Loss of S6K1 But Not S6K2 in the Tumor Microenvironment Suppresses Tumor Growth by Attenuating Tumor Angiogenesis.

Loss of S6K1 But Not S6K2 in the Tumor Microenvironment Suppresses Tumor Growth by Attenuating Tumor Angiogenesis.:

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Loss of S6K1 But Not S6K2 in the Tumor Microenvironment Suppresses Tumor Growth by Attenuating Tumor Angiogenesis.

Transl Oncol. 2020 Apr 03;13(4):100767

Authors: Lee S, Roh HS, Song SS, Shin J, Lee J, Bhang DH, Kim BG, Um SH, Jeong HS, Baek KH

Abstract

Two isoforms of the 70-kDa ribosomal protein S6 kinase, S6K1 and S6K2, have been identified and are considered key downstream effectors of the mTOR signaling pathway, which is involved in tumor growth and progression. However, their biological roles in the tumor microenvironment are poorly understood. In this study, utilizing tumor xenograft models in S6k1-/- and S6k2-/- mice, we show that loss of S6K1 but not S6K2 in the tumor stroma suppresses tumor growth, accompanied by attenuated tumor angiogenesis. We found that while S6K1 depletion had no effect on the proangiogenic phenotype of endothelial cells, the growth and angiogenesis of tumor xenografts were significantly reduced in wild-type mice upon reconstitution with S6K1-deficient bone marrow cells. Furthermore, upon S6K1 loss, induction of both mRNA and protein levels of Hif-1α and those of the downstream target, Vegf, was compromised in bone marrow-derived macrophages stimulated with lactate. These findings indicate that S6K1 but not S6K2 contributes to establishing a microenvironment that favors tumor growth through mediating angiogenesis, and suggest that attenuated tumor angiogenesis upon loss of S6K1 in the tumor stroma is, at least in part, attributable to impaired upregulation of Vegf in tumor-associated macrophages.

PMID: 32251993 [PubMed - as supplied by publisher]