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Apelin-driven endothelial cell migration sustains intestinal progenitor cells and tumor growth.

ABSTRACT: Stem and progenitor cells residing in the intestinal crypts drive the majority of colorectal cancers (CRCs), yet vascular contribution to this niche remains largely unexplored. VEGFA is a key driver of physiological and tumor angiogenesis. Accordingly, current anti-angiogenic cancer therapies target the VEGFA pathway. Here we report that in CRC expansion of the stem/progenitor pool in intestinal crypts requires VEGFA-independent growth and remodeling of blood vessels. Epithelial transformation induced expression of the endothelial peptide apelin, directs migration of distant venous endothelial cells towards progenitor niche vessels ensuring optimal perfusion. In the absence of apelin, loss of injury-inducible PROX1+ epithelial progenitors inhibited both incipient and advanced intestinal tumor growth. Our results establish fundamental principles for the reciprocal communication between vasculature and the intestinal progenitor niche and provide a mechanism for resistance to VEGFA-targeting drugs in CRCs.

SUBMITTER: Bernier-Latmani J

PROVIDER: S-EPMC7612746 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Apelin-driven endothelial cell migration sustains intestinal progenitor cells and tumor growth.

Bernier-Latmani Jeremiah J Cisarovsky Christophe C Mahfoud Samantha S Ragusa Simone S Dupanloup Isabelle I Barras David D Renevey François F Nassiri Sina S Anderle Pascale P Squadrito Mario Leonardo ML Siegert Stefanie S Davanture Suzel S González-Loyola Alejandra A Fournier Nadine N Luther Sanjiv A SA Benedito Rui R Valet Philippe P Zhou Bin B De Palma Michele M Delorenzi Mauro M Sempoux Christine C Petrova Tatiana V TV

Nature cardiovascular research 20220516 5

Stem and progenitor cells residing in the intestinal crypts drive the majority of colorectal cancers (CRCs), yet vascular contribution to this niche remains largely unexplored. VEGFA is a key driver of physiological and tumor angiogenesis. Accordingly, current anti-angiogenic cancer therapies target the VEGFA pathway. Here we report that in CRC expansion of the stem/progenitor pool in intestinal crypts requires VEGFA-independent growth and remodeling of blood vessels. Epithelial transformation i ...[more]

PMID: 35602406

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Project description:Cancer‑associated fibroblasts (CAFs) are pivotal in tumor progression. TP53‑deficiency in cancer cells is associated with robust stromal activation. The apelin‑apelin receptor (APJ) system has been implicated in suppressing fibroblast‑to‑myofibroblast transition in non‑neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin‑APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53‑wild colon cancer, HCT116, and Caco‑2; TP53‑mutant colon cancer, SW480, and DLD‑1; and colon fibroblasts, CCD‑18Co), resected human tissue samples of colorectal cancers, and immune‑deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co‑cultured with p53‑suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ‑suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast‑like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma‑ and Mad‑related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ‑suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR‑5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell‑derived exosomes induced CAF‑like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.

Dataset Information

Apelin-driven endothelial cell migration sustains intestinal progenitor cells and tumor growth.

Publications

Apelin-driven endothelial cell migration sustains intestinal progenitor cells and tumor growth.

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