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Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation.


ABSTRACT: Tumor metastasis is a hallmark of cancer. Metastatic cancer cells often reside in distal tissues and organs in their dormant state. Mechanisms underlying the pre-metastatic niche formation are poorly understood. Here we show that in a colorectal cancer (CRC) model, primary tumors release integrin beta-like 1 (ITGBL1)-rich extracellular vesicles (EVs) to the circulation to activate resident fibroblasts in remote organs. The activated fibroblasts induce the pre-metastatic niche formation and promote metastatic cancer growth by secreting pro-inflammatory cytokine, such as IL-6 and IL-8. Mechanistically, the primary CRC-derived ITGBL1-enriched EVs stimulate the TNFAIP3-mediated NF-?B signaling pathway to activate fibroblasts. Consequently, the activated fibroblasts produce high levels of pro-inflammatory cytokines to promote metastatic cancer growth. These findings uncover a tumor-stromal interaction in the metastatic tumor microenvironment and an intimate signaling communication between primary tumors and metastases through the ITGBL1-loaded EVs. Targeting the EVs-ITGBL1-CAFs-TNFAIP3-NF-?B signaling axis provides an attractive approach for treating metastatic diseases.

SUBMITTER: Ji Q 

PROVIDER: S-EPMC7058049 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation.

Ji Qing Q   Zhou Lihong L   Sui Hua H   Yang Liu L   Wu Xinnan X   Song Qing Q   Jia Ru R   Li Ruixiao R   Sun Jian J   Wang Ziyuan Z   Liu Ningning N   Feng Yuanyuan Y   Sun Xiaoting X   Cai Gang G   Feng Yu Y   Cai Jianfeng J   Cao Yihai Y   Cai Guoxiang G   Wang Yan Y   Li Qi Q  

Nature communications 20200305 1


Tumor metastasis is a hallmark of cancer. Metastatic cancer cells often reside in distal tissues and organs in their dormant state. Mechanisms underlying the pre-metastatic niche formation are poorly understood. Here we show that in a colorectal cancer (CRC) model, primary tumors release integrin beta-like 1 (ITGBL1)-rich extracellular vesicles (EVs) to the circulation to activate resident fibroblasts in remote organs. The activated fibroblasts induce the pre-metastatic niche formation and promo  ...[more]

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