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首页> 外文期刊>Cytokine >M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mT0RC2 and promotes tumor growth and metastasis
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M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mT0RC2 and promotes tumor growth and metastasis

机译：在缺氧肿瘤微环境中由癌塞拉蛋白M2巨噬细胞的M2偏振由MT0RC2介导并促进肿瘤生长和转移

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Oncostatin M (OSM), an inflammatory cytokine belonging to the interleukin-6 (IL-6) superfamily, plays a vital role in multitude of physiological and pathological processes. Its role in breast tumor progression and metastasis to distant organs is well documented. Recent reports implicate OSM in macrophage M2 polarization, a key pro-tumoral phenomenon. M2 polarization of macrophages is believed to promote tumor progression by potentiating metastasis and angiogenesis. In the current study, we delineated the mechanism underlying OSM induced macrophage M2 polarization. The findings revealed that OSM skews macrophages towards an M2 polarized phenotype via mTOR signaling complex 2 (mT0RC2). mTORC2 relays signals through two effector kinases i.e. PKC-a and Akt. Our results indicated that mTORC2 mediated M2 polarization of macrophages is not dependent on PKC-a and is primarily affected via Akt, particularly Aktl. In vivo studies conducted on 4T1/BALB/C mouse orthotropic model of breast cancer further corroborated these observations wherein iv. reintroduction of mT0RC2 abrogated monocytes into orthotropic mouse model resulted in diminished acquisition of M2 specific attributes by tumor associated macrophages. Metastasis to distant organs like lung, liver and bone was reduced as evident by decrease in formation of focal metastatic lesions in mTORC2 abrogated monocytes mice. Our study pinpoints key role of mTORC2-Aktl axis in OSM induced macrophage polarization and suggests for possible usage of Oncostatin-M blockade and/or selective mT0RC2 inhibition as a potential anti-cancer strategy particularly with reference to metastasis of breast cancer to distant organs such as lung, liver and bone.
机译：OncostatinM（OSM），属于白细胞介素-6（IL-6）超家族的炎性细胞因子，在众多生理和病理过程中起着至关重要的作用。它在乳腺肿瘤进展和转移到远处器官的作用得到了充分的记录。最近的报告致癌巨噬细胞M2极化中的OSM，是一个关键的促肿瘤现象。据信M2巨噬细胞的偏振通过增强转移和血管生成来促进肿瘤进展。在目前的研究中，我们描绘了巨大的OSM诱导巨噬细胞M2极化的机制。结果表明，OSM通过MTOR信号络合物2（MT0RC2）朝向M2偏振表型造成M2偏振表型的巨噬细胞。 MTORC2通过两种效应激酶继承信号I. .. PKC-A和AKT。我们的结果表明，MTORC2介导的M2巨噬细胞的偏振不依赖于PKC-A，主要受AKT，特别是AKT1的影响。在体内研究的4T1 / BALB / C小鼠正交模型的乳腺癌进一步证实了这些观察结果，其中inv。将MT0RC2废除单核细胞的重新引入正交小鼠模型导致肿瘤相关的巨噬细胞衰减M2特异性属性的收购。在MTORC2废除单核细胞小鼠中形成肺部，肝脏和骨等肺部，肝脏和骨等肺部，肝脏和骨骼的转移。我们的研究针对MTORC2-AKTL轴在OSM诱导的巨噬细胞极化中的关键作用，并表明了oncostatin-M阻断和/或选择性MT0RC2抑制作用作为潜在的抗癌策略，特别是参考乳腺癌转移到遥远的器官作为肺，肝脏和骨骼。

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