The regulation of inflammatory pathways and infectious disease of the cervix by seminal fluid

Abstract

The connection between human papillomavirus (HPV) infection and the consequent sequelae which establishes cervical neoplastic transformation and invasive cervical cancer has redefined many aspects of cervical cancer research. However there is still much that we do not know. In particular, the impact of external factors, like seminal fluid in sexually active women, on pathways that regulate cervical inflammation and tumorigenesis, have yet to be fully understood. HPV infection is regarded as the initiating noninflammatory cause of the disease; however emerging evidence points to resident HPV infections as drivers of inflammatory pathways that play important roles in tumorigenesis as well as in the susceptibility to other infections such as human immunodeficiency virus (HIV) infection. Moreover there is emerging evidence to support a role for seminal fluid, in particular, the inflammatory bioactive lipids, and prostaglandins which are present in vast quantities in seminal fluid in regulating pathways that can exacerbate inflammation of the cervix, speed up tumorigenesis, and enhance susceptibility to HIV infection. This review will highlight some of our current knowledge of the role of seminal fluid as a potent driver of inflammatory and tumorigenic pathways in the cervix and will provide some evidence to propose a role for seminal plasma prostaglandins in HIV infection and AIDS-related cancer.

Figure 1

A cartoon highlighting the role of seminal plasma and seminal plasma prostaglandins (PG) such as PGE₂ in regulating inflammatory and tumorigenic pathways in cervical cancer cells. Seminal plasma PGE₂, or PGE₂ endogenously produced by COX enzymes in response to inflammation or HIV infection via the induction of COX-2, binds to PG receptors on the surface of the cell to activate intracellular signal transduction pathways and target gene transcription and biosynthesis. Target genes which are known to be regulated in this manner include HIV chemokine receptors like CXCR4 as well as growth factors, angiogenic factors, chemokines, and cytokines. These latter factors all act in an autocrine/paracrine manner in the tumour microenvironment to facilitate local changes in tissue architecture, inflammation and enhance tumorigenesis. Elevated expression of HIV receptors could enhance virus entry into cells and enhance susceptibility to infection. HIV is also known to enhance inflammation by inducing COX-2 expression. The activity of COX-2 and subsequent inflammation can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). The activity of specific PG receptors can also be inhibited with selective receptor antagonists to inhibit subsequent activation of signal transduction pathways.