Gonadotropin and tumorigenesis: Direct and indirect effects on inflammatory and immunosuppressive mediators and invasion
Gonadotropin and tumorigenesis: Direct and indirect effects on inflammatory and immunosuppressive mediators and invasion
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DOI：
10.1002/mc.22499
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发表时间：
2017-02-01
影响因子：
4.6
通讯作者：
Pal, Rahul
中科院分区：
文献类型：
--
作者：
Khare, Priyanka;Bose, Anjali;Pal, Rahul
人绒毛膜促性腺激素（hCG）是妊娠必需的激素，也由多种癌症异位表达，并与预后不良相关;可能导致肿瘤进展的分子机制仍不明确。外源性hCG能增强人大肠癌和肺癌细胞的活力，并促进小鼠同源肿瘤的生长。它诱导VEGF、IL-8、基质金属蛋白酶（MMP）-2和MMP-9的合成，并以MMP依赖的方式增加侵袭力。在诱导肿瘤细胞分泌肿瘤相关的细胞外基质蛋白聚糖多功能蛋白聚糖的同时，hCG因此引起TLR-2介导的外周血粘附细胞产生炎性肿瘤相关细胞因子TNF-α和IL-6。该分子上调肿瘤细胞中Treg相关转录因子FOXP 3，增加TGF和IL-10的分泌，从而抑制T细胞增殖并诱导FOXP 3（-）CD 4（+）CD 25（-）细胞分化为功能性FOXP 3（+）CD 4（+）CD 25（+）抑制细胞。hCG处理的肿瘤细胞与成熟的骨髓来源的树突状细胞共培养诱导活性吲哚胺脱氧酶的产生。虽然抗hCG抗体限制了裸鼠中植入肿瘤细胞的生长，但用补充有布氏分枝杆菌的hCG-TT缀合物免疫免疫有免疫能力的小鼠在植入同基因的hCG反应性肿瘤细胞的动物中提供了协同的存活益处。这些研究阐明了hCG促进肿瘤发生的途径，为抗hCG疫苗接种治疗促性腺激素敏感性肿瘤提供了进一步的理论依据。(c)2016 Wiley Periodicals，Inc.
Human chorionic gonadotropin (hCG), a hormone essential for pregnancy, is also ectopically expressed by a variety of cancers and is associated with poor prognosis; molecular mechanisms which may contribute to tumor progression remain ill-defined. Exogenous hCG enhanced the viability of human colorectal and lung cancer cells and promoted the growth of syngeneic tumors in mice. It induced the synthesis of VEGF, IL-8, matrix metalloprotease (MMP)-2 and MMP-9, and increased invasiveness in an MMP-dependent manner. While inducing the secretion of the tumor-associated extra-cellular matrix proteoglycan versican from tumor cells, hCG consequently caused the TLR-2-mediated generation of the inflammatory, tumor-associated cytokines TNF- and IL-6 from peripheral blood adherent cells. The molecule up-modulated the Treg-associated transcription factor FOXP3 in tumor cells and increased the secretion of TGF and IL-10, thereby inhibiting T cell proliferation and inducing the differentiation FOXP3(-)CD4(+)CD25(-) cells into functional FOXP3(+)CD4(+)CD25(+) suppressor cells. Co-culture of hCG-treated tumor cells with mature bone-marrow derived dendritic cells induced the generation of active indoleamine deoxygenase. While anti-hCG antibodies restricted the growth of implanted tumor cells in nude mice, immunization of immune competent mice with a hCG-TT conjugate supplemented with Mycobacterium indicus pranii provided synergistic survival benefit in animals implanted with syngeneic, hCG-responsive tumor cells. These studies elucidate the pathways by which hCG can promote tumorigenesis, providing further rationale for anti-hCG vaccination in the treatment of gonadotropin-sensitive tumors. (c) 2016 Wiley Periodicals, Inc.