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Interleukin-34 Enhances the Tumor Promoting Function of Colorectal Cancer-Associated Fibroblasts.

ABSTRACT: The stromal compartment of colorectal cancer (CRC) is marked by the presence of large numbers of fibroblasts, termed cancer-associated fibroblasts (CAFs), which promote CRC growth and progression through the synthesis of various molecules targeting the neoplastic cells. Interleukin (IL)-34, a cytokine over-produced by CRC cells, stimulates CRC cell growth. Since IL-34 also regulates the function of inflammatory fibroblasts, we hypothesized that it could regulate the tumor promoting function of colorectal CAFs. By immunostaining and real-time PCR, we initially showed that IL-34 was highly produced by CAFs and to lesser extent by normal fibroblasts isolated from non-tumoral colonic mucosa of CRC patients. CAFs and normal fibroblasts expressed the functional receptors of IL-34. IL-34 induced normal fibroblasts to express ?-SMA, vimentin and fibroblast activation protein and enhanced fibroblast growth, thus generating a cellular phenotype resembling that of CAFs. Consistently, knockdown of IL-34 in CAFs with an antisense oligonucleotide (AS) decreased expression of such markers and inhibited cell proliferation. Co-culture of CRC cells with IL-34 AS-treated CAFs supernatants resulted in less cancer cell proliferation and migration. Among CAF-derived molecules known to promote CRC cell growth/migration, only netrin-1 and basic-fibroblast growth factor were induced by IL-34. Data suggest a role for IL-34 in the control of colorectal CAF function.

SUBMITTER: Franze E

PROVIDER: S-EPMC7761053 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Interleukin-34 Enhances the Tumor Promoting Function of Colorectal Cancer-Associated Fibroblasts.

Franzè Eleonora E Di Grazia Antonio A Sica Giuseppe Sigismondo GS Biancone Livia L Laudisi Federica F Monteleone Giovanni G

Cancers 20201127 12

The stromal compartment of colorectal cancer (CRC) is marked by the presence of large numbers of fibroblasts, termed cancer-associated fibroblasts (CAFs), which promote CRC growth and progression through the synthesis of various molecules targeting the neoplastic cells. Interleukin (IL)-34, a cytokine over-produced by CRC cells, stimulates CRC cell growth. Since IL-34 also regulates the function of inflammatory fibroblasts, we hypothesized that it could regulate the tumor promoting function of c ...[more]

PMID: 33260828

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Project description:The cancer‑stromal interaction has been demonstrated to promote tumor progression, and cancer-associated fibroblasts (CAFs), which are the main components of stromal cells, have attracted attention as novel treatment targets. Chitinase 3-like 1 (CHI3L1) is a chitinase-like protein, which affects cell proliferation and angiogenesis. However, the mechanisms through which cells secrete CHI3L1 and through which CHI3L1 mediates tumor progression in the cancer microenvironment are still unclear. Accordingly, the present study assessed the secretion of CHI3L1 in the microenvironment of colorectal cancer and evaluated how CHI3L1 affects tumor angiogenesis. CAFs and normal fibroblasts (NFs) established from colorectal cancer tissue, and human colon cancer cell lines were evaluated using immunostaining, cytokine antibody array, RNA interference, reverse transcription-quantitative PCR (RT-qPCR), ELISA, western blotting and angiogenesis assays. The expression and secretion of CHI3L1 in CAFs were stronger than those in NFs and colorectal cancer cell lines. In addition, interleukin-13 receptor α2 (IL-13Rα2), a receptor for CHI3L1, was not expressed in colorectal cancer cell lines, but was expressed in fibroblasts, particularly CAFs. Furthermore, the expression and secretion of IL-8 in CAFs was stronger than that in NFs and cancer cell lines, and recombinant CHI3L1 addition increased IL-8 expression in CAFs, whereas knockdown of CHI3L1 suppressed IL-8 expression. Furthermore, IL-13Rα2 knockdown suppressed the enhancement of IL-8 expression induced by CHI3L1 treatment in CAFs. For vascular endothelial growth factor-A (VEGFA), similar results to IL-8 were observed in an ELISA for comparison of secretion between CAFs and NFs and for changes in secretion after CHI3L1 treatment in CAFs; however, no significant differences were observed for changes in expression after CHI3L1 treatment or IL-13Rα2 knockdown in CAFs assessed using RT-qPCR assays. Angiogenesis assays revealed that tube formation in vascular endothelial cells was suppressed by conditioned medium from CAFs with the addition of human CHI3L1 neutralizing antibodies compared with control IgG, and also suppressed by conditioned medium from CAFs transfected with CHI3L1, IL-8 or VEGFA small interfering RNA compared with negative control small interfering RNA. Overall, the present findings indicated that CHI3L1 secreted from CAFs acted on CAFs to increase the secretion of IL-8, thereby affecting tumor angiogenesis in colorectal cancer.

Dataset Information

Interleukin-34 Enhances the Tumor Promoting Function of Colorectal Cancer-Associated Fibroblasts.

Publications

Interleukin-34 Enhances the Tumor Promoting Function of Colorectal Cancer-Associated Fibroblasts.

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