carcinogenesis of oral caner

2. Early History
of Cancer

3.  The earliest written record
generally regarded as describing
human cancer appeared in ancient
Egyptian.
 Edwin Smith papyri that describe
surgical operation.
 The Smith papyrus, possibly written
by Imhotep the physician-architect
who designed and built the step
pyramid at Sakkara in the 30th
century BC under Pharaoh Djoser, is
believed to contain the first reference
to breast cancer.

4. Incidence Of Cancer
• Cancer is the second leading cause of
death globally.
• Head and neck cancer (HNC)
constitutes a heterogeneous group of
cancers at the upper aerodigestive with
an annual incidence of 600.000 cases,
and 380,000 deaths each year
• HNC is the 6th most common
malignancy and responsible for 1-2%
of all cancer deaths worldwide

5. ** Tobacco in all form
5- to 25-fold increased risk of developing HNC when
compared to nonsmokers
** Alcohol:
Dose and time dependent.
Alcohol in combination with tobacco is a significant risk
factor.
1. Alcoholic cirrhosis “decrease detoxification of
carcinogens of tobacco”.
2. Increase permeability of oral mucosa to harmful effect
of tobacco.
** Phenolic agents:
Workers in wood products industry and those exposed
to chemicals as phenolic acid.
Etiology : Extrinsic factors

6. ** Premalignant lesion
** Radiation:
** Iron deficiency:
In chronic plummer-vinson syndrome.
Iron deficiency cause rapid epithelial cell turn
over causing atrophic mucosa which is subjected
to malignant transformation.
** Syphilis:
Tertiary stage of syphilis is associated with
dorsal tongue carcinoma.
** Arsenic agents and heavy metals used in
treatment have carcinogenic properties..

7. ** Candida infection:
Some strains of candida albicans produce
hyperkeratotic lesions on the dorsal surface of
the tongue.
They produce nitrosamine chemicals
** Oncogenic viruses :
1. human papilloma virus (HPVs) subtype 16, 18
are implicated in carcinoma of the pharynx,
larynx and esophagus.
2. EBV cause burkitts lymphoma and
nasopharyngeal carcinoma.
3. HHV type 8 causes Kaposi sarcoma.

8. ** Immunosuppression:
Patients with AIDS or under immunosuppressive
therapy are at risk of oral squamous cell carcinoma.
** Hereditary diseases:
Cancer is not a hereditary disease but some
hereditary syndromes increase susceptibility to oral
cancer as: Dyskeratosis congenita
** Age
** Gender
Intrinsic Factors

9. In normal conditions, various tightly controlled excitatory
and inhibitory pathways regulate cell biological activities such as
cell division, differentiation, and cell death (apoptosis).
An extracellular ligand like growth factor (a protein) binds with a
specific cell surface receptor. The receptor-ligand complex
generates excitatory or inhibitory signals sent through intracellular
and nuclear messengers that can alter cell biological activities.

10. Stages of Cell Signaling
Cell signaling can be divided into 3 stages.
1. Reception: the signal is detected when the chemical molecule
(ligand) binds to a receptor protein on the surface of the cell.
2. Transduction: when the ligand binds to receptor it changes the
receptor protein in some way. This change initiates the process of
transduction.
Signal transduction is usually a pathway of several steps. Each
molecule in the signal transduction pathway changes the next
molecule in the pathway.
3. Response: Finally, the signal triggers a specific cellular response

11.  Cancer is a genetic disease—that is caused
by certain alterations to genes that control
cells function, especially how they grow and
divide.
 Genes carry the instructions to
make proteins, which do much of the
activities in the cells.
 Mutation is permanent change/damage
within DNA in such a way as to alter the
genetic
message carried by the gene that passes to
daughter cells with each division.
 Accumulation of mutations give rise to a set

13. GENES PLAYING CRITICAL ROLE IN
CANCER DEVELOPMENT
Oncogenes
Genes that regulate programmed cell
death (apoptosis)
Tumor suppressor genes
DNA repair genes

14. Oncogenes
Proto-oncogenes - They are normal cellular
counterparts; genes in normal cells which
encode proteins that have normal function in cell
proliferation, division and differentiation.
Oncogenes : are defined as “altered growth-
promoting regulatory genes, that promote
autonomous cell growth in cancer cells.
Oncogenes are characterized by the ability to
promote cell growth in the absence of normal
mitogenic.

15. Proto-oncogenes can be activated by:
 Point mutations: single base pair substitution that causes single
A.A substitution in protein the gene becomes constitutively active
ex Ras
 Chromosome translocation a cross-recombination of
chromosomes occurs during replication. Ex bcr-abl
 Gene amplification when a gene has increased copy number, it.
overproduction of normal genes ex. c-myc

16. Tumor suppressor genes:
Normal function - inhibit cell proliferation
Mutation leads to absence/inactivation of inhibitor -->
cancer
Both gene copies must be defective to promote cancer
formation
The most important members of the group are the
retinoblastoma (Rb) and p53 genes.

17. Carcinogenesis is an complicated multi-step process initiated by
abnormal oncogenic signals in different signaling pathways. It
develops over many years, and during this period, there may be
multiple steps of neoplastic transformation.
The histologic progression from hyperplasia to dysplasia,
followed by severe dysplasia and eventual invasion and
metastases, are believed to reflect the accumulation of genetic
mutations.
It includes initiation, promotion, and malignant progression

18. Multiple steps of neoplastic transformation.
1. Initiation: gene mutation initiated in a cell due to exposure to any
carcinogen.
2. Promotion: accumulation of actively proliferating preneoplastic cells that
carry the same initial mutation(N.B: this stage is
lengthy & reversible).
3. Progression: development of additional multiple genetic mutations
in different cells, forming sub-clones with different characteristics

19. Compared with normal cells,
cancerous cells display a range
of ‘hallmarks’ which have
described in the year 2000, by
Hanahan and Weinberg.

20. Compared with normal cells, cancerous cells
display a range of ‘hallmarks’ which have
described in the year 2000, by
Hanahan and Weinberg.

22. Cancer Hallmarks
 Self-sufficiency in growth signals, implying the ability
of tumor cells to grow in the absence of the signals
that allow them to grow.
 Insensitivity to anti-growth signals, i.e., they resist the
signals to stop growth.
 Evading apoptosis, i.e., they resist their programmed
death
 Limitless replicative potential, so that they can
multiply indefinitely.
 Sustained angiogenesis, i.e., they stimulate the blood
vessel growth in order to supply nutrients to the
tumor cells
 Tissue invasion and metastases, i.e., they invade
surrounding tissues and spread to distant sites.

23. In 2011 Hanahan and Weinberg
 four additional hallmarks:
 Abnormal metabolic pathways
 Evading the immune system
 Genome instability
 Inflammation

25. Self-sufficiency in growth signals
Healthy cells undergo a regulate growth signals.
Cancer cells are characterized by autonomous, chaotic
growth because of deregulated growth signals.
Cancer cells acquire growth autonomy by mutations in
genes that encode various components of the signals.
Component of cell
signals
1. Ligands (Growth factors)
2. Receptors
3. 2 nd messengers
4. Transcription factors

26. Growth Factors
A growth factor is a naturally substance capable of stimulating cell
proliferation, wound healing, and cellular differentiation.
Ex.: Epidermal Growth Factor (EGF) and Transforming Growth Factor
α (TGF-α) • These two factors belong to the EGF family and share a
common receptor (EGFR).

28.  Cancer cell produce growth factor ligands themselves, to
which they can respond via the expression of cognate
receptors, resulting in autocrine proliferative stimulation
 Autocrine loop is type of interaction between growth factors,
cytokines and target cells, in which a cell produces the same
growth factors and cytokines for which it has receptors,
allowing the cell to stimulate itself

29. Growth Factor Receptor
 They are transmembrane proteins which bind to specific growth
factors and transmit the instructions conveyed by the factors to
intracellular.
 In cancer cells mutations of genes encoding cell surface receptors
Mutations of genes encoding cell-
surface receptors
Increase the
number of
receptors
Production of a
ligand-
independent
mitogenic signal
Hyper
responsive to
otherwise-
limiting amounts
of growth factor
ligand.
increased number of
receptors
production of a ligand-
independent mitogenic
signal.
hyper responsive to
otherwise-limiting amounts
of growth factor ligand.

30. Intracellular Signal Transduction
Pathways (2 Nd Messengers)
 The process by which
extracellular signals are
converted into intracellular
signals which reach the nucleus
and produce cellular responses.
 Cancer cells have mutations in
genes that encode the signaling
downstream pathways.
 Several oncogenes are known
to act on these pathways.
 The RAS proto-oncogenes
(HRAS, KRAS, and NRAS)
control signaling pathways that
are key regulators of several
aspects of normal cell growth
and malignant transformation,
including MAPK and PI3K,

31.  RAS family members are frequently found in their mutated,
oncogenic forms in human tumors. Activating mutations in the
RAS genes occur in approximately 20% of all human cancer
 Ras is in an inactive GDP (Guanosine di phosphate) changes to the
active GTP (guanosine tri phosphate) by linked to GEF and return
to an inactive form by GTPase. Instead of this mutated Ras don’t
have this mechanism and always exit in active form
 Mutated RAS continuously send activating signals to the nucleus,
stimulating cell proliferation

32. Transcription factors
 Transcription factor is a protein that binds to specific DNA
sequences, thereby controlling the rate of transcription of genetic
information from DNA to messenger RNA
 In tumor cells a transcription factor can be mutated and activated
independent of extracellular or cytoplasmic signals.
 NFkB is a transcription factor that regulates expression of several
genes and was activated in a series of tumors such as breast
tumors, pancreatic adenocarcinomas,
 Overexpression of c-myc has been involved in a series of human
tumors including colon, stomach, cervix, breast and hematological
neoplasm.

33. Insensitivity to growth-inhibitory
signals (Evading Growth
Suppressors)
 Cancer cells circumvent powerful programs that negatively
regulate cell proliferation; many of these programs depend
on the actions of tumor suppressor genes.
 The cell undergoes through a tightly controlled sequence of
events known as the cell cycle.
 The cell cycle consists four stages of G1 (presynthetic), S
(DNA synthesis), G2 (premitotic), and M (mitotic) phases.
 G1 (presynthetic): is the gap between M and S. Cell growth
is one of the important events of G1.
 The transition from G1 to S is the critical control point in the
cell cycle.
 S (DNA synthesis): during this phase DNA replication
occurs
 G2 is the gap between S and M, and provides time for
checking to ensure that DNA is properly replicated and
packaged prior to the cell division

34.  M phase : DNA packaging, chromosome segregation and
cell division
 Quiescent cells that have not entered the cell cycle are in the
G0 state.
 The G1 , S and G2 phases comprise interphase, which
accounts for most of the time in each cell cycle. •
 The M phase, mitosis, is relatively short (approximately 1
hour of a 24 hour cell cycle). •
 Mitosis is itself divided into several phases, i.e, prophase,
metaphase, telophase and anaphase.
 Checkpoints
 The G_1 checkpoint at the G1/S transition
 The G2 checkpoint at the G2/M transition.
 The spindle checkpoint, at the transition from metaphase
to anaphase.

36. Tumor suppressor genes
 Dozens of tumor suppressors that operate in
various ways to control cell cycle, limit cell growth
and proliferation

37. p53 gene
 p53 is the most important TSG and has been called the
‘Guardian of the Genome’
 It is located in chromosome 17p13
 p53 has a role in maintaining genome stability, an important
role in cell cycle, DNA repair and apoptosis.

38.  p53 is known to be mutated in approximately 70% of
oral tumors
 p53 gene can be inactivated by several mechanisms,
including point mutations, deletion, and binding with
cellular and viral proteins (E6 of HPV).
 Homozygous loss of the P53 gene (Both alleles are
non-functioning), DNA damage goes unrepaired →
mutations become fixed in dividing cells → the cell
turns onto a one-way street leading to malignant
transformation.

39. TP53
p21
&27
GAD
D
BAX
&
puma

41. Retinoblastoma protein (pRb)
** It is called the master tumor suppressor or( Govern the cell cycle)
Direct regulator of the cell division
** It play as a regulator of the G1/S transition and G2/M phases of the cell
cycle
** Rb protein binds regulatory transcription factor E2F.
E2F required for synthesis of replication enzymes
E2F + Rb bound = no transcription/replication
** Rb phosphorylation by CDK4–cyclin D and CDK2–cyclin E lead to
inactivation of Rb and induces S-phase entry

42.  Mutated Rb din not
bind to E2F
 Sequestration by viral
oncoprotein (E7 in
HVP)
 HPV especially 16 &
18) → produces
oncoprotein (E7) which
binds to RB gene,
stopping its function
which causes
uncontrolled cell
proliferation

45. CDK and cyclins control the cell cycle
**CDK are expressed continuously throughout the cell cycle
but in an inactive form
**Cyclins bind to CDK at specific periods and activate the CDK
**Cyclin/CDK complex lead to phosphorylate pRb protein thus it
releases E2F transcription factor.

47. E2F is bound to pRb E2F is
free
N.B. E2F enhances transcription of S

48. Inhibitors of cell cycle
p15 p16 p18 p19 inhibit CDK 4 & 6 called INK4
P21 p27 p 57 inhibit CDK broadly

50. Development of sustained
angiogenesis
 In normal tissues, the development of new blood
vessels is highly regulated by both positive and negative
signals.
 Tumors can’t enlarge beyond 1 to 2 mm unless they’re
vascularized.
 Tumor cells promote angiogenesis by upregulating the
pathways that promote blood vessel formation (e.g.,
increased expression of growth factors such as vascular
endothelial and fibroblast growth factors(VEGF) (FGF)
and reducing the activity of inhibitory pathways.
 As tumor grows, hypoxia occurs in some of its cells →
which stimulates secretion of the very potent angiogenic
factor: VEGF by tumor cells or stromal cells →
formation of new blood vessels → enhanced tumor

51.  Proteases and ECM are involved in promote
angiogenesis

53. Limitless replicative potential (Enabling
reproductive immortality)
 Most normal human cells have a capacity of 60-70 doubling, after
that the cells become arrested in a terminally non dividing state,
known as replicative senescence.
 Telomeres are short repeated sequences of DNA present at the
ends of linear chromosomes” (TTAGGG – repeated over and over
again, hundreds or even thousands of times).
 Telomeres act as caps that protect the internal regions of the
chromosomes, and they're worn down a small amount in each
round of DNA replication.

54.  Once the telomeres have degraded, the cell commits apoptosis,
repairs itself, or ceases to continue division, entering a G0-like state
called senescence
 This process, regulated by the p53 gene serves to protect the DNA
from accumulating too much damage.

55. Cancer cells bypass the replicative
senescence by
Overexpressing telomerase. Telomerase is an
RNA-dependent
DNA polymerase,
meaning an
enzyme that can
make DNA using
RNA as a
template.
 So that
maintaining
telomere length,
which protects the
ends of
chromosomes and
allows the cell to
continue
proliferating.

56. Evading Apoptosis
 Apoptosis is the programmed cell death that normally occurs
when a cell is damaged
 All cancer cells have the ability to evade apoptosis by
interfering with intrinsic and extrinsic signal pathways.
 This is important because it is a key part of what allows
cancer cells to grow and divide uncontrollably.
 Disabling death receptors
 P53 mutation
 Increasing expression of anti-apoptotic genes,
 Reducing expression of pro-apoptotic genes.
 Mutation in FAS gene which code for death receptor
 Caspase 8 is inhibited
 Decoy receptors for cell death signals
 Inhibition of pro apoptotic proteins
 Reducing cytochrome c

58. Consequently, carcinogenesis
has various changes:

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