Biology Reference
In-Depth Information
daunting task but certain model systems such as high-risk human papillomavirus
(HPV) oncoproteins have been particularly useful tools to understand the causes
and consequences of centrosome aberrations on both genomic stability and car-
cinogenic progression (Duensing and Munger
2004
).
Importantly, centrosome aberrations are observed in many non-HPV-associated
carcinomas such as breast, prostate, and colon cancer. In non-HPV-associated
lesions it is difficult to determine whether centrosome abnormalities are the driving
force for malignant progression or occur as secondary events following the initial
mutations promoting carcinogenesis. Studying HPV-associated malignant
progression presents a unique opportunity because expression of the two high-risk
HPV oncoproteins, HPV E6 and E7, by themselves has been shown to drive
genomic instability and malignant progression while at the same time being the
major transforming proteins in high-risk HPV-associated neoplasms (White et al.
1994
; zur Hausen
1996
).
Experiments analyzing high-risk HPV infection have demonstrated that cen-
trosome amplification is present in precancerous high-risk HPV-containing cells
and may potentially drive genomic alterations necessary for carcinogenesis
(Duensing et al.
2001
). Additionally, studies in HPV-associated anal tumors have
demonstrated that centrosome overduplication correlates with the frequency of cell
division errors (Duensing et al.
2008
). In line with this, multipolar, specifically
tripolar, mitoses are a hallmark of high-risk HPV-associated carcinomas (Duen-
sing et al.
2000
). Expression of the two viral oncoproteins drives high-risk HPV-
associated malignant progression and allows a detailed dissection of the role of
these drivers in promoting centrosome abnormalities, genomic instability and
ultimately carcinogenesis.
Recently, prophylactic vaccines have been developed against HPV-6, -11, -16,
and -18 and a small but growing proportion of the worldwide population are being
vaccinated to prevent HPV infection (Schiller and Lowy
2009
). However, the
vaccines are currently still expensive and prevention of HPV-associated carcinoma
is only effective in people with no prior exposure to high-risk HPV. Understanding
the exact mechanisms by which high-risk HPV oncoproteins promote centrosome
amplification and genomic instability will not only provide novel insights into
basic biological processes but may also contribute to the development of alter-
native preventive and improved therapeutic options.
12.2 General Biology of HPVs
HPV infection is associated with squamous cell carcinomas (SCCs) of the
anogenital, and a subset of oropharyngeal tract carcinomas. HPVs are small, cir-
cular double-stranded DNA viruses, approximately 8000 base pairs in length that
infect cutaneous and mucosal epithelial tissues (Longworth and Laimins
2004
).
Over 200 types of HPV have been characterized and classified into two groups
based on tissue tropism: cutaneous and mucosal. Infection with cutaneous HPVs,
