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Colon fibroblasts from Pirc rats (F344/NTac-Apc^am1137 ) exhibit a proliferative and inflammatory phenotype that could support early stages of colon carcinogenesis.

ABSTRACT: 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.

SUBMITTER: Tortora K

PROVIDER: S-EPMC9291568 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundChemotherapeutic bioassay for colorectal cancer (CRC) with a rat model bearing chemically-induced CRCs plays an important role in the development of new anti-tumor drugs and regimens. Although several protocols to induce CRCs have been developed, the incidence and number of CRCs are not much enough for the efficient bioassay. Recently, we established the very efficient system to induce CRCs with a chemically induced-colon carcinogenesis-prone Apc-mutant rat, Kyoto Apc Delta (KAD) rat. Here, we applied the KAD rat to the chemotherapeutic bioassay for CRC and showed the utility of the KAD rat.MethodsThe KAD rat has been developed by the ENU mutagenesis and carries a homozygous nonsense mutation in the Apc gene (S2523X). Male KAD rats were given a single subcutaneous injection of AOM (20 mg/kg body weight) at 5 weeks of age. Starting at 1 week after the AOM injection, they were given 2% DSS in drinking water for 7 days. Tumor-bearing KAD rats were divided into experimental and control groups on the basis of the number of tumors observed by endoscopy at week 8. The 5-fluorouracil (5-FU) was administrated intravenously a dose of 50 or 75 mg/kg weekly at week 9, 10, and 11. After one-week interval, the 5-FU was given again at week 13, 14, and 15. At week 16, animals were sacrificed and tumor number and volume were measured macroscopically and microscopically.ResultsIn total 48 tumors were observed in 27 KAD rats with a 100% incidence at week 8. The maximum tolerated dose for the KAD rat was 50 mg/kg of 5-FU. Macroscopically, the number or volume of tumors in the 5-FU treated rats was not significantly different from the control. Microscopically, the number of adenocarcinoma in the 5-FU treated rats was not significantly different (p < 0.02) from that of the control. However, the volume of adenocarcinomas was significantly lower than in the control. Anticancer effect of the 5-FU could be obtained only after the 16 weeks of experimental period.ConclusionThe use of the AOM/DSS-treated tumor-bearing KAD rats could shorten the experimental period and reduce the number of animals examined in the chemotherapeutic bioassay. The efficient bioassay with the AOM/DSS-treated tumor-bearing KAD rats would promote the development of new anti-tumor drugs and regimens.

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Colon fibroblasts from Pirc rats (F344/NTac-Apc^am1137 ) exhibit a proliferative and inflammatory phenotype that could support early stages of colon carcinogenesis.

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Colon fibroblasts from Pirc rats (F344/NTac-Apcam1137 ) exhibit a proliferative and inflammatory phenotype that could support early stages of colon carcinogenesis.

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OmicsDI is part of the ELIXIR infrastructure

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Colon fibroblasts from Pirc rats (F344/NTac-Apc^am1137 ) exhibit a proliferative and inflammatory phenotype that could support early stages of colon carcinogenesis.