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Cyr61 from adipose-derived stem cells promotes colorectal cancer metastasis and vasculogenic mimicry formation via integrin α_V β₅.

ABSTRACT: Adipose-derived stem cells (ADSCs) play a vital role in colorectal cancer (CRC) progression, but the mechanism remains largely unknown. Herein, we found that ADSCs isolated from CRC patients produced more cysteine-rich 61 (Cyr61) than those from healthy donors, and the elevated serum Cyr61 levels were associated with advanced TNM stages. Moreover, serum Cyr61 displayed a better diagnostic value for CRC compared to carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9). Mechanistically, integrin α_V β₅ was identified as the functional receptor by which Cyr61 promotes CRC cell metastasis in vitro and in vivo by activating the α_V β₅ /FAK/NF-κB signaling pathway. In addition, Cyr61 promotes vasculogenic mimicry (VM) formation, thereby promoting tumor growth and metastasis through a α_V β₅ /FAK/HIF-1α/STAT3/MMP2 signaling cascade. Histologically, xenografts and clinical samples of CRC both exhibited VM, which was correlated with HIF-1α and MMP2 activation. Notably, we demonstrated the synergistic effect of combined anti-VM therapy (integrin α_V β₅ inhibitor) and anti-VEGF therapy (bevacizumab) in patient-derived xenograft models. Further investigation showed that CRC cell-derived exosomal STAT3 promoted Cyr61 transcription in ADSCs. These findings indicate that Cyr61 derived from ADSCs plays a critical role in promoting CRC progression via integrin α_V β₅ and provides a novel antitumor strategy by targeting Cyr61/α_V β₅ .

SUBMITTER: Liang Z

PROVIDER: S-EPMC8637569 | biostudies-literature |

REPOSITORIES: biostudies-literature

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