The Biology of Head and Neck

Cancer
THE LECTURE

Head and Neck Cancer;

The Disease
HEAD AND NECK CANCER

Is a group of malignancies arising from the head and neck region.

The term “head and neck cancer” usually represents squamous cell
carcinomas originating from the squamous cells that line the
mucosal surfaces of the upper aerodigestive tract. These tumours
make up more than 90% of the cases of head and neck cancer.
This Group includes Cancers of

• the Oral Cavity

 tongue (about 20% to 25%) 
 floor of the mouth (about 15%) 
 lip (about 10% to 15%) 
 minor salivary glands (about 10% to 15%)
 rest are found in the gums, tonsils, and other sites.

• the Salivary Glands

• the Nasal Cavity and Paranasal Sinuses
• the Pharynx
• the Larynx
• the Thyroid Gland
Problems of Head and Neck Cancer

• Unlike some other types of cancer, the survival rate, of

50%, did not improve over the past two decades.
• Lack of early detection and the need of aggressive
surgical therapy, as well as the high rate of local-
regional recurrences and distant metastases, often
leaves the patient functionally and psychologically
handicapped.
Problems of Head and Neck Cancer

• The epidemiology of head and neck cancer receives

limited attention in the general medical literature. This is
not surprising because these cancers are rarely
represented as one entity.
THE “ICD-10” CODING OF HEAD & NECK
CANCER

This system is used internationally for reporting head and

neck cancer

Advised by the North American North American Association

of Central Cancer Registries (NAACCR)

Head and neck Cancer codes ranges from C00.0 to C14.8

Region ICD-O-3 Term

C00.0 External upper lip

Lip C00.1 External lower lip

C00.2 External lip, NOS

C00.3 Mucosa of upper lip

C00.4 Mucosa of lower lip

C00.5 Mucosa of lip, NOS

C00.6 Commissure of lip

C00.8 Overlapping lesion of lip

C00.9 Lip, NOS (excludes Skin of lip

C44.0)

C00.9 Lip, NOS (excludes Skin of lip

C44.0)
EPIDEMIOLOGY
• World-Wide
– Yearly, more than 10 million people are diagnosed with cancer,
and 5 million die because of cancer worldwide.
– Oral cancer is the sixth most common cancer worldwide and the
third most common in developing nations, second to
cardiovascular disease as a cause of death in developed
countries
• Saudi Arabia
Between the years 1999 and 2000, there was 39209
cases diagnosed with cancer.
52% among Males
48% among Females

Cancer Incidence among Saudis by Age Group and Sex (1994-2000)

Cancer Incidence Report, Saudi Arabia (1999-2000)

10 Most Frequent Types of Cancer among Saudis Adults (2002)

Cancer Incidence Report, Saudi Arabia (2002)

Distribution of Most Frequent Types of Cancer by Sex among Saudis (2002)

6.9 5.2
% %

Cancer Incidence Report, Saudi Arabia (2002)

Not only that:
• Oral cancer accounts for 32% of all head and neck
cancer.

• Incidence of Oral cancer differs according to

geographical regions:

– Jizan Region reported the highest rate (6.2/100,000 for males

and 9.82/100,000 for females), making oral cancer the
second most common cancer in males and first for females.
– Najran Region reported oral cancer as the third most
common cancer in females.

Brown et al., 2006

THE LECTURE

The Biology of Head

and Neck Cancer
 CANCER
American Cancer Association (ACA) defines cancer as
a group of diseases characterized by uncontrolled
growth and spread of abnormal cells.
If the spread is not controlled, it can result in death.
CANCER BIOLOGY

Tumour
Angiogenesis Invasion
Growth and
Progression and
+ Metastasis
Impaired
Apoptosis
 Fearon and Vogelstein Model

Benign
Hyperplasia
Normal Carcinoma Invasive
Dysplasia
Cells in situ Cancer
Alternate
Precursor
Lesion

Fearon and Vogelstein (1990) Calvino et al. (1996)

 Oncogenes are genes that are
Activated able of increasing the
Oncogene malignant potential.

GENETIC Tumor Suppressors or anti-

Inactive
ALTERATION Tumor
oncogenes are genes that
S prevent cells from acquiring
Suppressor
malignant characteristics.
IN CANCER Gene
CELLS

Faulty
Mismatch Mismatch Repair Genes are
Repair genes that repair mutations
Gene in cell.
 Oncogenes

Proto-Oncogenes
cancer cells are physiologically dependent on
activated oncogenes for their survival = Oncogene
addiction
• When the proto-oncogene is altered and
abnormally activated to become an oncogene, it
can promote uncontrolled cell proliferation,
leading to tumorigenesis.
• Oncogenes are genes derived through alteration
of cellular proto-oncogenes.
• They encode proteins that mediate positive cell
growth-regulatory and/or cell survival signals.
 Tumour Suppressor Gene
Tumor Suppressor Genes Stops cell growth by either of
two ways:

1. cell cycle arrest

2. apoptosis.
• Unlike oncogenes, which can be activated by mutation
of only one of the two gene copies, tumor suppressor
genes are inactivated by mutations in both alleles of the
gene, in a "two hit" fashion
• Tumor suppressor genes encode proteins that typically
transduce negative growth-regulatory signals
• Once these genes are inactivated, the cell escapes tight
cell-cycle control, predisposing it to uncontrolled
growth and division, which contributes to the malignant
phenotype
Apoptosis (programmed cell death) is a
tightly regulated process that eliminates
senescent or altered cells that have
become useless or harmful.
It represents a physiologic cellular
mechanism important for cellular
homeostasis.

Tumor cells are resistant to apoptosis

What Would Happen in a Normal
Cell if its Genetic Makeover was
Altered?
Commit Suicide = Programmed Repair Genetic Fault =
Cell Death (Apoptosis) Mismatch Repair Gene
Mismatch Repair Gene “Spell-checker”

In normal situation , cell usually identifies and

corrects damage to the DNA through an efficient
repair machinery.
ANGIOGENESIS VEGF

• What is it?

• What is its significance in cancer biology?

– Growth (more than 1/10 of an inch)

– Provide the necessary nutrition to tumor cells

– Provide a passageway for metastatic cells

TUMOUR INVASION
Integrins

detachment of localized proteolytic migration of tumour

tumour cells from the degradation of the cells through the
basement membrane basement membrane generated defects

Cadherins

MMPs
CELL ADHESION MOLECULES (CAMs)
Adhesion molecules are responsible for cell stability, and
contribute to their morphology, differentiation, motility and
internal signalling.

Cell-cell Cell
Cell stratification
differentiation

Cell-ECM Cell migration

CELL-CELL INTERACTIONS
CADHERINS

SYNDECANS

IMMUNOGLOBULIN SUPERFAMILY

HYALURONAN RECEPTOR CD44

SELECTINS

INTEGRINS
CELL-EXTRACELLULAR MATRIX
INTERACTIONS
CADHERINS

Cadherins
expressed by
keratinocytes are
E- and P-
cadherins
Decreased expression of E-cadherin is
seen as one of the main molecular
events involved in cell-cell adhesion
system dysfunction, triggering cancer
invasion and metastasis
 Some studies have demonstrated
the reappearance of E-cadherin
expression in metastatic cells

“Cadherin Switch”

Contraction

Adhesion

Re-expression
of E-cadherin

Down-regulation of Release
E-cadherin expression
 INTEGRINS

Integrins are one of the largest families of

cell-adhesion molecules providing
attachment between the cell and the
surrounding ECM. They are transmembrane
proteins that connect the ECM to the cell’s
cortical cytoskeleton and trigger numerous
intra-cellular pathways
 The main integrins expressed by the oral
epithelium are those of the β1 family, along
with α6β4 and αvβ5
(Thomas et al. 1997).
Carcinomas exhibit variable loss of
expression of some integrin.

The expression of the α6β4 integrin is

increased in some tumours such as oral
cancer. Expression of this integrin has
been shown to be
associated with early recurrence and
metastasis.
Matrix Metalloproteinases MMPs
Invasive cells

proteases

breaking down of stroma

Normal epithelium

Basement membrane

stroma
 Epithelial Mesenchymal Transition
As epithelial cells progress through the
process of carcinogenesis, they change
from an epithelial to a mesenchymal
phenotype exhibiting a more motile and
dynamic character. A hallmark of such
transition is the decreased expression
of E-cadherin.
Cellular Changes

• Genetic Alteration

• Alteration in cell-cell interactions

• Alteration in cell-ECM interactions

 Loss of cell adhesion

METASTASIS
Dissolution of the basement membrane

Cytoskeletal rearrangement

Cell migration

Intravasation

Survival in the blood stream

Extravasation at distant site

Growth at distant site + neo-angiogenesis

Multi-step Model of Oral Oncogenesis
It involves the transition from premalignant lesion to the metastatic
tumour phenotype
 It is now generally accepted that most sporadic solid tumors arise
from a multistep process of accumulated genetic alterations.
 Activation of oncogenes and Inactivation of tumour suppressor
genes. Each produce growth advantage of for a clonal population of
cells.

Benign
Hyperplasia
Normal Carcinom Invasive
Dysplasia
Cells a in situ Cancer
Alternate
Precursor
Lesion

Fearon and Vogelstein (1990) Calvino et al. (1996)

Waves of Clonal Expansion

Normal Benign Malignant Metastatic

 The cyclinD1 proto-
The EGFR family gene
oncogen gene locus is
locus is located at 7p13-
located at 11q13.
q22
Abundunt expression was
Gene amplification and over
observed in 36-66% of
expression was observed in
Benign oral cancer
30% of oral cancer
Hyperplasia

3p,7p, 11q,
Normal Carcinoma 6p, 8, 4q Invasive
9p Loss 17p Dysplasia 13q, 14q Loss
Cells Loss Loss in situ Cancer

Alternate
Precursor
Lesion
The p53 tumour suppressor The Rb tumour suppressor
gene locus is located at gene locus is located at
9p is the most common 13q14
17p13
chromosomal abnormality in
HNSCC LOH at locations 13q14 was
Mutations at locations
17p13 was reported in 60% reported in 14-37% of the
The p16 tumour suppressor HNSCC
of the OSCC
gene locus is located at
9p21
The repair genes MSH3 and hMSH6 located at 5q11–13
LOH at locations 9p21-p22
was reported in 72% of the They are proposed to be involved in the aetiology of
HNSCC HNSCCt. Nunn et al. (2003)

Calvino et al. (1996); Nunn et al. (2003); Bettendorf et al. (2004) Tsantoulis et al. (2007)
Common Chromosomal Aberrations In OSCC

Tsantoulis et al. (2007)

Theory of Field Cancerization

This theory was first proposed by slaughter et al.

(1953).

Scientists believe that these genetic changes happens

in wide variety of cells, a heterogeneous “field of
genetically altered cells”.

These cells will proliferate and expand into a non-

proliferative field that is at risk of further genetic
changes.

This field is a fertile ground for future evolution into

malignancy
PREDISPOSING FACTORS
Oncogeni Individual
Environmen
Genetic
tal c Viral Predispositi
Carcinogens infections on

Tobacc
HPV
●
●
o
●
Alcohol
●
EBV
THE LECTURE

Transfer of knowledge
from the Cell to the
Clinic
Existing Treatment of Cancer.

Surgery

Radiotherapy

Chemotherapy
The Ultimate Goal in Cancer Management

• No Cancer.

• Prevent the development of new

premalignant or cancerous lesions.

• Prevent premalignant lesions from

progressing to invasive cancers.

• Treatment of existing cancer.

The Approach

Risk Involves genetic testing to check for the

Assessmen
t presence of an inherited cancer syndrome.

Early Involves identification of early markers

Detection and development of diagnostic tools.

Treatment
 Tumours of familial origin are rare in the head
and neck.
Risk Assessment
HNSCC is strongly associated with environmental
risk factors.

Benign
Hyperplasia

11q,
Normal 9p Loss
3p,17p Carcinoma 6p, 8, 4q Invasive
Loss Dysplasia 13q, 14q
Loss
Cells Loss in situ Cancer

Alternate
Precursor
Lesion

Encoding p16 tumour suppressor gene

the most commonly altered gene in
HNSCC. This support establishment of familial
HNSCC
HNSCC showed nearly 80% somatic
p16 alterations

Also, showed germline mutation within

the p16 gene Sua´rez et al. (2006)
 Features that are suggestive of a
hereditary predisposition to cancer
include the following:

 Multiple family members affected

p16 with the same cancer or related
cancers (such as orther SCC).

 Earlier than average ages of

diagnosis

 Multiple primary cancers in the same

individual

 Cancer occurring in multiple

generations.
 Early markers:
Screening
Early + • Alteration in p53 tumour
Detection
Education suppressor gene
• Tolemerase Enzyme

Benign
Hyperplasia

11q,
Normal 9p Loss
3p,17p Carcinoma 6p, 8, 4q Invasive
Loss Dysplasia 13q, 14q
Loss
Cells Loss in situ Cancer

Alternate
Precursor
Lesion

Encoding p53 tumour suppressor gene

the Gaurdian of the geneome
Treatment

p53 Targeting Tumour Suppressor Gene

EGFR
Gene Targeting Oncogene

VEGF
Gene Targeting Angiogenesis Promoting Gene
 The Future

• Concept of Transforming Malignancies into

Chronic Illness

• Nanobiotechnology