Oral squamous cell carcinoma (OSCC) has been considered to be the most common malignancy of the head and neck region. OSCC develops as a result of certain genetic and epigenetic variations in the squamous epithelium, which in turn leads to a series of consequences leading to the definitive stage of invasive squamous cell carcinoma. Majority of oral malignancy cases have been associated with specific exposure to certain risk factors such as smoking, smokeless tobacco products, heavy consumption of alcohol, poor oral hygiene, human papilloma virus infection along with other lifestyle factors and dietary changes. There are certain genes named as BIRC2 and BIRC3 belonging to the inhibitors of apoptosis protein (IAP) family which become over-expressed and upregulated during the course of OSCC. The proteins made are pronounced as cIAPs which are inhibitors of specific caspases leading to the suppression of apoptosis induced by a variety of triggering factors. Current review has brought together all such concrete studies along with diagnostic and therapeutic relevance to OSCC at a single platform so as to understand the etiological factors, mechanism and regulation in oral squamous cell carcinoma. Moreover, the recent emergence of microbiome as a diagnostic and therapeutic target has also been discussed in order to find a sustainable and reliable therapeutic solution to OSCC.

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Review Paper:
Oral squamous cell carcinoma (OSCC) in humans:
Etiological Factors, diagnostic and therapeutic relevance
Sharma Anil Kumar1
*, Sharma Indu1
, Diwan Gautami1
and Sharma VarRuchi2
1. Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, 133207, Haryana, Mullana, Haryana, INDIA
2. Department of Biotechnology, Sri Guru Gobind Singh College, Sector 26 Chandigarh, 160019, INDIA
*anibiotech18@gmail.com
Abstract
Oral squamous cell carcinoma (OSCC) has been
considered to be the most common malignancy of the
head and neck region. OSCC develops as a result of
certain genetic and epigenetic variations in the
squamous epithelium, which in turn leads to a series of
consequences leading to the definitive stage of invasive
squamous cell carcinoma. Majority of oral malignancy
cases have been associated with specific exposure to
certain risk factors such as smoking, smokeless tobacco
products, heavy consumption of alcohol, poor oral
hygiene, human papilloma virus infection along with
other lifestyle factors and dietary changes. There are
certain genes named as BIRC2 and BIRC3 belonging
to the inhibitors of apoptosis protein (IAP) family
which become over-expressed and upregulated during
the course of OSCC. The proteins made are
pronounced as cIAPs which are inhibitors of specific
caspases leading to the suppression of apoptosis
induced by a variety of triggering factors.
Current review has brought together all such concrete
studies along with diagnostic and therapeutic
relevance to OSCC at a single platform so as to
understand the etiological factors, mechanism and
regulation in oral squamous cell carcinoma. Moreover,
the recent emergence of microbiome as a diagnostic
and therapeutic target has also been discussed in order
to find a sustainable and reliable therapeutic solution
to OSCC.
Keywords: Oral squamous cell carcinoma (OSCC),
etiological factors, diagnostic, therapeutic, microbiome,
dysbiosis.
Introduction
Cancer is a chronic inflammatory disease that is
distinguished by uninhibited abnormal cell growth. In a
normal healthy adult individual, cells normally grow and
divide to replace damaged or old cells, thereby maintaining
cellular homeostasis. Cells in normal scenario have a
definite life span and survive for a particular period of time
only after which they may undergo the process of
programmed cell death, also called as apoptosis. To the
contrary, unlike these healthy normal cells that follow a
distinct and specified growth pattern, cell division and
apoptosis, malignant or cancer cells have a tendency to grow
and divide continuously disrupting and altering the apoptotic
process as well. Cancer has been classified into various
categories based on the originally infected or inflamed cell71.
Classification of cancer basically comprises of either i)
carcinoma originating in the linings of tissue, skin or internal
origin ii) the sarcoma which is initiated in the supportive
tissues like bones, cartilages, fat, muscles and connective
tissues such as blood vessels iii) third condition is leukemia
which is having its origin in the blood-forming tissue such
as bone marrow iv) lymphoma and myeloma have their
origin in the cells of the immune system v) lastly glioma and
meningioma have their origin in the brain and spinal cord
tissues.
These cancerous cells are known to proliferate
uncontrollably, resulting in the formation of solid mass of
tissues also called as tumors. These tumors tend to grow and
further interfere with the vital physiological systems of our
body including nervous, circulatory and digestive systems.
Moreover, there is unregulated induction of the endocrine
system as well releasing hormones which are attributed to
altered body functions.
However, there is a clear distinction between the benign
tumors which remain localized to one spot and undergo
limited growth and proliferation from the malignant tumors
[Table 1]. These malignant tumors have a tendency to spread
uncontrollably throughout the body through lymphatic or
circulatory systems invading other healthy tissues as well.
The major characteristic features of benign and malignant
tumors are given in table 1. Cancerous cells have an inherent
tendency to undergo alterations at the genomic level along
with rapid cell cycle changes. Other transformations
observed in cancerous cell include accelerated cell mobility,
invasiveness in terms of growth, increased secretion of lytic
factors along with changes in cellular surface and
chemotactic behavior 69,77
.
One may see a structurally distinct large nucleus having
asymmetrical shape and size, prominent nucleoli and scanty
cytoplasm in such type of malignant cells2,78
. Some of the
prominent trademarks of cancer are reflected in malignant
cells during their development such as their ability to
proliferate consistently and uncontrollably evade the
responses of factors involved in suppressing growth and
oppose the process of programmed cell death. Moreover,
these malignant cells gain the ability to enable continuous
replication and hence immortality.

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Table 1
Characteristic features of benign and malignant tumors
Characteristics Benign tumor Malignant tumor
Invasion to tissues No invasion to surrounding tissues Highly invasive and penetrating to
surrounding tissues, disseminating to whole
body
Growth speed Slower growth, may take months or years to
change significantly in size
Vigorous, appreciable growth in few weeks
Macroscopic view Well-circumscribed with edges of the tumor
distinct and demarcated in a certain shape
Highly abnormal, irregular shape
Movement Freely movable within or on the tissue they
reside on
Difficult to move around due to local tissue
invasion
Life-threatening Typically, not Can be life-threatening
Treatment May or may not need treatment Aggressive treatment is required including
surgery, radiation, chemotherapy and
immunotherapeutic medications
Microscopic Cell shape, chromosomes and DNA appear
normal
Abnormal, irregular shape, DNA is
characterized by large, dark nuclei
Secretions Do not secrete hormones or other
substances (with an exception of
pheochromocytomas of the adrenal gland)
Hormone secretions take place along with
other substances causing fatigue and weight
loss (paraneoplastic syndrome)
Recurrence Unlikely to recur after removal Recurrence happens sometimes in areas other
than the original site
Typical examples Adenomas such as colon polyp, fibromas,
desmoids tumor, hemangiomas, moles or
nevi, lipomas, leiomyomas
Carcinoma, fibrosarcoma, liposarcoma,
leukemia, lymphosarcoma, hemangiosarcoma
chondrosarcoma, osteosarcoma
Furthermore malignant cells could induce angiogenesis, and
become more aggressive in invasion of the surrounding cells
and further spread to various tissues and organs resulting in
metastasis88
.
The hallmarks of malignant cells are further assisted by the
instability of the genome, wider genetic diversity, and
inflammation, promoting multiple trademarks functions3
.
There have been consistent developments in this field which
has given birth to four more emerging trademarks of cancer
viz. deregulation of pathways involved in cellular energetics,
evasion of the host response for the neutralization of the
immune response, inflammation promoted by tumor,
mutations and instability of the genomic as well. 79,88
Oral squamous cell carcinoma: Head and neck cancer is
the sixth leading cancer worldwide and around 620,000
patients are diagnosed yearly with a male to female ratio of
4:17,8,67
. Head and neck cancer mainly comprises of
epithelial malignancy that grows in the oral and nasal cavity,
pharyngeal and laryngeal regions as well as sinuses related
to paranasal region. Majority of such epithelial malignancies
are the squamous cell carcinoma of the head and neck
region5
. These cancers are mostly destructive in their
biological behavior and this lead to higher risk of developing
secondary tumors10
.
Oral squamous cell carcinoma (OSCC) is the main
malignant tumor for head and neck area. There are many
different subsites within oral cavity including buccal mucosa
(BM), alveolus, upper and lower gingiva (gum)
retromolartrigone (RMT), palate, tongue and floor of mouth
(FOM) according to International Classification of Diseases
(ICD version 9, categories: 140- 146). In Asian population,
predominantly the buccal mucosal cancer is most frequent
while in the western countries, either floor of the mouth or
the bottom part of the tongue is the major site (45-50% of
oral cancers) for the development of intraoral cancer11.
Epidemiology: When it comes to cancer, western countries
of the developed world have the maximum mortality rate
because of this chronic disease closely followed by
developing countries where it is rated as the second leading
cause of death globally12
. The wide incidence of cancer both
in lower and high income countries is because of the lifestyle
habits like smoking, excess body weight and dietary factors
as well. Oral cancer accounts for an estimate of 300,000
newer oral cancer cases and 145,000 deaths in 2012 and
702,000 active cases over five years period13
. Many
countries from Asia especially from the south central Asian
region and central eastern European region have been
reported to have the highest rate of oral cancer. On the other
hand, countries from the central African continent have the
lowest incidence of this cancer.
The major cause of oral cancer worldwide is consumption of
tobacco in many different forms, alcohol consumption as
well as the infection of human papilloma virus (HPV).

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Percentage mortality in low income countries because of
smoking is reported to be about 42% (70% in high income
countries) while heavy alcohol use is attributed to 16% of
the deaths in low-income countries (30% in high income
countries)15,16
. Smokeless tobacco in the form of oral snuff,
betal quid, areca nut, slaked lime and the substitutes for betel
quid like guktha, mawa and gudakhu are the main reasons
for the oral cancer in India, Sudan, Taiwan and other
neighboring countries17-19.
Oral cancer is main problem in Indian subcontinent with the
highest frequency of oral cancers in the world and
approximately 0.1 million new cases of oral cancer are
reported yearly20,21. Men have been found to be more prone
to oral cancer than women around the world as suggested by
many researches previously23
. These gender differences
could be because of more indulgence of males into
alcoholism and other risk habits leading to cancer. There is
a decline in the ratio of males to females diagnosed with oral
cancer in the last decade or so in most European and Asian
countries 24
which is now about 1.5:1 for mouth cancer and
2.8:1 for oropharyngeal cancer25
. Because of the extensive
use of tobacco, the oral cancer mortality rate in European
females has increased substantially24.
However, there is a decreasing trend observed in both males
and females in the United States and United Kingdom of all
ages26
. Though because of changes in oral sexual behavior,
increased incidence of oral cancer has been observed in
young adults in the United States while in some countries of
Europe, incidence is related to HPV infections of the tonsils,
tongue and oropharyngeal region27
.
Etiological factors: Majority of oral cancer cases are linked
to specific exposure to lifestyle behaviors and individual
predisposition28
. The most important reasons for oral cancer
are heavy alcohol intake, tobacco usage (Smoked and
smokeless), high risk human papilloma virus (HPV)
infection and poor oral hygiene 29
[Figure 1]. Other factors
such as dietary micronutrient deficiency also exist that
environmental factors, genetic factors etc. may harmonize
the risk of oral cancer development 29 [Figure 1].
Tobacco: In Indian subcontinent and other Asian countries,
oral neoplasia has been related to heavy consumption of
tobacco with betel quid (BQ), smoking of cigarettes, bidis
and alcoholism are the main risk factors30. Smoking of
tobacco in any of the forms such as cigarettes, bidi, pipes and
cigars is carcinogenic to humans and this has been confirmed
by the International Agency for Research on Cancer
(IARC)31
. Exposure to tobacco-specific nitrosamines
(TSNA) and nitrosamines derived from areca nut alkaloids
because of chewing of tobacco with BQ further increases the
chances of occurrence of oral cancer.
In addition, while chewing tobacco, reactive oxygen species
(ROS) is generated leading to multistage oral
carcinogenesis. For example, benzo-α - pyrenes are tobacco
smoke pro-carcinogens that are metabolized by oxidizing
enzymes (cytochrome P450 in particular), resulting in the
formation intermediates which are highly reactive and
carcinogenic in nature 48
.
Figure 1: Variety of etiological factors involved in the development and progression of
Oral Squamous Cell Carcinoma (OSCC)
Tobacco
Human papillomavirus
(HPV)
Radiations
Genetic alterations
Environmental
factors
Poor oral hygiene
Life Style factors
Betel Quid and Areca
Nut
Alcohol
Diet
Stem cell
transplantation
Metabolic/endocrine
/exogenous factors

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Betel Quid and Areca Nut: Another important etiological
factor behind oral carcinogenesis is the chewing of betel
quid which has been found to be the cause of oral submucous
fibrosis. The use of both areca nut and tobacco in betel quid
has been found to increase the chances of oral cancer to
about 4-fold30
. Chewing of betel quid leads to the production
of ROS which is harmful to oral mucosa and can be directly
involved in the beginning of tumor either by occurrence of a
mutation or by creating the mucosa vulnerable to BQ toxic
components. ROS is produced and released under alkaline
conditions during the auto-oxidation of areca nut (AN)
polyphenols, in the saliva of BQ chewer88
.
ROS plays an important role in the beginning of the tumor
as it has the potential of persuading genotoxicity, gene
mutation and it also attacks the salivary proteins cardinal to
structural changes in oral mucosa. Upon analysis of the
saliva of BQ chewers, the nitrosation of areca alkaloids was
reported to occur resulting in the formation of AN-specific
nitrosamines found to be strong mutagens having genotoxic
and tumorigenic properties32,33
.
Alcohol: With the fermentation of carbohydrates by yeast,
just like simple carbohydrates in fruits and starch in grains,
ethanol is produced which is the main active ingredient in
alcoholic beverages. Regular consumption of alcohol may
lead to oral cancer depending upon the amount of alcohol
consumed. With the consumption of 4-5 drinks daily,
individuals have the higher risk of oral cancer as compared
to non-drinkers 29
. Alcohol is generally known to be
metabolized by two major metabolizing enzymes named as
alcohol dehydrogenase and aldehyde dehydrogenase. While
alcohol dehydrogenase basically oxidizes ethanol to
acetaldehyde, on the other hand aldehyde dehydrogenase is
reported to detoxify acetaldehyde to acetate.
Acetaldehyde has been attributed to have oral carcinogenic
effects due to its mutagenic nature. Furthermore, apart from
ethanol, there are many minor components in the drinks
including polyphenols, acrylamide, and nitrosamines which
have been classified as having carcinogenic nature64
.
Human papilloma virus (HPV): Human papilloma virus
(HPV) infection has been one of the major etiological factors
associated with benign and malignant oral carcinoma. This
has been evidenced through various studies where HPV was
detected in many carcinogenic conditions including
condylomas, squamous cell papilloma, focal epithelial
hyperplasia and malicious oral abrasion80
. HPV viral
incidence was reported to be significantly higher in oral
cancer (59%) followed by pharyngeal (43%) and laryngeal
(33%) carcinoma conditions64
. Among the human papilloma
viruses, HPV16 and HPV18 have been labeled as high-risk
HPVs which are capable of invading human epithelial
tissues resulting in the oral carcinoma.
The probability of evolving oral cancer also increases with
high-risk sexual behavior. It has been postulated that oral
cancers follow at least two divergent pathways with varying
genetic events with higher frequency of 11q13 gains and
losses of 3p, 9p and 18q in HPV positive oral cancer patients
as compared to HPV negatives35,36
. Once the virus invades
the host cell and utilizes the host cellular machinery in order
to harmonize its nucleic acid genome into the nucleus of the
host cell, it persuades the expression of E6 and E7 onco-
proteins. The upregulated E6 protein further persuades
mortification of p53 through proteolysis which is ubiquitin-
mediated, cardinal to significant loss of p53 activity.
p53 is usually known either to arrest the cells in G1 phase or
may lead to induce programmed cell death or apoptosis so
that the host DNA could be allowed to repair. Cells
expressing E6 are not capable of holding the response of
p53-mediated DNA damage, therefore enhancing more
genomic instability. On the other hand, the E7 protein is
capable of binding to retinoblastoma tumor suppressor gene
product pRB making it inactive, thus, causing the cell to
enter S-phase, cardinal to cell-cylce disruption, escalation
and malicious transformation which in turn leads to tumor
formation 35
.
Poor oral hygiene: Poor oral hygiene has been one of the
key risk factors for the growth and development of an oral
carcinoma. It is well known that patients with oral carcinoma
in general have poor oral health and hygiene having caries
in their teeth along with other dental diseases like
periodontitis further increasing the risk for head and neck
cancer37
. Many pathogenic populations of specific microbes
have been implicated in oral carcinogenesis as there have
been stark differences in the microbial populations
prominently present in the oral mucosal linings of the
malignant patients in comparison to healthy controls.
Predominant presence of Streptococcus anginosus and
Treponema denticola was noticed in the gastrointestinal tract
carcinoma patients reflecting the association of such
microbial population with carcinoma.
Similarly syphilis, another disease was found to be
associated with carcinoma38
. In terms of mechanism,
microbes especially bacteria have the capability to induce
cellular proliferation which can inhibit apoptosis. This may
further act as promoting tumor formation or could lead to
formation of oral bio-films. These oral biofilms have the
capability to induce mutations and affect the complex
interaction network with saliva facilitating as cofactors in the
development of oral carcinogenesis. Oral microbiota also
has the capability to metabolize alcohol into acetaldehyde
which is again a potent carcinogen. However, it remains to
be seen whether controlling the above bacterial population
and the oral biofilms has any impact on the incidence of oral
carcinoma40,42,43.
Diet: Dietary factors have a strong influence upon the
incidence of cancer as diet comprising of unhealthy
components and ingredients along with sedentary life style
without any physical activity and growing cases of obesity

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are known to contribute upto 40% of global cases of cancer.
Even the daily consumption of fruits and vegetables
influences upon the cases pertaining to oral cancer as up to
fifteen percent of oral cancer cases have been attributed to
lesser intake of fruits and vegetables. There have been few
evidences supporting the linkage between oral cancer and
diet deficient in certain components in fruits, carotenoids
and starch-less vegetables.44-46
However the precise roles and the mechanistic details about
such micro nutrients are yet to be investigated.47
Some
studies in literature have convincingly shown that secondary
metabolites and phytochemicals (vitamins, flavonoids,
carotenoids etc.) derived from plant have potential
antioxidant and anti-carcinogenic properties, and could play
a pivotal role in negating adverse carcinogenic effects
induced by other etiological factors like smoking,
alcoholism and betel quid chewing 49-51,54
Genetic Alterations: Numerous alterations at the genetic
level have been reported during OSCC progression which is
greatly influenced by genetic predisposition and other
environmental factors (including alcoholism, smoking,
infections etc.) in a multiple step process. These genetic
alterations causing genomic instability predominantly affect
the tumor suppressor genes and oncogenes. Single or
multigenic mutations, deletions, loss of heterozygosity or
epigenetic modifications including methylation may result
in either inactivation or over expression of oncogenes and
tumor suppressor genes 53,55
.Development and progression
of cancer is a multistep process wherein there is sequential
accumulation of additional genetic defects followed by
clonal expansion 56
.Many genetic changes have been seen in
the squamous epithelium during oral carcinogenesis
comprising of a highly complex multi-focal process.
Additionally, many neoplastic transforming sites can be
noticed throughout in the oral cavity region. There is a
characteristic field cancerization (i.e. development of cancer
at multiple sites) in OSCC observed in tissues covered with
squamous epithelium. Variety of exogenous factors and
environmental influences may further lead to multi-focal
presentations and altered expression of tumor suppressor
genes. Smoking was found an underlying factor for the p53
gene mutation resulting in under-activity of the tumor
suppressor gene57
. Previously many chromosomal
aberrations were reported during the early development of
OSCC at 2q21-24, 2q33-35 and 9p21 alleles58
. Frequent loss
of heterozygosity at chromosomal loci 13q and 17p was also
found to be responsible for early signs and lesions of OSCC
58.
Another study reported the alteration in the regions of
chromosome number 9 such as 9p21 during the development
and progression of oral carcinoma leading to early signs and
lesions of oral carcinoma59. Chromosome 9p21 is also
known to harbor genes coding for p14 and p16 which are
also known as cyclin dependent kinase inhibitors.
Similarly, aberrations or alterations in chromosome 3 (3p13,
3p14,3p21,3p25) are responsible for the development and
progression of oral carcinoma. In a similar context, allelic
losses at 5q21, 5q22, 11q, 18q, 21q and 22q13 were
attributed to lead to poor differentiation of carcinomas and
assisting to advanced stages of the tumor development as
well. Another study observed polymorphism in HLA-B35
and HLA-B40 alleles which was shown to be associated with
tumor metastasis 68.
Hence one could easily conclude that alterations at the
chromosome are the key determinants for the development
and progression of OSCC. Anomalies in the tumor
suppressor gene were found to be responsible for the
malignant lesions as well. One could easily notice in case of
oral malignancy that there is aberrant expression of at least
one of the members of retinoblastoma (pRb) family of
growth suppressor proteins. The CDKN2A gene coding for
the protein p16 (located at locus 9p21) was recognized as the
most susceptible site as far as the oral carcinoma is
concerned while the alternative transcript of the same
gene,p14 was reported to be deleted more often in malignant
oral lesions70
. In variety of carcinoma cases including oral
malignancy, it has been seen more frequently that the tumor
suppressor gene TP53 expression is suppressed.
In another study, ATP6V1C1 54 gene over-expression was
found to be associated with OSCC. ATP6V1C1 54 gene was
reported to be mainly involved in the regulation of V-
ATPase enzymes and acidity of solid oral tumors 73
. In case
of epigenetic alterations, DNA methylation is the most
common one. The Ras association family gene (RASSF) was
found to be altered in OSCC with RASSF2 gene methylated
in about 26% cases of OSCC76.
Another epithelial adhesion molecule, cyclo-oxygenase2
(COX2) is expressed at high levels in dysplastic lesions and
has been well-correlated with tumor size, regional lymph
node metastasis, histological differentiation shown to be
associated with OSCC74
. The epithelial adhesion is along
with invasive profile of OSCC58
. Similarly, many other
molecules including connective tissue growth factor, and
CCN2 have been found to be associated with OSCC.
MMP-2 and MMP-9 genes were also found to be up
regulated in OSCC potentially involved in the invasive
potential of tumor. Moreover, alcohol was found to stimulate
MMP-2 and MMP-9 genes, thus having a role in oral
carcinogenesis. Similarly, another study affirmed advanced
glycation end products (AGEs) and their receptors (RAGEs)
to be associated with oral carcinogenesis75. There exists an
intricate relationship between the expression of RAGE and
OSCC differentiation with negligible levels of RAGE
expression observed in poorly differentiated OSCC cells.
In terms of association with OSCC, many candidate genes
have been discovered on chromosome 11 (11q22-q22.2)
such as YAP1, BIRC3, BIRC2, MMP7, MMP10 and MMP1

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which were expressed in tumorigenic conditions and have
been implicated in apoptosis, cell adhesion and cell
migration as well58-60
. BIRC2 and BIRC3 are known to play
an anti-apoptotic role and reported to be over-expressed in
human and mouse tumors60,66,68
. Cellular inhibitor of
apoptosis protein 1 (cIAP1) and cellular inhibitor of
apoptosis 2 (cIAP2) are the proteins encoded by BIRC genes
which constitute the TNF receptor signaling complex.
There are three N-terminal baculovirus IAP repeat (BIR)
domains and a C-terminal RING domain that confers E3
ubiquitin ligase activity in these anti-apoptotic molecules52
.
cIAP1 and cIAp2 have also been found to influence
ubiquitin (Ub)-dependent signaling and other cellular
processes as well. As a result, nuclear factor-κB (NF-κB)
transcription factor is activated which in turn drives the
expression of genes important for inflammation and cell
survival83,85
. Chromosomal 11q22 region has also been
implicated in resistance to radiotherapy cardinal to lymph
node metastasis and poor survival of patients86
.
Diagnostic and therapeutic options against oral
squamous cell carcinoma (OSCC): Surgery alone is the
widely adopted therapeutic option to manage OSCC.
However, sometimes adjunctive therapies including
radiations with or without chemotherapy are also given.
These therapeutic options are based upon the functional
outcome, and disease complication rates72
. More, recently
microbiome has been found to have a profound impact on
the outcome of many diseases including cancer [Figure 2].
An average of more than 700 different bacterial species
accounts to colonize the human oral cavity. The oral
microbiome thus certainly vectors dental problems including
dental caries and periodontal disease87
. These
oral microbiome signatures present in saliva form a potential
diagnostic biomarker for oropharyngeal (OP) and
hypopharyngeal (HP) squamous cell carcinoma. A non-
invasive diagnostic biomarker for OP and HP cancer patients
includes the presence of many microbes pertaining to higher
abundance of Haemophilus parainfluenzae, Haemophilus
influenzae and Prevotella copri while lower abundance of
Rothia mucilaginosa, Aggregatibacter segnis, Veillonella
dispar, Prevotella nanceiensis, Rothia aeria,
Capnocytophaga ochracea, Neisseria bacilliformis,
Prevotella nigrescens and Selenomonas noxia is found in
saliva of OP and HP cancer patients. Streptococcus
anginosus may be contemplated as a non-invasive diagnostic
biomarker for OP cancer patients only65
.
In the oral carcinogenesis cycle, the local microenvironment
is altered which results in change in its microbiota
composition. Many of the oral pathogens and the metabolites
including nitrosamine and acetaldehyde were reported to
stimulate inflammation, promote the cellular proliferation
and inhibit the cellular apoptosis. Oral microbiota is thus a
potent biomarker for the development and projection of
OSCC. The oral pathogens P. gingivalis and F. nucleatum
were found to establish chronic inflammation and disrupt the
local immune response by secreting virulence factors such
as FimA and FadA adhesins and hence facilitate cancer
progression. The detection of P. gingivalis or F. nucleatum
promising indicator of a poor prognosis90
.
Figure 2: Therapeutic intervention strategies employed in order to manage OSCC.

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Anti-programmed cell death protein 1 (PD-1) agents have
become the standard of care for platinum-refractory
recurrent/metastatic head and neck squamous cell carcinoma
(HNSCC) and are currently being evaluated in various
disease settings. The composition of the microbiota present
in the oro-gastrointestinal tract has been associated with
immune dysregulation and initiation and progression of
many cancers 62.
Oral mucositis (OM) is a substantial problem developed by
many patients undergoing radiotherapy (RT) to
the head and neck region. Oral microbes can lead to the
onset and severity of this acute side effect.
Salivary microbiota continue to be stable during
radiotherapy and are constantly dominated by
Streptococcus, Prevotella, Fusobacterium and
Granulicatella. Obligate and facultative anaerobic gram-
negative bacilli (GNB) Bacteroidales G2, Capnocytophaga,
Eikenella, Mycoplasma and Sneathia, as well as anaerobic
GNB in the periopathogenic genera Porphyromonas and
Tannerella, were all positively correlated with ≥ grade 2
OM. Significant increases in the relative abundances of
Bacteroidales G2, Fusobacterium and Sneathia were
identified in buccal mucosa swabs at sites of ≥ grade 2 OM.
Several GNB such as Fusobacterium, Haemophilus,
Tannerella, Porphyromonas and Eikenella on the buccal
mucosa may affect patient which are exposed to develop OM
82
.
An altered oral microbiota has been linked with the
development of several oral diseases such as dental caries,
periodontal disease, and oral stomatitis. Moreover, poor oral
health has been linked to head and neck cancer particularly
oral cancer. The therapy of head and neck cancer (HNC)
often leads to caries development. There is an increase in the
relative abundance of many bacterial genera
(including Dialister, Selenomonas, Streptococcus
and Treponema) that occur in the saliva of oral cancer
patients, although Streptococcus anginosus has been
involved in head and neck squamous cell carcinoma 81
.
Oral microbiota has an influence in the human microbiome
and human health. There is an imbalance of the microbial
ecosystem during cancer which may lead to oral and
systemic diseases along with chronic inflammation 89
. In a
study, composition of microbiota was compared in
tumorigenic sites and normal tissues of buccal mucosa in
OSCC patients. Diversity of microbiota was visualized
along with relationships between oral buccal mucosal
microbial profile and OSCC 63,84.
Another study assessed the nitrosation potential of Candida
strains isolated from oral leukoplakia lesions and reported
strains with high potential for nitrosation to be associated
with greater levels of dysplasia. The study revealed the
detection frequency and counts of Candida to be
considerably greater in dysplasia and OSCC and such
elevation in counts of yeast was correlated with the severity
of dysplasia1,41
. Furthermore, recent studies have established
the role of bacteria in oral carcinogenesis. A 16 S rRNA
metagenomics approach along with next generation
sequencing (NGS) has contributed significantly to the oral
microbiome signatures that drive oral cancer. The same
study identified the head and neck squamous cell carcinoma
(HNSCC)-related microbiome and further studied the
associated virulent properties and interaction with the host
immune system through the omics technologies14.
Considering these facts, the oral microbiome opens up a
therapeutic window for the management of OSCC [Figure
2].
A randomization trial was conducted based on the
information of the patients including age, gender, and the
oral site affected. In the study, thirty-two patients (24 males
and 8 females) were histopathologically confirmed as having
OSCC as the part of the study. It was observed that if the
growth of the OSCC is very rapid so that the mass of
malignant cells outpaces its blood supply, then the lesion
will become necrotic which further breakdowns into an
ulcer. But if the mass of malignant keratinocytes grows
slowly and has sufficient blood supply, an exophytic OSCC
is likely to be developed4,39.
As the occurrence of oral squamous cell carcinoma (OSCC)
is increasingly affecting people worldwide and already
existing chemotherapeutic drugs have been attributed to
have many side effects.This has further led the scientific
community to look for the natural bioactive products as a
therapeutic solution to OSCC. One of the study reported a
natural flavonoid, Hydroxygenkwanin (HGK) exhibited
anticancerous effects, inhibiting cell growth in OSCC
cells34. Oncogenic miRNAs (oncomiRs) are also known to
have therapeutic properties for the treatment of human
malignancies. In GFP‐SAS (human OSCC cell lines),
oncomiRs screening was performed. LNA‐miR‐361‐3p
exhibited significant growth inhibition of GFP‐SAS cells.
Therefore, targeting miR‐361‐3p could be a useful
therapeutic approach for the treatment of patients with
OSCC 22,61.
In contrast, another mutational spectrum study in OSCC
revealed that anti EGFR strategies may not be successful in
such carcinogenic tumors and newer agents and therapeutic
combinations need to be tried 6
. Another study utilized a
combinatorial approach using paclitaxel (PTX), 5-
fluorouracil (5-FU) and ascorbic acid (AA) for the treatment
of OSCC. PTX, 5-FU and AA loaded SLN was carried out
in which SLN loaded with PTX and SLN loaded with AA,
both displayed a greater potency for the treatment of OSCC
in-vivo9
.
Conclusion
Clinical screening for OSCC patients requires further
improvements so that physicians and oncologists may be
able to diagnose oral cancer patients having distinct lesions
associated with alcohol or tobacco consumption or HPV-

8. Research Journal of Biotechnology Vol. 15 (10) October (2020)
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148
induced ones or attributed to other conditions. Moreover,
preventive measures are to be accelerated in order to reduce
the morbidity and mortality rates because of OSCC.
Recent genomic advancements have been successful to
guide us about the development of novel therapies and new
drug discovery. The profound impact of the microbiome
dysbiosis and the associated disease such as OSCC has
certainly provided us lead in order to find a therapeutic
solution to the problem. However, one needs to understand
the intricate details and the underlying complexities in terms
of mechanism so as to manage and treat OSCC patients.
Acknowledgement
We greatly acknowledge Maharishi Markandeshwar
(Deemed to be University) Mullana (Ambala) Haryana,
India for providing the requisite platform to write this review
manuscript.
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