Cancer is caused by defects in cell division that result from genetic mutations. Normal cell growth becomes unregulated, as cells multiply uncontrollably and crowd out healthy tissue. If cancer cells invade surrounding areas or spread to other parts of the body through metastasis and angiogenesis, it is considered malignant. Staging and grading of tumors helps determine prognosis and appropriate treatment options like surgery, radiation, chemotherapy, or targeted therapies.

1. Overview of cancer

2. Point to be covered
1. Overview of cancer
2. Types and reason of cancer
3. Basic idea about progression of tumor
4. Cell division
5. Cell division regulation
6. Genetic instability
7. Mutation
8. Invasion
9. Angiogenesis
10. Metastasis
11. Grading and staging
12. Treatment

3. Cancer
• Cancer is a large group of diseases characterized by
uncontrolled growth and spread of abnormal cells
• Cancer cells:
– Lose control over growth and multiplication
– Do not self-destruct when they become worn out or
damaged
– Crowd out healthy cells

4. Cancer
• Cancer cells reproduce every 2-6
weeks
• Size of cancer cells:
One million cancer cells = head
of a pin
One billion cancer cells = a small
grape
• Five-year survival rate (starting
from the time of diagnosis)
2-6 weeks
2-6 weeks
2-6 weeks

5. Carcinogens
• Ionising radiation – X Rays, UV light
• Chemicals – tar from cigarettes
• Virus infection – papilloma virus can be responsible
for cervical cancer.
• Hereditary predisposition – Some families are more
susceptible LLiiffeessttyyllee
to getting certain cancers. Remember you
can’t inherit cancer its just that you maybe more
susceptible to getting it.
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HHiissttoorryy

6. Types Cancers
– Carcinoma: epithelial cells
– Adenocarcinoma: glandular tissue
– Sarcoma: connective tissue
– Lymphoma: lymph tissue
– Leukemia: blood forming tissue (marrow)
– Gliomas: cancer of brain glial cells
Carcinomas (cells that
cover internal and external
body surfaces)
Lung
Breast
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((MMeenn))
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Cells in supportive
tissues – bones &
muscles

7. Proliferation and differentiation
• Increase in the cell
number with exact
passages of genetic
information to their
daughter cells
• Different kinds of cells with
the specialized morphology,
metabolism and
physiological functions from
the cells of the same origin.

8. Hypertrophy, hyperplasia, Dysplasia vs Neoplasia

9. Tumor invasion of the basement membrane
• Benign lesion characterized by the continuous
basement membrane, that separate neoplastic
epithelium from the stroma
• Malignant tumor have loss of basement membrane
around tumor cell in stromal compartment

10. Benign and Malignant Tumors

11. Normal cell
Acquired DNA
Successful DNA repair
damaging agent
i.e. chemical,
radiation, virus DNA damage
mutation i.e. genes
Failure of DNA Repair
Mutation in somatic cells
Inactivation of tumor
suppressor gene
Activation of proto-oncogene
affecting DNA repair
and apoptosis
pathway
Alteration of apoptosis
gene
Unregulated proliferation Decreased apoptosis
Clonal expansion
Tumor progression
Malignant neoplasm
Invasion Metastasis
•Angiogenesis
•Escape from immunity Additional mutation

12. Phases of the cell cycle
Cell cycle have two phase
(1) S phase (Non-division phase)
(2) Division phase (Division phase)
Gap phase
•G1 devoted for metabolic activity for
cell growth and preparation for DNA
replication
•G2 preparation for mitotic cell
division takes place

13. Cell Cycle check points
Check Point
Check Point
Checks DNA damage
Before final commitment for replication:
defect can be repaired as chromatids are still
together
G1 arrest
Checks integrity of DNA
Check completion of DNA replication.
Are they ready for mitosis
G2 arrest

14. Control of the Cell Cycle
The passage of a cell through the cell cycle
is controlled by proteins in the cytoplasm.
These protein are:
• Cdks (Cyclin-dependent kinases)
• Cyclins
• CKIs(Cyclin dependent kinase inhibitor )

15. Complete regulation of cell cycle

16. CDK ( Cyclin dependent kinase) &Cyclins
• CDK contain two parts, an enzyme
(kinase) and a modifying protein
(Cyclin)
• Kinases are regulatory enzymes that
catalyze the addition of phosphate
groups to protein substrates
• Cyclins synthesize and degenerate at
each cycle, work as docking site for
substrate
• Cdk4 and Cdk6 regulate entry into
cell cycle
• Cdk1 and Cdk2 operate primarily in
M phase and S phase

17. CDK ( Cyclin dependent kinase) &Cyclins
• CDKI have capability of sensing problems
• Kip family: P21waf1/cip1, P27kip1 ,P57kip2
• Ink4 family: P16Ink4a,P15Ink4b,P18Ink4c,P19Ink4d
• INK4 proteins binds to CDK 4 & 6
• Cip –Kip proteins binds to CDK 1 & 2

18. Cyclins and CDKs
Kinase
complex
Vertebrate Yeast
Cyclin CDK Cyclin CDK
G1-CDK Cyclin D* CDK4 、6 Cln 3 CDK1(CDC28)
G1/S-CDK Cyclin E CDK2 Cln 1、
2
CDK1(CDC28)
S-CDK Cyclin A CDK2 Clb 5、
6
CDK1(CDC28)
M-CDK Cyclin B CDK1(CDC2
)
Clb 1-4 CDK1(CDC28)

19. Complete regulation of cell cycle

20. Tumor as result
• Overexpression of cyclins
• Overexpression of Cdks
• Deactivation of CkIs
• Abnormity of checkpoints

21. Normal cell
Acquired DNA
Successful DNA repair
damaging agent
i.e. chemical,
radiation, virus DNA damage
mutation i.e. genes
Failure of DNA Repair
Mutation in somatic cells
Inactivation of tumor
suppressor gene
Activation of proto-oncogene
affecting DNA repair
and apoptosis
pathway
Alteration of apoptosis
gene
Unregulated proliferation Decreased apoptosis
Clonal expansion
Tumor progression
Malignant neoplasm
Invasion Metastasis
•Angiogenesis
•Escape from immunity Additional mutation

22. Signs for Genomic Changes in Cancer
• Changes in chromosome numbers
• Aneuploidy
• Chromosomal changes
- Increase in DNA copy number
- Loss in chromosome
• Hypermethylation at promoter region is a common mechanism
by which tumor suppressor loci are epigenetically silenced in
cancer cells (aberrant gene transcription)

23. LOH (Loss of heterozygosity)
• LOH termed as pre-tumor cells are heterozygous for tumor suppressor gene,
alleles of genetic marker surround the gene
•Tumor cell will loss the normal tumor suppressor allele & surrounding markers
too
Pre-tumor cell Tumor cell
Inherited Rb Second hit
A
Rb Rb Rb
b
a
B
A
b

24. Telomere and telomerase
•Telomer
Telomer 6 nucleotide sequence at end of
chromosome to avoid the chromosomal end
to end fusion
•Telomerase (RNA containing enzyme)
Facilitate replication of telomer
•Mitotic clock
Normally telomer loss at each cell division,
serve as cellular mitotic clock to limit no. of
cell division and cellular life span
•Cellular crisis
In extended cell division, loss of capping
resulting into chromosomal instability which
leads to loss of cell viability and
proliferation capacity
Telomerase activity is detected in 80% to 90% most common
cancer

25. What are the genes responsible for tumorigenic
Normal cell growth?
+
-
Proto-oncogenes Cell growth
Cancer
and
Tumor suppressor genes proliferation
Mutated or “activated”
oncogenes Malignant
transformation
Loss or mutation of
Tumor suppressor genes
++

26. List of proto-Oncogene

27. List of tumor suppressor gene

28. Mutation leads to Oncogene
Each proto-oncogene is composed of 2
region:
• Structural region (SR) encodes AA
• Regulatory region (RR) modulate
expression as per stimuli
Change in either SR or RR create active
onco-gene
Regulatory region leads to inappropriate
level of growth inducing protein
Structural mutation leads change in
structure & function of protein
Proto-oncogene
oncogene

29. Ras is GTP binding protein act as digital
switch
Ras regulate cell growth
– Play a role in mitogenesis by 2
mechanism
• Nucleotide exchange (GDP by
GTP)
• GTP hydrolysis ( convert active
Ras to inactive Ras)
Mutated Ras:
Trapped in permanently active state due
to loss of GTP hydrolysis through
GAP binding
• Leads to continuous activation of
MAP kinase signaling

30. p53 maintain integrity of Genome
• P53 mutation is common in >50% human cancer
• Normal p53 maintain the genomic integrity via
• Response to DNA damage (cell cycle arrest) via P21 CDK
inhibitor
• Inducing apoptosis
• Disruption/deletion of p53 gene
• Uncorrected DNA damage
• Uncontrolled cell proliferation via decreased apoptosis

31. Loss of normal Apoptosis pathway
• Inactivation of p53, leads increase in BCl-2: causes
enhanced cell survival and genetic instability and
clonal suspension and diversification of tumor
without activation of death pathway

32. Normal cell
Acquired DNA
Successful DNA repair
damaging agent
i.e. chemical,
radiation, virus DNA damage
mutation i.e. genes
Failure of DNA Repair
Mutation in somatic cells
Inactivation of tumor
suppressor gene
Activation of proto-oncogene
affecting DNA repair
and apoptosis
pathway
Alteration of apoptosis
gene
Unregulated proliferation Decreased apoptosis
Clonal expansion
Tumor progression
Malignant neoplasm
Invasion Metastasis
•Angiogenesis
•Escape from immunity Additional mutation

33. Invasion and Metastasis
• Abnormal cells proliferate and
spread (metastasize) to other
parts of the body
• Invasion - direct migration and
penetration into neighboring
tissues
• Metastasis - cancer cells
penetrate into lymphatic
system and blood vessels

34. Cell migration via cell –cell intraction
•Majority of cancer occur in
epithelial cells, normally
maintenance of cell- cell contact
maintained by (TJ & AJ) Junction,
which maintains by cadherin
•Any disruption to cadherin to
catenin results in loss of cell
adhesion(Cadherin, integrins,
Immunoglobulin and CD-44)
•E-cadherin also considered as
metastatic suppressor

35. Cell- ECM (Extra cellular matrix)
interaction
ECM provides not only scaffolding
for the cellular constituents & also
initiates tissue morphogenesis,
differentiation and homeostasis
The ECM is composed of two main
classes
Macromolecules: Proteoglycans
Fibrous proteins i.e collagens,
elastins, fibronectins and laminins
Cell –ECM interaction mediated by
integrins receptor present on tumor
cell

36. Loss of cadherin
•Reduces the cells to adhere each other
•Facilitate cell detachment from tumor
•Advancing into surrounding tissue
Attached to the ECM component
•Laminin of ECM bind to integrins of tumor
• Activate the protease of tumor cell (MMPs)
•MMPs degrades the iv collagen and release
VEGF as angiogenic stimuli
•MMP release activate the GF (PDGF, TGF) of ECM
affect the growth of tumor
•Degradation of ECM creates the passage of
invasion & signal for angiogenesis
Tumor progression

37. Angiogenesis is a normal and necessary
process
Angiogenesis is pivotal in:-
•Tissue growth and development
•Plays role in normal physiology
•Wound healing,
•Female reproductive cycle
•Inflammation and embryogenesis

38. Angiogenesis-Pathological Disorders

39. VEGF helps in the formation of new blood
vessels that support tumor growth.

40. Function of Angiogenic factors
Recruitment of pericytes and
smooth muscle cell
Blood vessel formation
FGF
Tie 2 Blood vessel Stablization
and remodeling
Artery , vein differentiation,
vessel remodeling
Epherins

41. Angiogenesis controls tumor growth.
Angiogenic Switch dynamic balance of pro & anti-angiogenic factor tripped in favor of
blood vessel formation
• Tumor can stay in a ‘dormant’ state
for long periods.
• The angiogenic switch allows for
growth of the tumor to occur.
• Increased angiogenesis correlates
with worse prognosis.

42. Link b/w Inflammation & Malignancy
Chronic inflammation leads to cancer
• H. Pylori Stomach cancer
• Chronic reflux esophagitis Barrett syndrome
• Chronic pancreatitis Ca Pancreas
• Ulcerative colitis Colon cancer
• HCV, HBV Liver cancer (HCC)

43. The most common cancer arise in the skin, prostate,
breast, lung and colon
• More than 100 kinds of cancer
• Most common type is skin cancer
• Liver cancer
• Stomach cancer
• Prostate cancer
• Colon, breast, and lung

44. Grading and staging
• Grade:
GX: Grade cannot be assessed
(Undetermined grade)
G1 Well-differentiated (Low
grade)
G2 Moderately differentiated
(Intermediate grade)
G3 Poorly differentiated (High
grade)
G4 Undifferentiated (High grade)
• Staging systems
(various): carcinoma
– Stage 1: confined to organ
– Stage 2: locally invasive
– Stage 3: lymph node invasion
– Stage 4: spread to distant sites
Extent of the prim. tumor and extent of spread in the body
Helps planning treatment and Prognosis

45. TNM - system
• Most common (accepted by UICC, AICC)
• Based on : T  extent of the tumor
N  extent of spread to the lymph nodes
M  presence of metastasis
• Number  indicates size or extent of the prim. tumor and the extent
of spread of metastasis

46. Cancer Treatment and Prevention
When a person is diagnosed with cancer, a variety of
weapons are available to combat it
1-local therapy:
• Surgery.
• Radiation therapy
2-systemic treatment:
• chemotherapy.
• Hormonal therapy
• Monoclonal antibodies
• Radioactive material

47. Detection method of Cancer
• Amplification Technique
• Sequencing
• Microarray
• Protein array
• Tissue microarray Visualization
• Tissue microarray analysis

48. Summary
• Defect in cell division
• Mutation
Benign
Tumor
• Invasion , metastasis & Angiogenesis
Malignant
Tumor