Gonadotropin and tumorigenesis: Direct and indirect effects on inflammatory and immunosuppressive mediators and invasion.

ABSTRACT

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-α 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 TGFß 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 ßhCG-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. © 2016 Wiley Periodicals, Inc.