Molecular Basis of Neo

m Kumar, Abbas, Fausto, Mitchell. Robbins Basic Pathology. 7th ed.
2007
m Rubin, Strayer. Rubins pathology-clinicopathological foundation
of medicine. 5th ed. 2008.
m Parmus. Essential clinical pathology.1996
m Porth. Pathophysiology concepts of altered health state. 7th ed.
2005.
m rurrent Molecular roncept of Oral rarcinogenesis and Invasion.
2010 Volume 22 Number 01
m Molecular Biology of Oral ravity Squamous rell rarcinoma.
Otolaryngol rlin N Am 39 (2006) 229²247
m Medelson, Howley, Gray, Israel, Thompson. The molecular basis
of cancer. 3rd ed. 2008.

m ust as cell growth is regulated by growth promoting and
growth inhibiting genes, cell survival is conditioned by
genes that promote and inhibit APOPTOSIS.
m Apoptosis is a pathway of cell death that is induced
by a tightly regulated intracellular program in which
cells destined to die activate enzymes that degrade
the cells' own nuclear DNA and nuclear and
cytoplasmic proteins Kumar, Abbas, Fausto, Mitchell. Robbins Basic Pathology. 7th ed. 2007
5
Kumar, Abbas, Fausto, Mitchell. Robbins ë
Basic Pathology. 7th ed. 2007
Genes regulating apoptosis are altered in cancer and these are:
Br -2 ²
D It is a anti-apoptotic gene. Its mutation results in malignancy.
D For e.g translocation of Br 2 gene from 18q21 to the
immunoglobulin heavy chain locus on 14q32 causes B-cell
lymphomas of the follicular type.
p53 ²
D It increases the transcription of pro-apoptotic gene BAX and

Kumar, Abbas, Fausto, Mitchell. Robbins
BID. Hence mutation of this gene results in decreased apoptosis.
!
SErRET 4- DNA REPAIR DEFErT
m Though humans literally swim in a sea of environmental
carcinogens cancer is relatively rare outcome. This is fortunate
state of affairs results from the ability of normal cells to repair
DNA damage thus preventing mutations.
m a third class of genes in which mutations contribute to
pathogenesis of cancer are genes involved in DNA mismatch
repair., so called mutator genes or caretaker genes.

j0
m Normal versions of DNA repair gene exercise surveillance over
the integrity of genetic information by participating in the
cellular response to DNA damage.
m When a strand of DNA is replicating, mismatch repair genes act
as ´spell checkersµ. E.g if there is an erroneous pairing of G with
T instead of A with T the mismatch repair protein corrects the
defect. Without these proof readers errors slowly accumulate in
several genes.
jj
m rells with such defects in DNA repair are said to have the
replication error phenotype readily documented by examination
of microsatellite sequences in the tumor cell DNA.
m Microsatellites are tandem repeats of one to six nucleotides
scattered throughout the genome.
m Microsatellite instability is hallmark of defective mismatch
repair.

j2
m HPNrr-
m Hereditary Nonpolyposis rolonic cancer also known as ynch
syndrome is a familial predisposition to the development of
colorectal cancer.
m The genes that are mutated in patients with HNPrr have not yet
been completely characterized but include the genes encoding
TGF-B receptor II, the TrF component of the B-catenin
pathway, BAX, and other oncogenes and tumor suppressor genes.

j
m Xeroderma pigmentosum
m It is an autosomal recessive disease in which increased
sensitivity to sunlight is accomplished by a high incidence of skin
cancer, including basal cell carcinoma, Srr, malignant melanoma.
m UV light causes cross-linking of pyrimidine residues, thus
preventing normal DNA replication.

j
m Ataxia Telangiectasia
m A rare hereditary syndrome that features cerebellar
degenration, immunological abnormalities, occulocutaneous
telangiectasia. And predisposition to cancer.
m Gene ATM on 11q22-q23 codes for a nuclear phosphoprotein
that participates in multiple responses to DNA damage.

j5
m Bloom syndrome
m It is an autosomal recessive syndrome.
m rlinical features include small stature, sensitivity to sun,
immunodeficiency, and predisposition to array of cancers.
m BS gene encodes a protein that has helicase activity
involved in repair of DNA damage.

jë
m BRrA-1 & BRrA-2 gene:
m BRrA-1 is located on 17q21 and BRrA-2 is located on 13q12-13.
m Mutation of both the genes causes 80% of familial breast
cancer.

j7
j!
m After a fixed number of divisions, normal cells become arrested in a
terminally nondividing state known as replicative senescence.
m It has been noted that with each cell division there is some
shortening of specialized structures, called telomeres, at the ends
of chromosomes.
m Once the telomeres are shortened beyond a certain point, the loss
of telomere function leads to activation of p53-dependent cellcycle
checkpoints, causing proliferative arrest or apoptosis . thus,

telomere shortening functions as 7th
Basic Pathology. a clock
ed. 2007 that counts cell divisions.
j
m In germ cells, telomere shortening is prevented by the sustained
function of the enzyme telomerase, thus explaining the ability of
these cells to self-replicate extensively. This enzyme is absent from
most somatic cells,
m and hence they suffer progressive loss of telomeres. Introduction
of telomerase into normal human cells causes considerable extension
of their life span

20
m Telomerase activity and maintenance of telomere length are
essential for the maintenance of replicative potential in cancer
cells. Reactivation of telomerase in cells with abnormal genomes
confers an unlimited proliferative capacity to cells that have
tumorigenic potential.

2j
m Tumors stimulate the growth of host blood vessels, a process
called angiogenesis, which is essential for supplying nutrients to
the tumor. Even with genetic abnormalities that dysregulate
growth and survival of individual cells, tumors cannot enlarge
beyond 1-2 mm diameter or thickness unless they are
vascularized. Presumably the 1- to 2-mm zone represents the
maximal distance across which oxygen and nutrients can diffuse
from blood vessels.

22

Ú
m Beyond this size, the tumor fails to enlarge without
vascularisation because of hypoxia-induced cell death
m Tumor angiogenesis can occur by recruitment of endothelial cell
precursors or by sprouting of existing capillaries, as in
physiologic angiogenesis.
25

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á

á!

á

m However, tumor blood vessels differ from the normal
vasculature by being tortuous and irregularly shape and by being
leaky. The leakiness is attributed largely to the increased
production of VEGF." In contrast to normal mature vessels,
which are quiescent structures, tumor vessels may grow
continuously

2
m Tumor growth is controlled by a balance between angiogenic and
anti-angiogenic factors.
m The important angiogenic factors are VEGF and bFGF.
m The anti-angiogenic factors are thrombospondin-1, angiostatin,
endostatin and tumstatin

j
m Invasion and metastasis are biologic hallmarks of malignant
tumors. They are the major cause of cancer-related morbidity
and mortality and hence are the subjects of intense scrutiny.
m The metastatic cascade will be divided into two phases:
m (1) invasion of the extracellular matrix and
m (2) vascular dissemination and homing of tumor cells.

2
m Invasion ofthe ErM is an active process that can be resolved
into several steps
m X Detachment ("loosening up") of the tumor cells from each
other
m X Attachment to matrix components
m X Degradation of ErM
m X Migration of tumor cells

m Vascular Dissemination and Homing of Tumor rells
D Once in the circulation, tumor cells are particularly vulnerable to
destruction by innate and adaptive immune defenses.
D Within the circulation, tumor cells tend to aggregate in clumps.
This is favoured by homotypic adhesions among tumor cells as
well as heterotypic adhesion between tumor cells and blood cells,
particularly platelets.
D Formation of platelet²tumor aggregates may enhance tumor cell

survival and implantability.

m Arrest and extravasation of tumor emboli at distant sites
involve adhesion to the endothelium, followed by egress through
the basement membrane.
m The site at which circulating tumor cells leave the capillaries to
form secondary deposits is related, in part, to the anatomic
location of the primary tumor.
m rhemokines have a very important role in determining the target
tissues for metastasis

5
m Microenvironment of cancer plays a critical role in
determining its development.
m Supportive tissues (stroma) of cancer actively

collaborate with cancer cells.
m romposition of the stroma

- fibroblast
- myofibroblast
- inflammatory white blood cells
- endothelial cells of blood and
lymphatic vessels
m rancer cells and stromal cells evolve together.

ë http://www.lbl.gov/LBL-Programs/lifesciences/BissellLab/main.html
m Prior to the middle of the twentieth century, before DNA was
given a special status in biology, the developmental biologist and
evolutionist ronrad H. Waddington (1905-1975) emphasized that
genetics and developmental biology were related, hypothesizing
that patterns of gene expression, turning genes on and off, and
not the genes themselves, define each cell type, thus linking
genes and gene action to development.

m Waddington coined the term ¶epigenetics· from the Greek word
epigenesis, referring to embryology and genetics as ´a gradual
coming into being of newly formed organs and tissues out of an
initially undifferentiated massµ.
m Epigenetic changes set the stage for alterations in gene
expression and have been identified as important components of
carcinogenesis.
m It has become evident during the past few years that certain
tumor suppressor genes may be inactivated not because of
structural changes but because the gene is silenced by
hypermethylation of promoter sequences without a change in
DNA base sequence· .
m Methylation also participates in the phenomenon called genomic
imprinting, in which the maternal or paternal allele of a gene or
chromosome is modified by methylation and is inactivated.

m Some oral cancer patients develop Srr over a broad area
of the oral mucosa, with multiple lesions arising
simultaneously or over a period of time
m The mechanisms of ¶field cancerization are unkown ,
although three basic hypotheses were proposed recently
by Ogden

D !
m Firstly, ¶field changes· (molecular changes throughout the
oral mucosa of oral cancer patients) may predispose to
the development of multiple primary cancers.
m In this scenario, a large region of the oral mucosa may be
exposed to the etiological agent(s) which causes
independent transformation of multiple epithelial cells at
separate sites.

D !
m Different etiological agent
A single etiological agentsacting
acting at
at different
different sites
sites would
cause
cause multiple
multiple separate
separate cancers
cancers with
with different
identical genetic
defects,
defects, each
each arising
arising as
as aa separate clone within the oral
mucosa.
mucosa.
m Subsequent genetic modification (due to spontaneous
mutation or continued exposure to exogenous mutagens) may
render the separate clones genetically distinct.

D !
m Secondly, the etiological agent(s) may transform a single oral
epithelial cell.
m The expanding clone of cancer cells may spread through the
oral mucosa via local tissue spread, regional blood vessels,
seeding via the saliva into a mucosal erosion or seeding due to
the trauma of surgery.
m This would give rise to geographically distinct but genetically
identical cancers.

D !
m The clinical significance of p53 mutation within the normal oral
epithelium of oral cancer patients is unclear.
m Some reports suggest an association with the development of second
primary cancers while others find no such association.
m Recent molecular studies have shown that oral cancer is a clonal
proliferation of neoplastic keratinocytes (that is, oral cancers arise
from a single genetically altered cell) and that multiple primary tumours
result from the migration of clonally-related pre-neoplastic cells
through the oral epithelium

D !
m Thirdly, a tumor may have a paracrine effect on the adjacent
oral mucosa. Of great recent interest is that tumors have been
found to secrete tumor inhibitory factors including inhibitors of
neovascularization.
m Removal of the primary tumor would remove these inhibitors of
cancer development and hence promote second primary tumor
formation.

D !
m Alternatively, tumors may secrete promoters of apoptosis.
m Removal of the primary tumors would reduce the level of
apoptosis in adjacent tissue and hence promote second primary
tumor formation.

D
!
m The advent of technology and high-throughput analytical tools has
facilitated the dissection of the genetic pathways that govern
tumor biology. One such analytical tool is genomics.
m Genomic is the study of the patterns of gene expression in a
cellular system, which generally refers to the field of biology that
seeks to understand biologic processes from a global view,
evaluating all the transcriptional activity of a particular system
under certain conditions.

"
# $ % & ' %
m Its counterpart, proteomics, is the evaluation of the entire
network of proteins that contribute to cellular function.
m These two complementary fields brought tremendous advances
in the understanding of tumor biology, primarily by allowing
scientists to study the changes that occur in thousands of
genes or proteins in a single experiment.
"

# $ % & ' %
m One particular tool, which has identified genomic signatures of
lymphatic metastasis for OrSrr and may allow the early
detection of occult metastases in selected patients.
m The clinical usefulness of these technologies is currently under
evaluation in other tumor systems

m Gene therapy is a technique for correcting defective genes
which are responsible for genetic abnormalities and diseases.
The idea of gene transfer for treating human diseases was put
forward by rUSArK and TARNER in 1998. The idea envisages
the transfer of a therapeutic gene into cancer cells via a vector.
These processes delete the mutant alleles· and are replaced by
the therapeutic or functional gene.
Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol j No 2 Jul- Dec 20j0 50
m More specific
strategies based on
genetic instability of
cancer cells.
m More specific delivery

of anticancer drugs
using monoclonal
antibodies.
m Development of
specific small
molecules.
5j
m rancer treatment by targeting angiogenesis.
m rancer treatment by inducing immune responses.
m rocktail approaches to suppress drug resistance.
m Genomic profiling makes specific treatment

strategies possible.
m No magic solution. Still a long way to go«
52

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m Kumar, Abbas, Fausto, Mitchell. Robbins Basic Pathology. 7th ed.

m Rubin, Strayer. Rubins pathology-clinicopathological foundation

of medicine. 5th ed. 2008.

m Parmus. Essential clinical pathology.1996

m Porth. Pathophysiology concepts of altered health state. 7th ed.

2010 Volume 22 Number 01

m Molecular Biology of Oral ravity Squamous rell rarcinoma.

Otolaryngol rlin N Am 39 (2006) 229²247

m Medelson, Howley, Gray, Israel, Thompson. The molecular basis

of cancer. 3rd ed. 2008.

growth inhibiting genes, cell survival is conditioned by

genes that promote and inhibit APOPTOSIS.

m Apoptosis is a pathway of cell death that is induced

by a tightly regulated intracellular program in which

cells destined to die activate enzymes that degrade

the cells' own nuclear DNA and nuclear and

D It is a anti-apoptotic gene. Its mutation results in malignancy.

D For e.g translocation of Br 2 gene from 18q21 to the

immunoglobulin heavy chain locus on 14q32 causes B-cell

lymphomas of the follicular type.

D It increases the transcription of pro-apoptotic gene BAX and

m Though humans literally swim in a sea of environmental

carcinogens cancer is relatively rare outcome. This is fortunate

state of affairs results from the ability of normal cells to repair

DNA damage thus preventing mutations.

m a third class of genes in which mutations contribute to

pathogenesis of cancer are genes involved in DNA mismatch

repair., so called mutator genes or caretaker genes.

Kumar, Abbas, Fausto, Mitchell. Robbins

the integrity of genetic information by participating in the

cellular response to DNA damage.

m When a strand of DNA is replicating, mismatch repair genes act

as ´spell checkersµ. E.g if there is an erroneous pairing of G with

T instead of A with T the mismatch repair protein corrects the

defect. Without these proof readers errors slowly accumulate in

replication error phenotype readily documented by examination

of microsatellite sequences in the tumor cell DNA.

m Microsatellites are tandem repeats of one to six nucleotides

scattered throughout the genome.

m Microsatellite instability is hallmark of defective mismatch

Kumar, Abbas, Fausto, Mitchell. Robbins

m Hereditary Nonpolyposis rolonic cancer also known as ynch

syndrome is a familial predisposition to the development of

been completely characterized but include the genes encoding

TGF-B receptor II, the TrF component of the B-catenin

pathway, BAX, and other oncogenes and tumor suppressor genes.

m It is an autosomal recessive disease in which increased

sensitivity to sunlight is accomplished by a high incidence of skin

cancer, including basal cell carcinoma, Srr, malignant melanoma.

m UV light causes cross-linking of pyrimidine residues, thus

preventing normal DNA replication.

Kumar, Abbas, Fausto, Mitchell. Robbins

m A rare hereditary syndrome that features cerebellar

degenration, immunological abnormalities, occulocutaneous

telangiectasia. And predisposition to cancer.

m Gene ATM on 11q22-q23 codes for a nuclear phosphoprotein

that participates in multiple responses to DNA damage.

Kumar, Abbas, Fausto, Mitchell. Robbins

m It is an autosomal recessive syndrome.

m rlinical features include small stature, sensitivity to sun,

immunodeficiency, and predisposition to array of cancers.

m BS gene encodes a protein that has helicase activity

involved in repair of DNA damage.