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ORAL CANCER
INTRODUCTION:
The oral cavity is a part of upper aerodigestive tract that begins at the lips and end at the anterior
surface of the faucial arch
...
The primary site of origin of oral cancers is submucous tissues, the epithelium and
the minor salivary glands
...
There are several types of oral cancers, but around
90% are squamous cell carcinomas, originating in the tissues that line the mouth and lips
...
It may also occur on the floor of the mouth,
cheek lining, gingiva (gums), lips, or palate (roof of the mouth)
...
Other
factors include poor oral hygiene, irritation caused by ill-fitting dentures and other rough
surfaces on the teeth and poor nutrition
...
As the tumour enlarges, it
may become an ulcer and bleed
...
Surgeries for oral
cancers include:
 Maxillectomy
 Mandibulectomy
 Glossectomy
 Radical neck dissection
 Mohs surgery or CCPDMA
 Combination of above
 Reconstructive surgery
 Following treatment, rehabilitation may be necessary
...

PROGNOSIS:
Prognosis depends on stage and overall health
...
5
54
...
2
53
...

Almost half (45%) of oral cancer cases in the UK each year are diagnosed in people aged 65
and over (2011-2013)
...

1 in 75 men and 1 in 150 women will be diagnosed with oral cancer during their lifetime
...

Around two-thirds of oral cancer deaths in the UK in 2012 were in men
...

Worldwide, more than 145,000 people were estimated to have died from lip and oral cavity
cancer in 2012, with mortality rates varying across the world
...
It has 53 amino acid residues and three
intramolecular disulphide bonds
...
EGF is found in many
human tissues including submandibular gland, parotid gland
...

 Biological sources: Epidermal growth factor can be found in urine, saliva, milk, and plasma
...

 Mechanism: EGF acts by binding with high affinity to epidermal growth factor receptor (EGFR)
on the cell surface
...
The tyrosine kinase activity, in turn, initiates a signal
transduction cascade that results in a variety of biochemical changes within the cell - a rise in
intracellular calcium levels, increased glycolysis and protein synthesis, and increases in the
expression of certain genes including the gene for EGFR - that ultimately lead to DNA synthesis
and cell proliferation
...


TGF α:
 Transforming growth factor α is a member of the EGF family, TGF-α is a mitogenic polypeptide
...
TGF-α
activates a signalling pathway for cell proliferation, differentiation and development
...
This gene has been
associated with many types of cancers, and it may also be involved in some cases of cleft
lip/palate
...
TGF-α induces
epithelial development
...
When TGF-α binds
to EGFR it can initiate multiple cell proliferation events
...
TGF-α is also involved in
tumorigenesis and believed to promote angiogenesis
...
The activity of protein-tyrosine kinase
influence activation and signalling of other proteins that interact in many signal transduction
pathways
...

EGFR is a member of the ErbB family of receptors
...

 Function: Epidermal growth factor receptor (EGFR) exists on the cell surface and is activated by
binding of its specific ligands, including epidermal growth factor and transforming growth factor
α (TGFα)
...
EGFR dimerization stimulates its intrinsic
intracellular protein-tyrosine kinase activity
...
This auto-phosphorylation elicits downstream
activation and signalling by several other proteins
...
Such proteins modulate phenotypes such as cell migration,
adhesion, and proliferation
...
These somatic
mutations involving EGFR lead to its constant activation, which produces uncontrolled cell
division
...


EXPRESSION OF EGFR IN OSCC:
EGFR is a member of the ErbB family of transmembrane cell-surface receptor tyrosine kinases
...
These pathways mediate various cellular responses,
including cell proliferation, survival, cell motility, invasion, and adhesion (Yarden and Sliwkowski
2001)
...
It is widely
accepted that EGFR and its ligands are overexpressed in a number of epithelial tumours (Hynes and
Lane 2005)
...
1998)
...
1989)
...
Recombinant
amphiregulin can increase the growth, invasive capacity, and migration of oral cancer cells, at least
in part, via induction of the inflammatory mediator COX-2 (Tsai et al
...
Two major
mechanisms of cell–cell adhesion are adherence junctions and desmosomes
...
2003)
...
Disruption of adherence junctions
through the reduced expression of E-cadherin, a-catenin, and b-catenin is associated with regional
lymph node metastasis in HNSCC (Tanaka et al
...
EGFR signalling pathways play a critical role in
the regulation of these adhesive complexes
...

E-cadherin has proven to be an important molecule in the progression of cancer and can serve as an
indicator of the metastatic potential of a primary tumour
...
2003)
...
2002; Lee et al
...
In three-dimensional organotypic models, suppression of E-cadherin leads to a more invasive
phenotype of squamous cell carcinoma cell lines, whereas maintenance of E-cadherin expression can
prevent invasion both in vitro and in vivo (Margulis et al
...
EGFR and its ligands have been
shown to be the key regulators of E-cadherin expression
...
A common downstream target of EGFR is the phosphoinositide 3 kinase (PI3K)/Akt pathway
...
2005)
...
2003)
...
9
...

Furthermore, E-cadherin is likely endocytosed through the EGFR/caveolin-1 dependent pathway
leading to cell–cell detachment and increased invasive capacity
...
There is accumulating
evidence implicating desmosomes in the progression of cancer
...

This is most likely due to the multiple roles desmosomes can play in the cell
...
1995)
...
FAK has been found to be overexpressed in highly invasive HNSCC compared
with normal oral mucosa (Kornberg 1998)
...
This enables primary cancer
cells to move through the matrix and target distant sites
...
These enzymes have been widely implicated in a number of invasive tumours
...
2005)
...
2000)
...
1996)
...

1996)
...
2000b)
...

2000a)
...

2007b)
...

2006)
...
2004; Lee et al
...
EGFR signalling can modulate the expression and activation of various
MMPs, which are critical in HNSCC metastasis
...
EGFR signalling mediates cell motility through the
activation of PLC-g1 and subsequent hydrolysis of phosphoinositide 4,5-bisphosphate (PIP2)
releasing gelsolin, which modifies the actin cytoskeleton (Chou et al
...
In HNSCC, both PLC-g1
and phosphorylated PLC-g1, the active form of PLC-g1, are overexpressed
...
2003)
...
2003)
...
2007)
...


Ligands (EGF,
TGF , HB-EGF, AR)

Receptor tyrosine
kinases

Cell adhesion
molecules

UV-induced reactive
oxygen species

G-protein-coupled
receptors

P

P

Src

PI3K/AKT
PLC

Jak/STAT
MAPK

Apoptosis, Survival, Proliferation, Differentiation, Migration
Diag: EGFR family members are activated by multiple mechanisms to regulate diverse biological
functions
...
The genetic basis of cancer is now well-established
...
Basic
cellular functions under these controls include cell division, differentiation, senescence, and
adhesion
...
These signals
either directly alter cell function or stimulate the transcription of genes whose proteins effect
change (Bishop, 1991)
...
It has been estimated
that from three to six somatic mutations are needed to transform a normal cell into its malignant
counterpart (Vogelstein and Kinzler, 1993)
...
The normal cellular functions tightly controlled by these regulatory

pathways are subverted in tumour cells, thus enhancing the cell's ability to proliferate, stimulate
neo-vascularization, and grow by invading locally or metastasizing to distant sites (Weiner and
Cance, 1994)
...

In adult tissues, the growth of cell is determined by the rates of cell proliferation, differentiation,
and death by apoptosis
...
In addition to stimulating
cell proliferation, growth factors may also have effects on cell locomotion, contractility,
differentiation, and angiogenesis, activities that may be as important as their growth promoting
effects
...
Neoplastic tumour can be a benign tumour or malignant tumour depending on various
characteristics as differentiation and anaplasia, rate of growth, local invasion and metastasis
...
Self-sufficiency in growth signals
2
...
Evasion of apoptosis
4
...
Limitless replicative potential
6
...
Ability to invade and metastasize

CONCLUSION:
EGFR signalling plays a major role in tumour progression and invasion
...
EGFR signalling disrupt cellular adhesion complexes by acting on E-cadherin
through the PI3K-Akt and MAPK pathways
...
And is also involved in degradation of ECM
through the action of MMPs
...
Furthermore, EGFR activation of PLC-g1
stimulates MMP-3 expression through the protein kinase C/Raf/ERK pathway, leading to degradation
of basement membrane
...


REFERENCES:
1) Biology of oral cancer – key apoptotic regulators; Prakash S
...


2)
3)

4)

5)
6)

7)
8)

9)

10)

Biology of oral cancer – key apoptotic regulators; Prakash S
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Growth Factor Receptor Signaling and Metastasis of Oral Cancer; Ali Razfar and Jennifer R
...
Myers (ed
...
1007/978-1-4419-0775-2_9, ©
Springer Science+Business Media, LLC 2010
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Repertinger, Justin G
...
Bichsel, and Laura A
...
B
...
Van
Waes (eds
...
1007/978-1-4419-7203-3_5, ©
Springer Science+Business Media, LLC 2011
...
"Epidermal growth factor"
...
PMID 2186024
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"Epidermal growth factor-urogastrone:
biological activity and receptor binding of derivatives
...
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Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA (2003)
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PMID
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"Review of epidermal growth factor receptor biology"
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ijrobp
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PMID
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Syst
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doi:10
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PMC 1681468
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