Seminal Plasma Enhances Cervical Adenocarcinoma Cell Proliferation and Tumour Growth In Vivo

Abstract

Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A(VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.

TGF-β Mediates Proinflammatory Seminal Fluid Signaling in Human Cervical Epithelial Cells

“…These include effects on the VEGF pathway involved in angiogenesis and neovascularization, with compelling evidence for upregulation of genes VEGFA and PTGS2 (COX-2). This extends earlier findings that SP induces these genes (3,4), and indicates that TGF-b might contribute to possible effects of seminal fluid exposure on neoplastic transformation and tumor progression in the cervix of sexually active women.…”

“…Through secretion of chemotactic and immune-regulating cytokines, epithelial cells at the cervical surface have a pivotal role in activating defense against bacterial and viral pathogens, and in the generation and maintenance of immune tolerance toward spermatozoa and other antigenic material present in the ejaculate. The responsiveness of cervical epithelial cells to introduced stimuli and their subsequent influence over the cervical immune environment is also implicated as a determinant of neoplasia and development of cervical cancer (2)(3)(4).…”

Seminal Fluid and the Generation of Regulatory T Cells for Embryo Implantation

“…In this way, the balance of bioactive agents in an individual's seminal fluid would influence cytokine production, DC regulation, and generation of Treg cells in his partner's cervix. Ultimately, this may impact her fertility, as well as potentially defence to sexually transmitted infection and progression of any neoplastic disease …”

TGF-β1 in Seminal Plasma Promotes Endometrial Mesenchymal Stem Cell Growth via p42/44 and Akt Pathway in Endometriosis

“…Endometriotic implants were collected, xed in 10% formalin-acetic acid, and embedded in para n for histopathological examination. Immunohistochemical staining was performed according to well-established protocols 1 . Anti-human leukocyte antigen (HLA) antibody (1:100; Abcam) was used to identify human cells within…”

“…Endometriosis, a major cause of infertility, is a prevalent gynecologic disease characterized by the existence of functional endometrial tissue outside the uterine cavity, which causes pain and affects fertility in almost 10% of reproductive women 1,2 . The precise mechanisms that cause endometriosis remain unknown.…”