Pathophysiology of Cervical Cancer Every

Pathophysiology of Cervical Cancer

Every two minutes, somewhere in the world, a woman dies from cervical cancer (GlaxoSmithKline 2007). Caused by persistent or continuous infection by human papillomavirus (HPV), cervical cancer progresses slowly over a number of years (GlaxoSmithKline 2007) and is the second most common cancer for women around the world (Ivansson E.L. et al. 2008) . Due to its slow progression, observable symptomology usually translates into late stage illness, and indeed, within the 1940's invasive cervical cancer was the major cause of death for child bearing women in the United States (National Cancer Institute 2010). As of 2009 the number of cervical cancer diagnoses stood at 11,270 with 4,070 resultant deaths (National Cancer Institute 2010).

Prior to HPV being targeted as the main culprit of cervical cancer, mitotic abnormalities and chromosome rearrangements showed a stepwise progression of tumorigenesis (Therman, E. et al. 1983) and later statistical analysis showed that the chromosome abnormalities were nonrandom, implicating viral sites and proto-oncogene locations within the chromosomes (Sreekantaiah, C. et al. 1991). Now it is known that HPV is a necessary step in the acquisition of cervical cancer and is present in 99.7% of all invasive cervical carcinomas (Gius, D. et al. 2007). Up to 80% of women will acquire HPV infection by age 50 (GlaxoSmithKline 2007) and for women between the ages of 20-24 years old, the infection rate is 44.8% (Steben 2007).

Over 120 types of HPV exist and over 40 of those infect the epithelial lining of the anogenital tract along with other mucosal areas of the cervix (Steben 2007). Eighteen types of HPV are known to be oncogenic: 16, 18, 45, 31, 33, 52, and 58 with types 16 and 18 accounting for 70% of all cervical cancer cases (GlaxoSmithKline). The virus itself is a non-enveloped double stranded DNA virus (Steben 2007) containing 8,000 base pairs and encoding for two separate protein classes (Ellenson, L.H. & Wu, T.C. 2004).

Because most women infected with HPV do not actually develop invasive cervical carcinoma, additional exogenous or genetic factors may be required to keep the infection persistent enough to progress into cancer (Gius, D. et al. 2007). Risk factors include, "Individual susceptibility, immune status, exogenous hormones, tobacco smoking, parity, co-infection with other sexually transmitted agents such as HIV, herpes simplex virus type 2, and Chlamydia trachomatis," (Steben 2007).

The histological changes occurring within cervical tissue as a result of HPV infection and other factors are separated into three stages of cervical intraepithelial neoplasias (CINs). Following the invasion of the basement membrane by HPV-containing epithelial cells, lesions become malignant and are thus classified as squamous cell carcinoma (Gius, D. et al. 2007). Proteomic analysis using mass spectroscopy of this squamous cell carcinoma has shown 55 significantly changed protein spots, with 24 upregulated and 31 downregulated proteins, suggesting that using direct tissue samples may be the most persuasive way to find biomarkers and therapeutic targets (Xueqiong, Z. et al. 2009).

Preceded by precursor legions, invasive cervical cancer is characterized by disturbances of the "cellular maturation, stratification, and nuclear atypia…" (Boulet, G.A.V. et al. 2008). Using genomic analysis, a model of cervical cancer carcinogenesis as been illuminated across all three CIN stages with early viral infection leading to CIN-1 including the altered expression of genes associated with cellular proliferation and suppression of the immune system which may allow the HPV virus to replicate without detection or destruction (Gius D. et al. 2007).

Genetic risk factors for cervical cancer reflect the genetic variation influencing immune response toward HPV infection with a number of genes involved in inflammation and immunity contributing to susceptibility (Ivansson, E.L. et al. 2008). CIN-2 favors the growth of new blood vessels in both the epithelial and stromal cells suggesting communication, while CIN3 has the most pro-invasive genomic signature with changes in cell adhesion proteins and enzymes involved in the extracellular matrix remodeling of both epithelial and stromal cells (Gius, D. et al. 2007).

Figure 1. Specific alterations of host tissue during CIN stages 1-3 (Gius, D. et al. 2007)

Specific protein classes affected by HPV are the early and late proteins. Early proteins encode for viral DNA replication (E1, E1), RNA transcription (E2), and cell transformation (E5, E6, E7) while late proteins (L1, L2) are the structural components of the viral capsid (Ellenson, L.H. & Wu, T.C. 2004). While most viral DNA replicates extrachromosomally, HPV integrates into the cellular DNA and results in the deletion of large areas of the viral genome including L1 and L2 along with E2 and E5 which leaves E6 and E7 as the primary remaining open reading frames (Zur Hausen, et al. 2002). E2 is a functional elimination as it acts as a viral repressor, while E6 and E7 act as promoters (Yu, T. et al. 2005).

Figure 2. Loss of the E2 gene during viral integration (Boulet, G.A.V. et al. 2008)

The left over oncogenic proteins, E6 and E7 are implicated in proliferation with E6 expression leading to unregulated cell growth through the blocking of p53, a tumor suppressing protein, and proapoptotic BAK (Ellenson, L.H. & Wu, T.C. 2004). Indeed, HPV types and 16 and 18 have been found to complex with p53, resulting in its ubiquitin-dependent degradation, taking away its control of the cell cycle -- a hallmark of most cancers (Hu, X. et al. 2010). With these checkpoint proteins blocked, E6 activates telomerase and inhibits SRC family kinase degradation, leading to growth stimulation (Ellenson, L.H. & Wu, T.C. 2004). E7 activates genes: cyclin a and E. which stimulate S. phase while simultaneously blocking the cyclin-dependent kinase inhibitors KIP1 and WAF1 breaking down cell growth regulation.

It is the co expression of both E6 and E7 that increases transforming activity (Zur Hausen, et al. 2002) as their overexpression contributes to malignant phenotype (Yu, T. et al. 2005). Additionally, alterations such as the activation of ras mutations or the deletion of DCC are required. All of this remodeling is common to viral integration of not only the HPV genome, but the surrounding integration site (Yu, T. et al. 2005).

In terms of genetic heritability and susceptibility, studies have investigated TP53, MDM2, NQO1, SNPS, and ICC in conjunction with CIN-3 finding that Caucasians had a significant association between TP53 codon 72 and cervical cancer, with that association stronger in subjects infected with HPV types 16 and 18 pointing to molecular level evidence for the heritability of cancer risk (Hu, et al. 2010). Genetic predisposition had been seen prior in the observation that biological first-degree relatives of women who had been previously diagnosed with cervical cancer had double the risk of contracting it themselves (Ivansson, E.L. et al. 2008).

TP53 produces the tumor suppressing protein p53 which regulates DNA repair, cell cycle arrest and apoptosis and has been observed to be blocked by E6, the oncogenic protein of HPV. Ubiquitin degradation of p53 is controlled by both MDM2 and NQO1 with the latter acting as a back up for the former since it does not need ubiquitin and is instead regulated by H. quinone oxidoreductase 1 (Ivansson E.L. et al. 2008). MDM2 traditionally works by binding directly to p53 with its promoter SNP309 T/G rs2279744 increasing its affinity (Ivansson E.L. et al. 2008).

Weakening of the immune system by viral integration, in conjunction with a patients internal immunity are also risk factors in the acquisition of cervical cancer. Immune response is inherently regulated by the genes that code for proteins involved with the major histocompatibility complex (MHC), which in turn encodes for leukocytic antigens (HLA) I and II with cervical cancer being linked to the HLA II region (Ivansson, E.L. et al. 2008). When tumors lose the expression of certain MHC class I molecules, as seen in cervical cancers, the reason may be because of an immunoselection by T cells specific for he peptides presented by MHC I. The loss of the MHC I expression invariably results in non-recognition by cytotoxic T cells (Janeway, C.A. et al. 2005).

The reality of cervical cancer acquisition points at HPV being a main player; however, while it is a necessary step, it is not the only sufficient risk factor since disease progression is variable among those infected with the virus. Host genetics along with environmental, hormonal, and even nutritional factors may have an influence in creating a situation wherein HPV is allowed to become a continuous infection. To date, the only way to routinely test for cervical cancer is by using HPV as a biomarker through the Pap smear procedure which involves scraping of the transformation zone of the cervix and transferring those cells to a glass slide (Boulet, G.A.V. et al. 2008).

Within the past fifty years Pap smears have played a vital role in the decrease of cervical cancer incidence and mortality and its increased use worldwide is helping a number of nations, like Mexico decrease mortality to the disease (Lazcano, P.E. 2008). The test itself, however, is high subjective with a limited sensitivity of 50% along with a number of inherent individual variability (Boulet, G.A.V. et al. 2008). Indeed better screening is necessary due to the number of false-negatives from women with precancerous lesions among the most frequent reasons of medical malpractice in the United States (Steben, M. et al. 2007).