This document discusses the molecular basis of cancer and the hallmarks of cancer. It describes 8 fundamental changes that cancers display, including excessive autonomous growth, evading growth inhibitory signals, and avoiding apoptosis. It explains how proto-oncogenes become oncogenes through mutations like point mutations, deletions, and translocations. Oncogenes cause abnormal cell proliferation through cell signaling pathways like MAPK/ERK and JAK-STAT pathways. Oncogenes encode for oncoproteins that can be growth factors, receptors, signaling proteins, transcription factors, or cell cycle regulators. Mutations in these genes and proteins allow cancer cells to proliferate uncontrollably.

1. MOLECULAR BASIS OF CANCER

2. • HALLMARKS OF CANCER
- 8 FUNDAMENTAL CHANGES
• PROTOONCOGENES AND ONCOGENES AND
ONCOPROTEINS.
- ROLE OF ONCOGENES IN CANCER

3. HALLMARKS OF CANCER
Cancers display following fundamental changes:
1. Excessive &
Autonomous
Growth
2. Insensitivity to
Growth Inhibitory
signals
3. Growth
Promoting
metabolic changes
4. Evasion of
Apoptosis
5. Avoiding
Cellular Ageing.
6. Sustained
Angiogenesis
7. Invasion and
Metastasis
8. Evasion of
immune system

4. 1. Excessive & Autonomous Growth- Growth promoting
Oncogenes.
PROTOONCOGENES
Normal Cell Proliferation
Genes
ONCOGENES
UNREGULATED
PROLIFERATION/AUTONOMOUS
CELL GROWTH
NORMAL GROWTH
PROTEINS
POINT MUTATIONS/DELETIONS
CHROMOSOMAL TRANSLOCATIONS
GENE AMPLIFICATION
ONCOPROTEINS
MALIGNANT GROWTH

5. PROTOONCOGENES:
• Most of the protooncogenes encode for
components of cell signaling system for
promoting cell proliferation.
• They encode for proteins which play a major
role in cell proliferation.
• They become oncogenes due to mutations.

6. POINT MUTATIONS/DELETIONS
A mutation affecting one or very few
nucleotides/bases in a gene sequence.

8. CHROMOSOMAL TRANSLOCATION
In Chromosomal translocation:
• A chromosomal segment is moved from one
position to another, either within the
same chromosome or to another chromosome.

9. GENE AMPLIFICATION?
• Gene amplification refers to number of copies
of a gene is increased "without a proportional
increase in other genes".

10. HOW ONCOGENES CAUSE ABNORMAL
CELL PROLIFERATION ?

11. CELL PROLIFERATION SIGNALING SYSTEMS

12. • In cell biology, there are several signalling pathways. Cell signalling is part of the molecular
biology system that controls and coordinates the actions of cells.
1. Akt/PKB signalling pathway
2. AMPK signalling pathway
3. Insulin signal transduction pathway
4. JAK-STAT signalling pathway
5. MAPK/ERK signaling pathway
6. PI3K/AKT/mTOR signalling pathway
7. TGF beta signalling pathway
8. TLR signalling pathway
9. VEGF signalling pathway
• And few more…

13. MAPK/ERK SIGNALING PATHWAY:
• The MAPK/ERK pathway is a chain
of proteins in the cell that communicates a
signal from a receptor on the surface of the cell
to the DNA in the nucleus of the cell.

14. Mechanism:
• Growth signals (eg: EPIDERMAL GROWTH FACTOR (EGF),
PDGF, FGF) are received from outside the cell by GROWTH
RECEPTORS (Eg: EPIDERMAL GROWTH FACTOR
RECEPTOR, PDGFR, FGFR) at the cell surface.
• The activated receptors transfers the signal to intracellular Ras
protein.(G protein)
• Ras is usually stays in "off" state by binding to a
nucleotide guanosine diphosphate (GDP) (inactive form), while
in the "on" state i.e. on receiving a signal, Ras will be binding
to guanosine triphosphate (GTP) (active form).

15. • The activated Ras protein now activates the
MAPKinase in cytosol.
• Once Ras proteins activate MAPKinase they become
inactive to enzymatic action of GTPase.
• The activated MAPKinase activate MYC proteins in
nucleus.
• The activated MYC proteins regulates DNA
transcription and induces the cell to enter into S phase.

16. PLASMA MEMBRANE
GROWTH FACTOR ( eg: EGF, PDGF, FGF)
GROWTH
FACTOR
RECEPTOR
(eg: EGFR, PDGFR
, FGFR)
BINDING
PROTEIN
INACTIVE
RAS
FARNESYL PROTEIN
ACTIVE
RAS
GTP
DNA
TRANSCRIPTION
(NUCLEAR
TRANSCRIPTION
FACTORS)
CYTOPLASMIC SIGNAL TRANSDUCTION PROTEINS
GDP
Activation of MAPKinase
Activation of MYC proteins

17. • OTHER CELL SIGNAL PATHWAYS:
2. JAK-STAT Signaling Pathway:
• The JAK-STAT signalling pathway is a chain of
interactions between proteins in a cell, and is
involved in processes such as immunity, cell
division, cell death and tumour formation.

18. • The pathway communicates information from chemical
signals outside of a cell to the cell nucleus, resulting in the
activation of genes through a process called transcription.
The key parts of JAK-STAT signalling:
1. Receptors (which bind the chemical signals).
2. Janus kinases (JAKs),
3. Signal transducer and activator of transcription
proteins (STATs),

19. Mechanism of Signal transduction in JAK-STAT PATHWAY
PLASMA MEMBRANE
JAK JAK
STAT PROTEINS
(SIGNAL TRANSDUCER
AND ACTIVATOR OF TRANSCRIPTION
PROTEINS)

20. PLASMA MEMBRANE
P P
JAK JAK
STAT PROTEINS
CYTOKINE BINDING TO RECEPTOR IN MEMBRANE
PHOSPHORYLATION OF RECEPTORS BY JAK
PROTEINS BY ADDING PHOSPHATES TO
THEM LEADS TO DIMERISATION OF
RECEPTORS

21. PLASMA MEMBRANE
P P
JAK JAK
TWO STAT PROTEINS THEN BIND TO
THE PHOSPHATES

22. PLASMA MEMBRANE
P P
JAK JAK
P P
AND THEN THE STATS ARE
PHOSPHORYLATED BY JAKS TO FORM A
DIMER.

23. PLASMA MEMBRANE
P
JAK JAK
P
STAT DIMER
THE DIMER ENTERS THE NUCLEUS.

24. PLASMA MEMBRANE
JAK JAK
P
P
IT BINDS TO DNA, AND CAUSES
TRANSCRIPTION OF TARGET GENES.

25. PLASMA MEMBRANE
JAK JAK
DNA TRANSCRIPTION

26. Clinical importance
• Disrupted JAK-STAT signalling may lead to a
variety of CANCERS, and disorders affecting
the immune system.
• High levels of STAT activation have been
associated with cancer

27. ONCOGENES AND ONCOPROTEINS
• Oncoproteins are formed from their respective
Oncogenes either due to Over-expression, Point Mutation,
Translocation, Gene amplification.
PROTOONCOGENES Proteins for cell growth and division
PROTOONCOGENES
Over-expression, Point Mutation,
Translocation, Gene amplification.
ONCOGENES Abnormal proteins
(Oncoproteins)

28. ONCOPROTEINS: can be
1. Growth factors
2. Receptors of Growth Factors
3. Cytoplasmic Signal Transduction Proteins
4. Nuclear Transduction Factors
5. Cell Cycle regulatory proteins

29. 1. Growth factors
• They act by binding to cell surface receptors to activate cell
proliferation cascade within the cell.
• GFs are small polypeptides elaborated by many cells and they
normally act on another cell than the one which synthesized it
to stimulate its proliferation i.e. paracrine action.
Cell Cell
GF
Paracrine action.

30. • However, a cancer cell may synthesize a GF
and respond to it as well; this way cancer cells
acquire growth self-sufficiency (AUTOCRINE).
Cell CellGF
Autocrine action

31. • Most often, growth factor genes in cancer act by
OVEREXPRESSION which stimulates large secretion of GFs
that stimulate cell proliferation.
gene Normal GFs
gene
Abnormal levels of GFs
Over expression

32. • Example:
SIS Oncogene
(Over Expression)
INCREASED SECRETION OF PDGF-B
SIS Protooncogene
Platelet-Derived Growth Factor-b (PDGF-b)
GLIOMAS AND SARCOMAS.
Normal
Abnormal
PRODUCTION OF

33. 2. Receptors for GFs.
• Growth factors cannot penetrate the cell directly and require to
be transported intracellularly by GF-specific cell surface
receptors.
• Mutated form of growth factor receptors stimulate cell
proliferation even without binding to growth factors i.e. with
little or no growth factor bound to them.
• Oncogenes encoding for GF receptors include various
mechanisms: Overexpression, Mutation and Gene
Rearrangement.

34. • Examples of tumours by mutated receptors for
growth factors:
ERB B1 PROTO-ONCOGENE
EGFR or HER1
(i.e. Human Epidermal
Growth Factor Receptor
Type 1)
ERB B1 ONCOGENE
EGFR or HER1
NORMAL PRODUCTION of ABNORMAL PRODUCTION OF
80 % SQUAMOUS CELL CARCINOMA OF LUNG
50 % GLIOBLASTOMAS

35. 3. Cytoplasmic Signal Transduction Proteins
• The normal signal transduction proteins in the
cytoplasm transduce signal from the GF receptors
present on the cell surface, to the nucleus of the cell,
to activate intracellular growth signaling pathways.
• However mutated forms of these proteins cause
abnormal signaling to nucleus causing cell division.

36. • Examples of oncogenes having mutated forms of
cytoplasmic signaling pathways located in the inner
surface of cell membrane in some cancers.
Eg:
1. RAS Oncogene
2. JAK Oncogenes/STAT Oncogenes.

37. Normal RAS Protooncogene
RAS protein
Normally active RAS protein is bound to
GTP and it is inactivated by GTPase
enzyme to prevent further signaling to
nucleus.

38. RAS Proto-oncogene
RAS Oncogene
RAS oncoprotein bound to
GTP is uneffected by
GTPase enzyme.
CONTINUES SIGNAL TO THE NUCLEUS
CAUSING CELL DIVISION
CARCINOMA COLON, LUNG AND PANCREAS.
LEADS TO
Mutations
RAS Oncoproteins

39. 2. JAK ONCOGENES /STAT ONCOGENES:
• Mutations in JAK genes cause:
- Leukaemia,
- Lymphoma
• Mutations in STAT genes cause:
- SKIN CANCERS,
- PROSTATE CANCER

40. 4. Nuclear Transcription Factors
• The signal transduction pathway that started with GFs
ultimately reaches the nucleus where it regulates DNA
transcription and induces the cell to enter into S phase.
• Out of various nuclear regulatory transcription proteins
described, the most important is MYC gene located on long
arm of chromosome 8.
• Normally MYC protein binds to the DNA and regulates the
cell cycle by transcriptional activation and its levels fall
immediately after cell enters the cell cycle.

41. MYC protein
MYC protein
Target gene

42. MYC Proto-Oncogene MYC Proteins
Binds to DNA and
cause its transcription
Cell division
MYC Oncogene Excessive
MYC Proteins
Binds to DNA and
cause continuous
transcription
Excessive
Cell division
Mutations
EG: Burkitt’s lymphoma, small cell
carcinoma lung.

43. 5) Cell Cycle Regulatory Proteins
• Normally, the cell cycle is under regulatory
control of proteins called Cyclins (A,B,C,D)
and Cyclin-dependent Kinases (CDKs).
• Cyclins activate as well as work together with
CDKs.

45. G1
S
PHASE
G2
M
PHASE
Cyclins D, E, A Cyclin A Cyclin B
CDKs CDKs CDKs

46. • Although all steps in the cell cycle are under regulatory
controls, G1 → S phase is the most important checkpoint
and it is under the control of protein CYCLIN D (majorly).
• Mutations in Cyclins (in particular Cyclin D) and CDKs
(in particular CDK4) are most important growth promoting
signals in cancers.
The example of tumour having such oncogenes are as under:
• Mutated form of CYCLIN D by Translocation seen in
CARCINOMA OF BREAST, LIVER, MANTLE CELL
LYMPHOMA

49. 2. Insensitivity to Growth Inhibitory signals.
• Normally, dividing cells are under control of
proteins coded by certain genes which prevent the
abnormal cell division by making them to enter
into G0 phase.
• These genes which control the cell cycle are
called Antioncogenes/Tumour Suppressor Genes.

50. • Normally, anti-oncogenes act by either inducing the
dividing cell from the cell cycle to enter into G0
(resting) phase.

51. FUNCTION OF TUMOUR SUPRESSOR
GENES/ANTIONCOGENES
TUMOUR SUPRESSOR
GENES/ANTIONCOGENES
TUMOUR SUPRESSOR PROTEINS
PRODUCES
REGULATES CELL GROWTH BY
APPLYING BRAKES TO CELL
PROLIFERATION (INHIBITS CELL
GROWTH)

52. MAJOR ANTI-ONCOGENES/
TUMOUR SUPPRESSOR GENES:
1. p53 gene (Short arm p53 Antioncogene)
2. RB gene (Retinoblastoma Antioncogene)
3. APC gene (Adenomatous polyposis coli
Antioncogene)
4. TGF-β gene ( Transforming growth factor- β
Antioncogene

53. • Mutations in Anti-oncogenes/Tumour Suppressor
Genes leads to Cancers.
ANTIONCOGENES/TUMOUR SUPPRESSOR GENES
ACT AS
GROWTH PROMOTING ONCOGENES
MUTATIONS
CANCERS.

54. • Loss of tumour suppressor actions of
antioncogenes can be due to
- Chromosomal deletions,
- Point mutations and
- Loss of portions of chromosomes.

55. 1. p53/TP53 gene (Short arm p53 Antioncogene)
• LOCATION: on the short arm (p) of chromosome
17.

56. • TP53/p53 GENE codes for a protein (p53
protein) that regulates the cell cycle and hence
functions as a tumor suppression.
• P53 has been described as “THE GUARDIAN
OF THE GENOME”.

57. DNA DAMAGE
p53 activation
DNA REPAIR
(hence guardian
of the genome)
CELL CYCLE
ARREST
By inhibiting the action of
Cyclins and CDK’s
prevents the cell to enter G1 phase
APOPTOSIS
by Activating BAX GENES
FUNCTION OF p53 GENE:
P53 Proteins

58. Mutation of p53 Gene:
BOTH NORMALALLELES OF
p53 GENES
NORMAL FUNCTION OF
p53 GENE
ONE ALLELE IS ACTIVE AND
ANOTHER ALLELE IS INACTIVE
i.e., HETEROZYGOUS STATE
STILL NORMAL FUNCTION OF
p53 GENE IS SEEN

59. WHEN BOTH ALLELES ARE
INACTIVE/MUTATED
i.e., HOMOZYGOUS STATE
ABNORMALACTION OF p53
GENE
MOST HUMAN CANCERS, COMMON IN
CA LUNG, HEAD AND NECK, COLON,
BREAST
In its mutated form, p53 ceases to act as
protector or as growth suppressor but
instead acts like a growth promoter or
oncogene.

60. Li-Fraumeni syndrome:
HERE THE OFF SPRING RECIEVES
ONE INHERITED ALLELE OF p53 GENE WHICH IS MUTATED
WHEN MUTATION (ACQUIRED) OF
SECOND ALLELE OF P53 GENE TAKES PLACE
MULTIPLE ORGAN CARCINOMAS

61. RB gene
• RB gene is located on long arm (q) of
chromosome 13.
• First discovered tumour suppressor gene.

62. • RB Gene encodes for Rb tumor suppressor
protein (pRb).
• It is called as GOVERNER OF THE CELL
CYCLE.
• RB gene is termed as MASTER ‘BRAKE’ IN
THE CELL CYCLE.

63. FUNCTION OF pRb PROTEIN.
• The Rb tumor suppressor protein (pRb) binds to the
E2F1 transcription factor preventing it from
interacting with the cell's transcription process
preventing cell transition from G1 to S phase.
• E2F1 targets genes that encode proteins involved in
DNA replication (for example DNA polymerase) and
chromosomal replication.

64. E2F1 Transcription factor

65. E2F1 Transcription factor
E2F1 Target Genes

66. E2F1 Transcription factor
pRb
Protein

67. • In the absence of pRb, E2F1 mediates the
trans-activation of E2F1 target genes that
facilitate the G1/S transition and S-phase.

68. ACTIVE FORM OF
RB GENE
pRb
pRb binds to
transcription factor, E2F
Inhibits cell cycle at G1 → S
phase i.e. cell cycle is arrested at
G1 phase.
E2F1 Transcription factor
pRb
Protein

69. INACTIVE FORM OF RB
GENE
defective pRb
(PHOSPHORYLATED FORM)
FREE E2F
Transition from G1 → S phase
E2F1 Transcription factor
DNA replication
pRb
Proteinp p

70. Mutated RB GENE
• Mutations of two alleles of RB gene is
required for the development of tumours.
• Example: RETINOBLASTOMA occurs due
to mutation of two alleles of RB gene.

71. • Tumours can be HEREDITARY TYPE OR SPORADIC
TYPE:
HEREDITARY TYPE
INHERITED MUTATION OF ONE
RB GENE ALLELE
(1ST HIT MUTATION)
ACQUIRED MUTATION OF
2ND RB GENE ALLELE
(2ND HIT MUTATION)
Tumour

72. SPORADIC TYPE:
ACQUIRED MUTATION OF ONE
RB GENE ALLELE
(1ST HIT MUTATION)
ACQUIRED MUTATION OF
2ND RB GENE ALLELE
(2ND HIT MUTATION)
Tumour

73. • Besides retinoblastoma, children inheriting
mutant RB gene have 200 times greater risk of
development of other cancers in early adult
life, most notably osteosarcoma; others are
cancers of breast, colon and lungs.

74. BRCA 1 and BRCA 2 genes:
• BRCA1 is a human tumor suppressor gene.
• It is also known as a CARETAKER GENE and is
responsible for repairing DNA.
• Breast Cancer Type 1 Susceptibility Protein is
a protein that in humans is encoded by the BRCA1 gene.
• BRCA1 and BRCA2 are unrelated proteins, but both are
normally expressed in the cells of breast and other tissue,
where they help repair damaged DNA, or destroy cells if
DNA cannot be repaired.

75. • BRCA1 GENE Location: Long Arm (q) of
Chromosome 17

76. • BRCA2 GENE Location: Long Arm (q) of
Chromosome 13.

77. • If BRCA1 or BRCA2 itself is damaged by
a BRCA mutation, damaged DNA is not
repaired properly, and this increases the risk
for breast cancer.
• BRCA1 and BRCA2 have been described as
- “Breast cancer susceptibility genes" or
- “Breast cancer susceptibility proteins".

78. • Females with an abnormal BRCA1 or BRCA2
gene have:
- 80% risk of developing BREAST CANCER.
- 55% risk of developing OVARIAN CANCER in
females with BRCA1 mutations.
- 25% risk of developing OVARIAN CANCER
females with BRCA2 mutations.

79. 3. Growth Promoting Metabolic Changes:
THE WARBURG EFFECT
• The Warburg Effect refers to the fact that
cancer cells prefers fermentation as a source of
energy rather than the more efficient
mitochondrial pathway of oxidative
phosphorylation (OxPhos).

80. IN NORMAL TISSUES:
• Cell may either use OxPhos which generates 36
ATP or anaerobic glycolysis which gives 2 ATP.
• Anaerobic means ‘without oxygen’ and glycolysis
means ‘burning of glucose’.
• Normal tissues only use this less efficient
pathway in the absence of oxygen — eg. muscles
during sprinting.

82. In Cancers:
• Even in the presence of oxygen it uses a less efficient
method of energy generation i.e.. Anaerobic
glycolysis.

83. 4. Avoiding Cellular Ageing: Telomeres and
Telomerase in Cancer
• Telomeres are the caps at the end of each
strand of DNA that protect our chromosomes.
• They function to protect the ends of
chromosomes from sticking to each other.
They

84. • Telomerase is a cellular reverse transcriptase
(molecular motor) that adds new DNA onto the
telomeres that are located at the ends of chromosomes.
• Stem cells also show progressive shortening of
telomeres with increased age, while embryonic stem
cells maintain telomeres due telomerase enzyme which
is sufficiently present in them.

85. Telomeres and Cell Ageing:
• Normal human cells progressively lose telomeres
with each cell division until a few short telomeres
become uncapped leading to a growth arrest.
• After repetitive mitosis for a maximum of 60 to
70 times, telomeres are lost in normal cells and
the cells cease to undergo mitosis and die (CELL
AGEING).

87. Telomeres and Tumour cells:
• Cancer cells in most malignancies have
markedly upregulated/more telomerase
enzyme, and hence telomere length is
maintained.
• Thus, cancer cells avoid ageing, mitosis does
not slow down or cease, thereby immortalising
the cancer cells.