Autophagy-dependent regulation of tumor metastasis by myeloid cells.

Masahisa Jinushi,Tomoko Morita,Hideo Yagita,Hirotoshi Dosaka-Akita,Ichiro Kinoshita,Yutaka Kawakami,Zhihang Xu,Li Yang

doi:10.1371/journal.pone.0179357

Abstract

Autophagy is a vital process controlling the lysosomal degradation of cellular organelles and thereby regulating tissue homeostasis in an environment-dependent fashion. Recent studies have unveiled the critical role of tumor cell-derived autophagy in regulating pro-tumor and anti-tumor processes depending on different stages and tumor microenvironments. However, the precise mechanism whereby autophagy regulates tumor progression remains largely unclear. Since myeloid cells contribute to tumor progression and metastasis, we evaluated the role of myeloid cell-specific autophagy in the regulation of tumor progression. We found that the number and size of metastatic lesions were smaller in myeloid cell-specific autophagy-deficient mice. Furthermore, autophagy-mediated regulation of TGF-β in myeloid cells was associated with the induction of epithelial-mesenchymal transition (EMT), which increases the invasive and metastatic potentials of tumor cells. Myeloid-derived autophagy also plays a critical role in impairing antitumor immune responses and promoting the survival and accumulation of M2 macrophages in tumor tissues in a CSF-1 and TGF-β-dependent manner. Taken together, our findings elucidate previously unrecognized mechanisms by which myeloid cells promote tumor progression through autophagy-mediated regulation of malignancy and immune tolerance.

Highlights

Tumor microenvironments (TME) regulate the tumorigenic activities of transformed cells in coordination with multiple tumor-infiltrating normal cells such as endothelial cells, fibroblasts, mesenchymal stem cells and inflammatory cells [1,2]
To characterize the role of myeloid cell autophagic pathways in tumor progression, we generated a myeloid cell-specific targeted deletion of the autophagic gene Atg5 by crossing mice carrying the lox-P flanked Atg5 allele to mice carrying lysozyme M (LysM) promoter-driven Cre recombinase [16]. In this myeloid cell-specific autophagy-deficient model (LysM-Atg5-/-), the Atg5 expression was deleted in granulocytes, macrophages and Ly6Chigh inflammatory monocytes, and the defect of autophagy was confirmed in the Lysozome M (LysM)-Atg5-/- macrophages under amino acid starvation (Fig 1A)
Splenic inoculation of MC38 colon carcinoma cells resulted in decreased numbers of liver metastatic tumors in LysM-Atg5-/- mice compared to their Atg5flox/flox counterparts (Fig 1D)

Summary

Introduction

Tumor microenvironments (TME) regulate the tumorigenic activities of transformed cells in coordination with multiple tumor-infiltrating normal cells such as endothelial cells, fibroblasts, mesenchymal stem cells and inflammatory cells [1,2]. Recent studies have revealed the importance of tumor-associated myeloid cells (TAM) in tumor progression. TAM support tumor progression through various mechanisms including tumor angiogenesis, immune suppression, matrix remodeling and the epithelial-mesenchymal transition (EMT) of malignant cells [3,4]. The detailed evaluation of molecular mechanisms that govern the complex interplay between TAM and transformed cells must be defined in order to control.

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Results

Conclusion