Viruses in oral squamous cell carcinoma: A review

Abstract

Oral cancers are one of the most commonly occurring neoplasm in the world. These conditions have a high mortality rate which is rapidly increasing. Factors like tobacco consumption, alcohol, genetics, etc., play a role in etiopathogenesis of these lesions, currently there is a lot of growing interest in role of viruses like Epstein-Bar virus, human papilloma virus, herpes simplex virus, hepatitis C virus etc., in oral carcinogenesis. Viruses can induce cancers through various methods. Thus knowing the exact role of viruses in cancers can affect the treatment plans and prognosis of the treatment.

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Pravara Med Rev 2016;8(1)
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Viruses in Oral Squamous Cell Carcinoma : A Review
Sneha P. Patil*, ,Sonia J.Sodhi**, Suraj D.Tambe***,Viral Gada****,Deepak Vikhe******
Introduction
Oral squamous cell carcinoma (OSCC) is the sixth most
common malignancy world wide and accounts for
approximately 5% of malignant tumors in developed
countries. Prevalence and anatomic distribution of these
lesions are associated with habits like tobacco, smoking,
alcohol, etc., Thus the use of tobacco and alcohol are
considered as a risk factors for OSCC, but it does not
always show a positive correlation. Individual that
develops the OSCC without past habit history suggests
that others factors can play a role in head and neck
carcinogenesis.[1]
It has been suggested that habit as well as chemical
carcinogens, radiation energy, chronic irritation, and
viruses play an important role in their etiology.[2] Viruses
such as herpes simplex virus (HSV), human papilloma
viruses (HPV), hepatitis C, Epstein– Barr viruses (EBVs)
have shown close association with the development of
premalignant lesions/conditions and OSCC.[3]
*PG Student, **Professor
Dept of OMDR ,CSMSS Dental College Aurangabad,
***Senior Lecturer ****PG student, *****Senior Lecturer
Dept of Prosthodontics, Rural Dental College PIMS(DU)
Corresponding author:
Dr Sneha P Patil,
Dept of OMDR ,CSMSS Dental College Aurangabad,
Email: patil.snehapatil.sneha28@gmail.com
Review Article
Oral squamous cell carcinoma and viruses
OSCC usually originates from the stratified squamous
epithelium. The etiology or OSCC is complex and involves
many factors. As it has been proved that betel quid, and
alcohol consumption are the major risk factors for
developing OSCC, However, additional factors such as
genetic predisposition, diet or oncogenic viruses causes
impairment of physiological mechanisms of cellular
proliferation control.[4]
The viruses are classified under two categories: Viruses
strongly associated with oral squamous cell carcinoma
i.e. Human PapillomaVirus, Herpes Simplex Virus (HSV)
and viruses less frequently associated with oral squamous
cell carcinoma are Epstein barr virus (EBV) and Hepatitis
C virus (HCV).
A. Human Papilloma virus
The exact role of HPV in the development OSCC is still
unknown. Papilloma viruses are members of the
papovaviridae family, which also includs other viruses like
polyoma viruses. The papilloma viruses are nonenveloped,
circular, double-stranded DNA viruses.
Classification
Papilloma viruses are classified according to their host
range and the relatedness of their nucleic acids:
i. Papilloma virus was first named according to its
natural host, e.g. cotton tail rabbit papilloma virus,
bovine papilloma virus etc.
Abstract:
Oral cancers are one of the most commonly occurring neoplasm in the world. These conditions have a high
mortality rate which is rapidly increasing. Factors like tobacco consumption, alcohol, genetics, etc., play a
role in etiopathogenesis of these lesions, currently there is a lot of growing interest in role of viruses like
Epstein–Bar virus, human papilloma virus, herpes simplex virus, hepatitis C virus etc., in oral carcinogenesis.
Viruses can induce cancers through various methods. Thus knowing the exact role of viruses in cancers can
affect the treatment plans and prognosis of the treatment.
Keywords: Carcinogenesis, oral cancer, viruses.

Pravara Med Rev 2016;8(1)
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ii. Based on clinical prognosis of their associated lesion
they can be: Low-risk HPVs, which cause benign
epithelial hyperplasia, and high-risk HPVs, e.g. HPV-
16 and -18 infected lesions have high rate of
malignant transformation
iii. According to the International Agency for Research
on Cancer:
• Group 1: HPV-16 and -18 as carcinogenic in humans
• Group 2A: HPV 31 and 33 as probably carcinogenic
in humans
• Group 2B: Remaining HPVs as possibly
carcinogenic.[3]
Carcinogenic potential of human papillomaviruses
Studies have shown that almost 100 distinct types
of HPV have been identified. However, not all types are
associated with OSCC. High prevalence of HPV-16 and
HPV-18 with OSCC is seen in Indian betel quid chewers.
The constant detection of the HPV in OSCC patients
who do not habitually use tobacco or consume alcohol
has also indicated the close association of HPV with
OSCC. Among various strains of HPV, HPV-16 is most
commonly associated in these patients.[4]
DNA is the genetic constituent of HPV. When the host
tissues get infected with HPV, E6 protein and E7 protein
are formed following complete degradation of host
genome. E6 protein forms a complex that causes
degradation of p53 gene by inhibiting apoptosis while E7
protein causes an increase in DNA synthesis and
proliferation which leads to disturbance in the
retinoblastoma tumor suppressor gene.
Basal keratinocytes are the target cells for HPV where
new virions are produced and released subsequently when
the superficial cells flake off. These HPV altered
keratinocyte as well as koilocytes are also found in
patients with OSCC.[5]
B. Herpes Simplex virus
HSV is a double-stranded DNA virus that is
enveloped. The two most common forms are HSV 1 and
HSV 2. Both viruses have similar structures. HSV 1
mainly causes oral and ocular infections while HSV 2
causes genital infection. They have a difference in the
ability to transform cells. The transforming region of HSV
1 is located in the left third of the genome. It is also known
as minimum transforming region (mtr) 1, while in HSV 2,
mtr 2, mtr 3 are close to the center of the genome.[6]
Herpes Simplex Virus and Oral Squamous Cell
Carcinoma
The association between oral cancer and HSV is still a
topic of debate except for the fact that HSV can transform
some animal cells to a malignant phenotype in vitro.
Actually HSV has shown cocarcinogenic activity in
combination with chemicals in vivo. But it is difficult to
study, because cells that are transformed by HSV do not
express specific virus antigens or retain any specific genes
of the virus. Instead it seems likely that the transformation
is due to the virus acting as a mutagen, and a region of
the viral genome has been isolated, which raises the
mutation frequency in cultured cells. This results in
features of malignancy. Also the mutations and the
phenotypic changes are not sufficiently specific to act as
markers by which a herpes-induced malignancy could be
diagnosed.[7]
Herpes Simplex Virus In Cell Transformation
The transforming mechanisms of HSV 1 and 2 remain
unclear. The viruses have not been shown to encode an
oncogene or related gene and furthermore the
transforming regions of the genome are not retained in
transformed cells. Few other mechanisms that are
proposed in cell transformations of HSV are induction of
cellular proteins, host cell shut off process, stimulation of
other viruses by HSV, chromosomes as targets.
C. Epstein–Bar virus
It is one of the most common viruses in humans. It is
enveloped double-stranded DNA and also known as
human herpes virus-4. EBV is named after Michael
Anthony Epstein and Yvonne Barr, who discovered and
documented the virus in 1964. It belongs to the genus
Lymphocrypto viridae and a gamma 1 subtype of the
subfamily Gamma herpes viridae. EBV is commonly
associated with a number of malignancies such as
Burkitt’s lymphoma, Hodgkin’s disease, stomach
carcinomas, and nasopharyngeal carcinoma.[7]
Epstein–Bar virus and carcinogenesis
First stage in the mechanisms of EBV tumorigenesis is
establishment of a persistent infection. The primary
infection starts within the oropharyngeal epithelial cells
with viruses subsequently passing to subepithelial B-cells
through direct contact. The invasion of the immune system
by EBV stimulates CD8 T-cell response. The
development of a virus-specific adaptive immune response
reduces the number of EBV-infected B-cells subsequently
leads to the elimination of EBV infection. This elimination
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Pravara Med Rev 2016;8(1)
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of infection remains as a latent infection after
incompletely persistent EBV infection in peripheral blood
lymphocytes and/or as a lytic infection in the oral cavity.
It leads to shedding of infectious viruses via oral
secretions. EBV infects B-cells and converts them to
lymphoblastoid cells which have tendency to proliferate
continuously. They express nine latency-associated viral
proteins which includes six nuclear antigens (Epstein–
Barr nuclear antigen [EBNA] - 1, 2, 3A, 3B, 3C and
leader protein [LP]) and three membrane proteins (latent
membrane protein (LMP) - 1, 2A and 2B).[8]
Genomic instability is a hallmark of malignant
transformation and is frequently associated with
chromosomal aberrations such as reciprocal
translocations, deletions, inversions, and duplications.
They deregulate the expression of oncogenes or tumor
suppressor genes. It has been demonstrated that the EBV
nuclear antigens (EBNA 1 and EBNA 3C, and the LMP
1) promotes genomic instability, breaking of DNA and
phosphorylation of histone H2AX.[9]
EBNA causes DNA damage by inducing reactive oxygen
species and also there is inhibition of DNA repair in LMP
1 expressing cells through down regulation of the DNA
damage-sensing kinase, reduction of phosphorylation of
its downstream targets Chk2 and inactivation of the G2
checkpoint. EBNA 3C enhances the propagation of
damaged DNA. Thus, it has been postulated that EBV
independently targets multiple cellular functions involved
in the maintenance of genome integrity which causes
genomic instability which considered as a critical event
in viral oncogenesis. Also role of EBV in neoplastic
transformation in oral cancers is indicated by a positive
correlation between different grades of OSCC and EBV
DNA positivity. A percentage positivity of EBV DNA
increases from well differentiated OSCC to poorly
differentiated OSCC.[9]
D. Hepatitis C virus
It is an enveloped single-stranded positive sense RNA
virus belongs to genus (hepacivirus) within the Flaviviridae
family. It is an etiological agent for most cases of non-a,
non-b hepatitis, liver cirrhosis, and hepatocellular
carcinoma. The oral cavity is frequently exposed to HCV
viruses, thereby causing an increase in the risk of genetic
instability in the cells. In HCV-positive patients, the
squamous cells of oral cavity are continuously exposed
to HCV from saliva as well as from serum. This might
leads to the development of OSCC. Anti-HCV antibodies
were also detected in patients with OSCC, but the exact
mechanism is unclear.[10]
Conclusion
Viruses are important risk factors for oral cancerous.
While diagnosing these lesions one should always consider
the possible role of viruses in their etiopathogenesis which
can alter treatment plan for the patients. Recently,
vaccines against HPV for prevention of cervical cancer
has been invented. Similarly, future research should be
carried out to develop a vaccine against these viruses in
order to prevent the occurrence of oral malignancies.
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