Autophagy Drives Galectin-1 Secretion From Tumor-Associated Macrophages Facilitating Hepatocellular Carcinoma Progression.

Goutham Venkata Naga Davuluri,Yuh-Ling Chen,Nina Tsao,Chih-Peng Chang,Yen-Cheng Chiu,Pei-Jane Tsai,Wan-Ting Kuo,Hung-Wen Tsai,Hung-Chih Chiu,Chien-Chin Chen,Yee-Shin Lin

doi:10.3389/fcell.2021.741820

Abstract

Galectin-1 (Gal-1) is a secretory lectin with pro-tumor activities and is associated strongly with hepatocellular carcinoma (HCC) development. Although Gal-1 is a well-known soluble pro-tumor factor in the tumor microenvironment (TME), the secretion mode of Gal-1 is not clearly defined. On the other hand, in addition to cancer cells, Gal-1 is widely expressed in tumor stromal cells, including tumor-associated macrophages (TAMs). TAMs are a significant component of stromal cells in TME; however, their contributions in producing Gal-1 to TME are still not explored. Here we reveal that TAMs can actively secrete Gal-1 in response to stimuli of HCC cells. Gal-1 produced by TAMs leads to an increase of the systemic level of Gal-1 and HCC tumor growth in mice. Mechanistically, TLR2-dependent secretory autophagy is found to be responsible for Gal-1 secretion from TAMs. Gal-1 acts as a cargo of autophagosomes to fuse with multivesicular bodies via Rab11 and VAMP7-mediated vesicle trafficking before being secreted. This autophagy-regulated Gal-1 secretion in TAMs correlates to poor overall survival and progression-free survival rates of HCC patients. Our findings uncover the secretion mode of Gal-1 via secretory autophagy and highlight the pathological role of TAM-produced Gal-1 in HCC progression.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies
Since Gal-1 mRNA was not down-regulated at 24 h in MCMtreated bone marrow-derived macrophages (BMDMs) (Figure 1B), we examined whether the reduction of the protein level of Gal-1 was caused by protein instability
These results indicate that Gal-1 produced by hepatocellular carcinoma (HCC)-associated macrophages facilitates HCC progression

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies. A significant subpopulation of immune cells in TME is that of tumor-associated macrophages (TAMs), whose function is to promote the tumor progression, even though it was first thought to be a host immune response against the growing tumors. These TAMs are associated with poor prognosis of HCC patients, which makes them potential therapeutic targets to abrogate the development of cancer (Zhang et al, 2019; Allavena et al, 2021; Huang et al, 2021). TAMs can secrete various immunosuppressive mediators, such as interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), and prostaglandin E2 (PGE2), into the TME to further inhibit anti-tumor immunity (Zhou et al, 2021)

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Results

Conclusion