Mechanisms of HPV and other risk factors in oncogenesis

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Figure 3.5. Mechanism of HPV and other risk factors in development of cervical cancer (Figure 4 from zur Hausen 2002)

The key proteins coded by HPV DNA

HPV DNA is 6800-8000 base pairs long, which when translated, codes for 8 Genes. The genes are broken down in to early and late phase, indicating which stage of basal cell infection they are introduced. E1, E2, E4, E5, E6, and E7 make up the early phase genes, L1 and L2 are the late phase genes. The key proteins are shown in Figure 3.6.

Figure 3.6 Key proteins in HPV16 (Figure 1 from Frazer 2004)

Mechanism of HPV infection

As previously mentioned, the squamous epithelium acts as a protective skin to keep pathogens from infecting the underlying tissue. Even though the cervix is not an externally exposed tissue it is still subject to the external environment, especially during sexual intercourse. The HPV is able to get through the protective layers of the squamous epithelium through epithelial abrasions to commence its infective life cycle.

Figure 3.7 Schematic diagram of infection of squamous epithelium by HPV (Figure 2 from Frazer 2004)

HPV integration into the host genome

There are two main outcomes from the integration of viral DNA into the host genome that can eventually lead to tumour formation.

Blocking the cells apoptotic pathway
Blocking synthesis regulatory proteins leading to uncontrolled mitosis

There are two integral genes in the HPV genome that play a central role in tumour formation, E6, which inhibits the role of p53 and E7, which inhibits the role of the retinoblastoma protein (Rb). In normal physiology, p53 and Rb are involved in the regulation of cells with damaged/mutated DNA.

The p53 gene codes for a protein that is vital in protecting us from cells with damaged DNA. In health, the p53 protein binds to damaged DNA and becomes active. Activation of p53 leads to the attraction of other proteins, which ultimately leads to apoptosis (programmed cell death) of the cell that has damaged DNA. When E6 protein of HPV binds to the host p53 protein, it causes a structural change and the variant of p53 is no longer able to bind to damaged DNA. As a consequence of this, the apoptosis cascade involving p21 is unavailable to act as the ‘stop signal’ in mitosis so the mutated cell is able to divide uncontrollably.

The Rb gene codes for a protein that restricts the cells ability to replicate: Rb prevents inhibiting progression from the gap phase to the synthesis phase of the G1 mytotic cycle. Simply put, when the E7 protein binds to and degrades Rb protein, it is no longer functional and cell proliferation is left unchecked.

Learning points from Chapter 3

Incidence in Europe as a whole was seventh in frequency and mortality fifth.
Incidence and mortality between countries in Europe varies according to the risk of disease and effectiveness of population screening.
HPV 16 is the most frequent high-risk type in cervical cancer Europe; HPV 16, 18 and 45 are the most frequent types in adenocarcinoma.
Apart from factors related to exposure to high-risk HPV, cigarette smoking, immunosuppression and poor diet are among risk factors for cervical cancer and its precursors.
HPV gains access to the basal layer of the cervical epithelium in order to infect the cervix.
Productive infection with high-risk and low-risk types of HPV is usually self-limiting; persistent HPV carries a risk of progression.
Development of high-grade precancerous lesions and cancer in a minority of women depends on integration of viral DNA into the host genome and consequent blocking of regulatory enzymes.