressed. These data show for the first time that a proliferative and inflammatory phenotype characterizes Apc+/− colon fibroblasts since very early stages of colon tumorigenesis, and indicate a role of Apc mutation in driving fibroblast phenotypic alterations that could support the establishment of a protumorigenic environment. Early pharmacological targeting of these dysfunctions might impact on tumor prevention in FAP patients. What's new? Heterozygous mutations in APC represent the earliest event in sporadic colorectal carcinogenesis onset and cause familial adenomatous polyposis syndrome. However, the role of APC‐mutated fibroblasts remains unclear. Here, Apc+/‐ fibroblasts isolated from apparently‐normal colon tissue of Pirc rats showed proliferative, inflammatory features and resistance to oxidative DNA damage, although they did not show cancer‐associated fibroblast features. These data suggest that, at the very early stages of colon tumourigenesis, Apc‐mutated colon fibroblasts favour the establishment of a pro‐tumourigenic environment for pre‐neoplastic lesion development. Early pharmacological targeting of these dysfunctions might be valuable for tumour prevention in familial adenomatous polyposis patients. [ABSTRACT FROM AUTHOR]

The role of fibroblast APC mutation in carcinogenesis is not clear. Apc +/- colon fibroblasts have been previously characterized: however, little is known about their behavior at very early-stage of colon carcinogenesis. We cultured colon mucosa fibroblasts (PCF, Apc +/- ) of Pirc rats (F344/NTac-Apc am1137 ) at an early stage of tumorigenesis, in absence of preneoplastic lesions, and of age-matched wt (WCF): DNA damage levels, inflammatory phenotype and the expression of known markers of CAFs were analyzed. The latter were also assessed by microarray analysis on colon normal mucosa of Pirc and wt animals. PCF exhibited higher proliferative rates (P < .001) and delayed replicative senescence onset (P < .05) compared to WCF, along with a lower level of oxidative DNA damage (P < .05). Furthermore, a constitutively higher expression of COX-2 and sensitivity to inflammatory stimuli was found in PCF compared to WCF (P < .05), accompanied by higher invasive capability (P < .05) and presence of cytoplasmic chromatin foci (cytoplasmic chromatin foci, P < .05). However, they neither expressed CAFs markers (α-SMA, IL-6) nor responded to CAFs activating stimuli (TGF-β). Accordingly, CAFs markers and activating stimuli resulted down-regulated in Pirc normal mucosa compared to wt, whereas DNA damage response and tolerance pathways were overexpressed. These data show for the first time that a proliferative and inflammatory phenotype characterizes Apc +/- colon fibroblasts since very early stages of colon tumorigenesis, and indicate a role of Apc mutation in driving fibroblast phenotypic alterations that could support the establishment of a protumorigenic environment. Early pharmacological targeting of these dysfunctions might impact on tumor prevention in FAP patients., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)