Unveiling the role of hypoxic macrophage-derived exosomes in driving colorectal cancer progression

Jiang Jiang; Wenfang Wang; Lan Zhu; Bowen Shi; Yong Chen; Yihan Xia; Weiming Feng; Weiwu Yao; Aiguo Lu; Huan Zhang

doi:10.3389/fimmu.2023.1260638

Unveiling the role of hypoxic macrophage-derived exosomes in driving colorectal cancer progression

Front Immunol. 2023 Nov 9:14:1260638. doi: 10.3389/fimmu.2023.1260638. eCollection 2023.

Authors

Jiang Jiang^#¹, Wenfang Wang^#¹, Lan Zhu^#¹, Bowen Shi¹, Yong Chen¹, Yihan Xia¹, Weiming Feng¹, Weiwu Yao², Aiguo Lu³, Huan Zhang¹

Affiliations

¹ Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Imaging, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

^# Contributed equally.

Abstract

The crosstalk between tumor cells and macrophages under hypoxic conditions has been acknowledged as a pivotal determinant in the progression of colorectal cancer (CRC). Previous research has underscored the significance of exosomes derived from hypoxic tumor cells in facilitating tumor progression through inducing the polarization of macrophages towards the M2-like phenotype. The precise influence of hypoxic macrophage-derived exosomes (HMDEs) on the progression of CRC has not yet been fully elucidated. The objective of this study was to investigate the role of HMDEs in the progression of CRC. We discovered that there was an elevated release of exosomes derived from macrophages in hypoxic conditions. Additionally, the hypoxia-induced macrophage-derived exosomes played a crucial role in promoting the progression of CRC. We have also demonstrated that HMDEs have the ability to induce cell cycle transition and inhibit cell apoptosis, thereby promoting the growth of CRC cells. Furthermore, the underlying molecular mechanisms of these effects have been identified. The overexpression of Hif-1α results in its direct interaction with distinct regions (-521- -516 bp and -401- -391 bp) of the Hsp90 promoter during hypoxic circumstances. This binding event led to the overexpression of Hsp90 and the subsequent elevation of Hsp90 protein levels within HMDEs. Importantly, the crucial interaction between Hsp90 and Lats1 resulted in the deactivation of Lats1 and the inhibition of Yap phosphorylation. Ultimately, this series of events lead to the deactivation of the Hippo signaling pathway. Our in vivo and in vitro studies presented compelling evidence for the crucial role of hypoxic macrophage-derived exosomal Hsp90 in promoting CRC progression through the inhibition of the Hippo signaling pathway. These findings represented a significant advancement in our comprehension of the complex interplay between macrophages and CRC cells under hypoxic conditions.

Keywords: Hsp90; Yap; colorectal cancer; exosomes; hypoxia; macrophages.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms* / pathology
Exosomes* / metabolism
Humans
Hypoxia / metabolism
Macrophages / metabolism
Protein Serine-Threonine Kinases / metabolism

Substances

Protein Serine-Threonine Kinases

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by grants from National Natural Sciences Foundation of China (No. 81771789, No. 82271934, No. 82101986 and No. 82000138), the Yangfan Project of Science and Technology Commission of Shanghai Municipality (20YF1427200 and 20YF1426700), and Medical Engineering Cross Research Foundation of Shanghai Jiao Tong University (No. ZH2018QNA52 and No. YG2021QN08).