Viral Clearance Vs Oncogenic Progression

Although, epidemiological studies show that more than 80% of HPV infections are benign and cleared within 12-18 months (32), a fraction of infections persists and can

Chlamydial Ophthalmia

Fig. 4 (Color Plate 5, following p. 50). Examples of abnormal cervical cytopathology. (A) LSIL: A cluster of cells demonstrating the enlarged nuclei, hyperchromasia, smudgy chromatin pattern, even some koilocytosis (cytoplasmic clearing) typical of an LSIL lesion. (B) HSIL: A cluster of cells with markedly enlarged nuclei, hyperchromasia associated with coarse chromatin, and irregular nuclear membranes typical of an HSIL lesion (35).

Fig. 4 (Color Plate 5, following p. 50). Examples of abnormal cervical cytopathology. (A) LSIL: A cluster of cells demonstrating the enlarged nuclei, hyperchromasia, smudgy chromatin pattern, even some koilocytosis (cytoplasmic clearing) typical of an LSIL lesion. (B) HSIL: A cluster of cells with markedly enlarged nuclei, hyperchromasia associated with coarse chromatin, and irregular nuclear membranes typical of an HSIL lesion (35).

initiate cellular transformation. It is the persistent infection with high-risk type HPVs that is necessary (but not sufficient) for the development of squamous carcinomas of the cervix and their precursor intraepithelial lesions (33,34).

Premalignant lesions of the cervix are characterized by abnormal cellular or epitheilial architecture in the areas surrounding the junction between the squamous and columnar epithelium (the transformation zone) of the uterine cervix. Nuclear enlargement, hyperchromasia, binucleation, presence of abnormal mitoses, high nuclear to cytoplasm ratios, cytoplasmic clearing (koilocytosis reflecting E4 expression), abnormal epithelial differentiation, increased mitotic activity, and irregular cellular orientation are all typical features of dysplasia. Low-grade SIL (LSILs, previously CIN Grade 1) reflect the pathological changes observed in the cervical epithelium with HPV replication (Fig. 4A; see Color Plate 5, following p. 50) (35) and rarely progress to invasive cancer. At this stage, HPV DNA is still episomal. In women who are immunocompetent, many LSILs regress without medical intervention (33,36). In contrast, patients with HSIL, particularly those with immune deficiencies (e.g., HIV positive) or immune suppression (e.g., organ transplant patients), exhibit more persistent and severe HPV-related disease. Resolution of HPV infection involves specific immune responses, although this response is generally both weak and delayed. The poor immune recognition of HPV probably reflects its relatively "immune privileged" site of replication and the absence of a systemic infection (viremia). Furthermore, HPV neither kills keratinocytes nor appears to readily produce "danger signals" that induce inflammatory responses. Finally, the virus has several strategies to evade immunity. Papillomavirus oncoproteins have been implicated in the downregulation of MHC expression (37) and the production of type I interferons (38,39).

HSILs are associated with higher rates of progression to invasive cervical cancer and less frequent spontaneous regression (40) (Fig. 4B; see Color Plate 5, following p. 50) (35). Patients with low HPV viral loads are more likely to clear high-grade lesions as compared with patients with high viral loads (40). Epidemiological evidence exists for several risk factors, which may promote the progression from infection and CIN to invasive cancer, including: human leukocyte antigen (HLA) haplotype (34,40), HPV-16 positive HSILs (40), tobacco (41), oral contraceptives (42,43), age, parity (44,45), and infection with Chlamydia trachomatis (for a more complete review, see ref. 34). The identification of potential risk factors for the progression of HPV infection to cancer remains especially important to consider in the context of the developing world, where cervical cancer is common, but few women have access to proper cytological screening resources.

The role of sex steroids in carcinogenesis has received special attention in the literature. Recent case-control studies of patients with histologically-confirmed invasive cervical carcinoma or carcinoma in situ (histological equivalent to a cytologically-identified precancerous SIL) have consistently found that long-term use of oral contraceptives increases risk of cervical carcinoma by up to fourfold in women who were positive for cervical HPV DNA (46-48). Other reproductive factors in the progression of HPV infection to cervical cancer have been studied, showing that high parity (defined as seven full-term pregnancies or more) increases the risk of squamous-cell carcinoma of the cervix among HPV-positive women by two to four times (as compared with women with one or two full-term pregnancies and nulliparous women, respectively) (49). Long-term oral contraceptive use and high parity was not associated with higher rates of HPV infection or HPV persistence. This suggests that the role for sex steroids in development of cervical cancer lies in carcinogenesis (progression of a persistent infection to cancer) rather than in increased risk of HPV infection (50,51). Whether it is progesterone, estrogen, or both hormones that contribute to cervical cancer etiology remains unclear.

The progression to invasive cervical cancer is associated with integration of the viral genome into the host genome. During the normal viral life cycle, E6 and E7 are maintained at low levels under transcriptional regulation by E2 (52-54). Integration typically disrupts the viral E2 gene, thereby negating E2-mediated repression of E6 and E7 and triggering their overexpression. Derepression of E6 and E7 exacerbates genomic instability through aberrant centrosomal duplication and suppression of cell-cycle checkpoints and activation of telomerase.

Ectopic expression of E6 and E7 of high-risk HPV types is sufficient for immortalization of human keratinocytes (Table 2) (8). One of the best-characterized functions of the E6 gene product is binding of the p53 tumor suppressor gene (55), promoting its degradation leading to subsequent genomic instability. Normally, p53 transcriptionally activates the expression of various regulators that induce cell-cycle arrest and apoptosis in response to chromosomal damage. Binding of high-risk HPV E6 facilitates the rapid turnover of p53, resulting in a reduction of the steady-state levels of p53, alleviating restrictions on cellular DNA synthesis and augmenting viral replication.

One of the best-characterized functions of the E7 gene product is formation of a complex with pRB (56), which when phosphorylated, limits cell proliferation and suppresses the neoplastic properties of various HPV types. E7 binding releases E2F and promotes entry into the cell cycle (57). However, it is important to note that both E6 and E7 are involved in numerous other activities that promote cellular transformation and prevent apoptosis, which are reviewed elsewhere (58-61).

Was this article helpful?

0 0
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment