JCSM Shareware Collection 1993 November/JCSM Shareware Collection - 1993-11.iso/cl760/reflst4j.lzh/EXAMPLE.TXT

Text File | 1989-06-15 | 10KB | 178 lines

In 1990 in the United States, it is estimated that 30,200 people
will develop oral cancer and that 9,050 will die of the disease
(Silverberg and Lubera, 1988).  This population of oral cancer
patients represents approximately 5% of the total cancer
population in the United States.  Based on statistics collected
between 1979 and 1984, the five-year survival rate for oral
cancer patients is 54% for caucasians and 31% for blacks
(Silverberg and Lubera, 1988).  Oral cancer is an important
problem not only because of the significant mortality associated
with the disease, but also because of the often disfiguring and
functional defects associated with the disease.

Substantial epidemiologic research has investigated major factors
in the development of oral cancer.  Tobacco and alcohol use are
the two major risk factors.  Studies have proposed a direct dose-
related carcinogenic effect of tobacco, a close correlation
between alcohol intake and cancer, and the possibility of a
synergistic effect of tobacco and alcohol when used together
(Rothman and Keller, 1972, Wynder and Hoffman, 1976, Bross and
Coombs, 1976, Schottenfeld, 1979, Spitz et al., 1988).
Nonetheless, oral cancer develops in a significant proportion of
individuals who do not use alcohol or tobacco, suggesting the
importance of other factors.

Herpes simplex virus type 1 (HSV-1) has been implicated in the
etiology of oral cancer.  Patients with oral leukoplakia have
increased cell-mediated immune responses to HSV-1, smokers have
higher levels of neutralizing antibody to HSV-1 than do non-
smokers, and patients with oral cancer have higher levels of IgA
and IgM antibody to cells infected with HSV-1 (Smith et al.,
1976, Shillitoe et al., 1984).

During the last few years, evidence has been provided that human
papillomavirus (HPV) can infect the oral mucosa and is associated
with several different benign epithelial tumors and hyperplasias
of the oral cavity.  There are now in excess of 50 genotypes of
HPV, a family of viruses that infect only keratinocytes and are
generally associated with benign epithelial proliferations.  In
addition, substantial evidence supports the hypothesis that HPV
may be responsible for some of the changes leading to malignant
growth.  Although HPV cannot be cultured in vitro, the genomes of
most of the types have been cloned allowing for studies of genome
structure and gene function.

The general organization of the papillomavirus genes is conserved
among the types and all putative protein-coding sequences are on
one DNA strand.  The early (E) segment of the DNA contains up to
eight open reading frames (ORF) and the late segment (L) contains
two ORFs (Danos et al., 1984).  Studies of the functions of the
HPV genes have been modeled after those done with bovine
papillomavirus (BPV).  The E1 ORF is necessary for maintenance of
HPV as episomal DNA (Saver et al, 1984, Lusky and Botchan, 1985).
E2 is the most conserved HPV gene and has a regulatory function.
The full-length E2 protein serves to transactivate early gene
expression by binding to the transcriptional enhancer in the non-
coding region (Phelps and Howley, 1987).  A smaller protein
transcribed from the 3' end of E2 acts as a repressor and
competes with the transactivating protein for binding in the non-
coding region (Lambert et al., 1987).  The E4 gene appears to be
involved in virus maturation (Doorbar et al., 1986).  Both E5 and
E6 gene products have transforming ability (Schiller et al.,
1986, Yang et al., 1985).  The E7 gene is important in the
establishment of a high copy number of viral DNA in infected
cells and may have a role in maintaining the transformed state
(Lusky and Botchan, 1985).  The L1 and L2 ORFs code for the
capsid proteins of the virus (Giri and Danos, 1986).

HPV DNA has been demonstrated in oral verruca vulgaris, condyloma
acuminatum, squamous cell papilloma, leukoplakia, and focal
epithelial hyperplasia (reviewed by Syrjanen, 1987).  A possible
role of HPV infection in the etiology of oral cancer was
suggested in 1983 when cytopathic changes characteristic of HPV
infection were described in 14 cases (Syrjanen et al., 1983).
This same study found HPV capsid antigens in eight oral squamous
cell carcinomas.  With the availability of DNA cloning and
hybridization techniques, more direct evidence for the presence
of HPV in oral cancer has been provided.  Loning et al. found HPV
DNA in three cases of carcinoma of the buccal mucosa; one lesion
had HPV 16 DNA, one HPV 11, and one was not typed (Loning et al.,
1985).  A follow-up study showed HPV 16-related DNA in four of
seven oral cancers (Milde and Loning, 1986).  A similar study by
de Villiers et al. found HPV 16 DNA in two cases of squamous cell
carcinoma of the tongue and HPV 2 DNA in one case (de Villiers et
al., 1985).  There are other isolated reports of HPV 16 in a
single buccal mucosa carcinoma and a tongue carcinoma (Syrjanen
et al., 1986, Lookingbill et al., 1987) and of HPV 11 in  a lymph
node metastasis of an oral squamous cell carcinoma (Dekmezian et
al., 1987).  Studies of larger numbers of oral cancers
found HPV 2 DNA in three of nine cases of verrucous carcinoma
(Adler-Storthz et al., 1986), Maitland et al. (1987) found HPV
16-related DNA in seven of fifteen carcinomas, and Syrjanen et
al. (S. Syrjanen, personal communication) found HPV 16 in three
cases and HPV 18 in three cases of carcinoma.

The most substantial data implicating HPV in the etiology of
epithelial cancers comes from studies of cervical cancer where
evidence of HPV infection has been found in the majority (up to
90%) of cases examined (reviewed by Syrjanen, 1987).  The most
severe lesions are associated with HPV types 16 and 18, whereas
the dysplastic, less severe lesions are associated with HPV types
6 and 11.  In most cases, the HPV 16 and 18 DNA is integrated
into the host cell genome, whereas the genomes of HPV 6 and 11
appear to persist in an episomal state.  The progression from
precancer to cancer in the uterine cervix is well established
and, in HPV-positive cases is thought to reflect the ability of
the HPV to integrate into the host cell genome (Syrjanen, 1987).
Integration may not be required for transformation in all
papillomavirus species.

In some tumors and cell lines that contain HPV DNA in an
integrated state, the E6 and E7 genes appear to be selectively
maintained and expressed and the E2 gene is interrupted,
partially deleted or absent (Takebe et al., 1987, Shirasawa et
al., 1986, Schwarz et al., 1985, Choo et al., 1987).  Several
studies have shown that HPV 16 can transform established mouse
and rat fibroblast lines as well as primary human fibroblasts and
keratinocytes (Kanda et al., 1987, Yasumoto et al., 1986, Prisi
et al., 1987). More recent in vitro culture models have shown the
transforming functions to reside in the E6 and/or E7 genes
(Bedell et al, 1987, Kanda et al., 1988).  It can be postulated
that as a result of integration and loss of the E2 repressor
function, the expression of the E6 and E7 proteins in an
unregulated manner leads to the development of the malignant
phenotype.

Other co-factors probably act synergistically with HPV in tumor
induction.  For example, in BPV-4-infected cattle that feed on
bracken fern, which contains a protent mutagen, alimentary tract
carcinomas develop from benign papillomas (Jarrett et al., 1978).
HSV is a co-carcinogen that could interact with HPV (zur Hausen,
1982).   In humans with epidermodysplasia veruciformis, exposure
of the skin to sunlight is associated with the development of
skin carcinomas in which HPV types 5, 8, and 14 are found
(Pfister et al., 1981, Claudy et al., 1982).  Immunosupression
may also be a cofactor as evidenced by the finding of increased
numbers of benign and malignant HPV-positive tumors in renal
transplant recipients (Rudlinger et al., 1986, Van der Leest et
al., 1987).

The mucosal epithelium in the oral cavity is histologically
similar to that of the female genital tract and like the female
genital tract, it is continuously exposed to various
environmental factors such as irritants and microorganisms.  Thus
there may be parallels in the oral cavity with respect to the
capacity of HSV and HPV to participate in malignant
transformation most likely in association with other cofactors.
Clearly, there is a need to examine a large number of oral
carcinomas to ascertain the frequency of infection with the more
oncogenic HPV types and to show any correlation between HPV
infection and progression from premalignancy to malignancy.  It
is also very important to study the relationship between the
presence or absence of human papillomavirus in oral tumors as it
relates to the prognosis for the patient. oral cancer.  In
addition, if HPV is found in histologically normal mucosa from
oral cancer patients  It will be most useful to know if the
presence of the virus effects the tumor-free interval following
treatment, the incidence of recurrent tumors, the incidence of
second primary tumors, and the five-year survival rate.  The
virological data can be analyzed in the context of other risk
factors such as alcohol and/or tobacco use to look for possible
associations.  By examining an appropriate number of samples of
histologically normal oral mucosa, it will be possible to
determine if virus infection is a potential risk factor for
development of following treatment, it will be important to
document if these patients have more recurrences of the disease.

At the molecular level, information is needed regarding the
physical state of the viral DNA in oral carcinomas since
integration of the viral DNA into the host cell genome is thought
to be an essential step in the transformation process.
Information regarding which viral genes are retained in oral
carcinomas and expressed as mRNA and as protein would be most
useful in defining the role HPV may play in events leading to
oral cancer.