a Department of Biological Sciences , School of Dental Medicine, Case Western Reserve University , Cleveland , OH , USA.
b Hubei Collaborative Innovation Center for Green Transformation of Bio-resource , College of Life Sciences, Hubei University , Wuhan , Hubei , China.
Cell Cycle. 2017;16(17):1611-1621. doi: 10.1080/15384101.2017.1356509. Epub 2017 Jul 27.
Tumor associated macrophages (TAMs) promote angiogenesis, tumor invasion and metastasis, and suppression of anti-tumor immunity. These myeloid cells originate from monocytes, which differentiate into TAMs upon exposure to the local tumor microenvironment. We previously reported that Kaposi's sarcoma-associated herpes virus (KSHV) infection of endothelial cells induces the cytokine angiopoietin-2 (Ang-2) to promote migration of monocytes into tumors. Here we report that KSHV infection of endothelial cells induces additional cytokines including interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-13 (IL-13) that drive monocytes to differentiate and polarize into TAMs. The KSHV-induced TAMs not only express TAM-specific markers such as CD-163 and legumain (LGMN) but also display a gene expression profile with characteristic features of viral infection. More importantly, KSHV-induced TAMs enhance tumor growth in nude mice. These results are consistent with the strong presence of TAMs in Kaposi's sarcoma (KS) tumors. Therefore, KSHV infection of endothelial cells generates a local microenvironment that not only promotes the recruitment of monocytes but also induces their differentiation and polarization into TAMs. These findings reveal a new mechanism of KSHV contribution to KS tumor development.
肿瘤相关巨噬细胞（TAMs）促进血管生成、肿瘤侵袭和转移，并抑制抗肿瘤免疫。这些髓样细胞起源于单核细胞，当暴露于局部肿瘤微环境时，它们分化为 TAMs。我们之前报道过，卡波济肉瘤相关疱疹病毒（KSHV）感染内皮细胞可诱导细胞因子血管生成素-2（Ang-2）促进单核细胞迁移进入肿瘤。在这里，我们报告称，KSHV 感染内皮细胞还会诱导其他细胞因子，包括白细胞介素-6（IL-6）、白细胞介素-10（IL-10）和白细胞介素-13（IL-13），这些细胞因子促使单核细胞分化并极化为 TAMs。KSHV 诱导的 TAMs 不仅表达 TAM 特异性标志物，如 CD163 和溶酶体半胱氨酸天冬氨酸蛋白酶（LGMN），而且还表现出具有病毒感染特征的基因表达谱。更重要的是，KSHV 诱导的 TAMs 增强了裸鼠肿瘤的生长。这些结果与卡波济肉瘤（KS）肿瘤中 TAMs 的大量存在一致。因此，KSHV 感染内皮细胞产生了一种局部微环境，不仅促进单核细胞的募集，而且还诱导它们分化和极化为 TAMs。这些发现揭示了 KSHV 促进 KS 肿瘤发展的新机制。
