Molecular basis of tumor and carcinogenesis by : Amr Mohammed Ahmed Omar Ragheb Mohammed Osama Mohammed Youssef Mohammed Mostafa Hassan

1. Molecular pathogenesis of cancer
Amr Mohammed
Ahmed Omar Ragheb
Mohammed Osama
Mohammed Youssef Mohammed
Mostafa Hassan

2. Objects to discuss
 What DNA means ?
 What Gene and Genome means ?
 Mutation of DNA and relation with Tumor Pathogenesis
 Cancer Hallmark
 Oncogene and proto oncogene
 Tumor supressor genes
 Cancergensis

3. What Does “DNA” mean !
Primary structure
 Chemical structure of DNA
 Primary structure consists of a linear sequence of nucleotides that are linked
together by phosphodiester bonds. It is this linear sequence of nucleotides
that make up the primary structure of DNA or RNA.
Nucleotides consist of 3 components:
 Nitrogenous base
 Adenine
 Guanine
 Cytosine
 Thymine(present in DNA only)
 Uracil (present in RNA only)
 5-carbon sugar which is called deoxyribose (found in DNA) and ribose (found in RNA).
 One or more phosphate groups

4. What Does “DNA” mean !
Secondary structure
 Secondary structure is the set of interactions between bases, i.e., parts of
which is strands are bound to each other. In DNA double helix, the two
strands of DNA are held together by hydrogen bonds. The nucleotides on
one strand base pairs with the nucleotide on the other strand. The
secondary structure is responsible for the shape that the nucleic acid
assumes. The bases in the DNA are classified as Purines and Pyrimidines. The
purines are Adenine and Guanine. Purines consist of a double ring structure,
a six membered and a five membered ring containing nitrogen. The
pyrimidine are Cytosine and Thymine. It has a single ringed structure, a six
membered ring containing nitrogen. A purine base always pairs with a
pyrimidine base (Guanosine (G) pairs with Cytosine(C)and Adenine(A) pairs
with Thymine (T) or Uracil (U). DNA's secondary structure is predominantly
determined by base-pairing of the two polynucleotide strands wrapped
around each other to form a double helix. There is also a major groove and
aminor groove on the double helix.

5. What Does “DNA” mean !

Tertiary structure
 Tertiary structure is the locations of the atoms in three-dimensional space, taking into
consideration geometrical and steric constraints. A higher order than the secondary
structure in which large-scale folding in a linear polymer occurs and the entire chain
is folded into a specific 3-dimensional shape. There are 4 areas in which the
structural forms of DNA can differ.
 Handedness - right or left
 Length of the helix turn
 Number of base pairs per turn
 Difference in size between the major and minor grooves[3]
 The tertiary arrangement of DNA's double helix in space includes B-DNA, A-DNA
and Z-DNA.

6. What Does “DNA” mean !
Quaternary structure
 The quaternary structure of nucleic acids is similar to that of protein
quaternary structure. Although some of the concepts
are not exactly
the same, the quaternary structure refers to
a higher-level of organization of nucleic acids.
Moreover, it refers to interactions of the nucleic acids
with other molecules.
The most commonly seen form of higher-level
organization of nuclei
c acids is seen in the form of chromatinwhich leads to its interactions
with the small proteins histones. Also, the quaternary structure refers
to the interactions between separate RNA units in
the ribosome or spliceosome

7. Gene and Genome
 A gene is the molecular unit of heredity of a living organism. It
is used extensively by the scientific community as a name
given to some stretches of deoxyribonucleic acids (DNA)
and ribonucleic acids (RNA) that code for a polypeptide or for
an RNA chain that has a function in the organism. Living beings
depend on genes, as they specify all proteins and functional
RNA chains. Genes hold the information to build and maintain
an organism's cells and pass genetic traits to offspring. All
organisms have genes corresponding to various biological
traits, some of which are instantly visible, such as eye color or
number of limbs, and some of which are not, such as blood
type, increased risk for specific diseases, or the thousands of
basic biochemical processes that comprise life. The
word gene is derived from the Greek word genesis meaning
"birth", or genos meaning "origin"

8. Gene and Genome
 In modern molecular
biology and genetics, the genome is the
genetic material of an organism. It is
encoded either in DNA or, formany
types of viruses, in RNA. The genome
includes both the genes and the non-coding
sequences of the DNA/RNA

9. Mutation

10. Mutation
 Point Mutations – changes in
one or a few nucleotides
 Substitution
THE FAT CAT ATE THE RAT
THE FAT HAT ATE THE RAT
 Insertion
THE FAT CAT ATE THE RAT
THE FAT CAT XLW ATE THE RAT
 Deletion
THE FAT CAT ATE THE RAT
THE FAT ATE THE RAT

11. Mutation
Frameshift Mutations – shifts the
reading frame of the genetic
message so that the protein
may not be able to perform its
function.
Insertion
THE FAT CAT ATE THE RAT
THE FAT HCA TAT ETH ERA T
Deletion
THE FAT CAT ATE THE RAT
TEF ATC ATA TET GER AT

12. Chromosome Mutations
 Changes in number and structure of entire chromosomes
 Original Chromosome ABC * DEF
 Deletion AC * DEF
 Duplication ABBC * DEF
 Inversion AED * CBF
 Translocation ABC * JKL
GHI * DEF

14. Significance of Mutations
• Most are neutral
• Eye color
• Birth marks
• Some are harmful
• Sickle Cell Anemia
• Down Syndrome
• Some are beneficial
• Sickle Cell Anemia to Malaria
• Immunity to HIV

15. What Causes Mutations !!
 Four classes of mutations are
(1) spontaneous mutations (molecular decay)
(2) mutations due to error prone replication bypass of naturally occurring DNA damage)
(3) errors introduced during DNA repair
(4) induced mutations caused by mutagens
 Spontaneous mutation
 Spontaneous mutations on the molecular level can be caused by
 Tautomerism — A base is changed by the repositioning of a hydrogen atom, altering the hydrogen
bonding pattern of that base, resulting in incorrect base pairing during replication.
 Depurination — Loss of a purine base (A or G) to form an apurinic site (AP site).
 Deamination — Hydrolysis changes a normal base to an atypical base containing a keto group in
place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can
be corrected by DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is less likely to be
detected as a mutation because thymine is a normal DNA base.
 Slipped strand mispairing — Denaturation of the new strand from the template during replication,
followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.

16. What Causes Mutations !!
 Error prone replication by-pass
 There is increasing evidence that the majority of spontaneously arising mutations are due to error
prone replication (translesion synthesis) past a DNA damage in the template strand. As
described in the article DNA damage (naturally occurring), naturally occurring DNA damages
arise about 60,000 to 100,000 times per day per mammalian cell. In mice, the majority of
mutations are caused by translesion synthesis Likewise, in yeast, Kunz et al found that more than
60% of the spontaneous single base pair substitutions and deletions were caused by translesion
synthesis
 Errors introduced during DNA repair
 Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA
(see DNA damage (naturally occurring)) their repair often causes mutation. Non-homologous
end joining (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal
of a few nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining
followed by addition of nucleotides to fill in gaps. As a consequence, NHEJ often introduces
mutations

17. What Causes Mutations !!
 Induced mutation
 Induced mutations on the molecular level can be caused by:-
 Chemicals
 Hydroxylamine
 Base analogs (e.g., BrdU)
 Alkylating agents (e.g., N-ethyl-N-nitrosourea) These agents can mutate both replicating and non-replicating
DNA. In contrast, a base analog can mutate the DNA only when the analog is incorporated in replicating the
DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions,
or deletions.
 Agents that form DNA adducts (e.g., ochratoxin A metabolites)
 DNA intercalating agents (e.g., ethidium bromide)
 DNA crosslinkers
 Oxidative damage
 Nitrous acid converts amine groups on A and C to diazo groups, altering their hydrogen bonding patterns,
which leads to incorrect base pairing during replication.
 Radiation
 Ultraviolet radiation (nonionizing radiation). Two nucleotide bases in DNA — cytosine and thymine — are most
vulnerable to radiation that can change their properties. UV light can induce adjacent pyrimidine bases in a
DNA strand to become covalently joined as a pyrimidine dimer. UV radiation, in particular longer-wave UVA,
can also cause oxidative damage to DNA

18. Blood smear (normal)
Image Credit:
http://lifesci.rutgers.edu/~babiarz/
Sickle cell anemia
Image Credit: http://explore.ecb.org/

19. Fundamental principles of carcinogenesis:
 Nonlethal genetic damage lies at the heart of carcinogenesis-Such genetic damage (or
mutation) may be acquired by the action of environmental agents, such as chemicals,
radiation, or viruses, or it may be inherited in the germ line.
 Four classes of normal regulatory genes are the principal targets of genetic damage—
the growth-promoting proto-oncogenes, the growth-inhibiting tumor suppressor
genes, genes that regulate apoptosis, and genes involved in DNA repair.
 tumors are monoclonal: A tumor is formed by the clonal expansion of a single
precursor cell that has acquired genetic damage.

20. Normal cell Proliferation
The binding of a growth factor to its specific receptor
Transient and limited activation of the growth factor receptor
Activates several signal-transducing proteins on the inner leaflet of the plasma membrane
Transmission of the transduced signal across the cytosol to the nucleus via second
messengers or by a cascade of signal transduction molecules
Induction and activation of nuclear regulatory factors that initiate DNA transcription
Entry and progression of the cell into the cell cycle, ultimately resulting in cell division

21. Hallmark of Tumor : Molecular basis of Cancer
 1. Self-sufficiency in growth signals: Tumors have the capacity to proliferate without external
stimuli, usually as a consequence of oncogene activation.Will discussed in oncogenes
 2. Insensitivity to growth-inhibitory signals : Tumors may not respond to molecules that are
inhibitory to the proliferation of normal cells such as transforming growth factor β (TGF-β) and
direct inhibitors of cyclin-dependent kinases (CDKIs).Will discussed in Tumor suppressor genes
 3. Evasion of apoptosis: Tumors may be resistant to programmed cell death, as a consequence of
inactivation of p53 or activation of anti-apoptotic genes.
 4. Limitless replicative potential: Tumor cells have unrestricted proliferative capacity, avoiding
cellular senescence and mitotic catastrophe.

22. • 5. Sustained angiogenesis: Tumor cells, like normal cells, are not able to grow without
formation of a vascular supply to bring nutrients and oxygen and remove waste products.
Hence, tumors must induce angiogenesis.
• 6. Ability to invade and metastasize : Tumor metastases are the cause of the vast majority
of cancer deaths and depend on processes that are intrinsic to the cell or are initiated by
signals from the tissue environment.
• 7. Defects in DNA repair : Tumors may fail to repair DNA damage caused by carcinogens
or incurred during unregulated cellular proliferation, leading to genomic instability and
mutations in proto-oncogenes and tumor suppressor genes.
Another important change for tumor development is escape from immune attack .

23. Flowchart depicting a simplified scheme of
the molecular basis of cancer

24. Self-sufficiency in growth signals
(Oncogenes)
 In a normal cell, Proto-oncogenes have multiple roles, participating in
cellular functions related to growth and proliferation.
 Self sufficiency for growth to a cancerous cell is provided by oncogenes,
which are the mutant proto-oncogenes.
 Mutations convert inducible proto-oncogenes into constitutively active
oncogenes, which is responsible for progressive cell divisions.

25. Limitless Replicative Potential
most normal human cells have a capacity of 60 to 70 doublings. After this, the cells
lose their ability to divide and become senescent. This phenomenon has been
ascribed to progressive shortening of telomeres at the ends of chromosomes.

26. Insensitivity to Growth-Inhibitory Signals
(Tumor Suppressor Gene)
 Tumor-suppressor genes, or more precisely, the proteins they code for, either have a
dampening or repressive effect on the regulation of the cell cycle or promote apoptosis,
and sometimes do both. The functions of tumor-suppressor proteins fall into several
categories including the following:
 Repression of genes that are essential for the continuing of the cell cycle. If these genes
are not expressed, the cell cycle does not continue, effectively inhibiting cell division.
 Coupling the cell cycle to DNA damage. As long as there is damaged DNA in the cell, it
should not divide. If the damage can be repaired, the cell cycle can continue.
 If the damage cannot be repaired, the cell should initiate apoptosis (programmed cell
death) to remove the threat it poses for the greater good of the organisms produced
 Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss
of contact inhibition, and inhibit metastasis. These proteins are known asmetastasis
suppressors.
 DNA repair proteins are usually classified as tumor suppressors as well, as mutations in their
genes increase the risk of cancer, for example mutations in HNPCC, MEN1and BRCA.
Furthermore, increased mutation rate from decreased DNA repair leads to increased
inactivation of other tumor suppressors and activation of oncogenes

28. Sustained angiogenesis
 Like normal tissues, tumors require delivery of oxygen and nutrients and removal of waste
products. So, Even with all the genetic abnormalities discussed above, solid tumors cannot
enlarge beyond 1 to 2 mm in diameter unless they are vascularized.
 Neovascularization has a dual effect on tumor growth: perfusion supplies needed nutrients
and oxygen, and newly formed endothelial cells stimulate the growth of adjacent tumor cells
by secreting growth factors (IGFs, PDGF, and GM-CSF).
 Tumor angiogenesis is controlled by the balance between angiogenesis promoters and
inhibitors. Early in their growth, most human tumors do not induce angiogenesis. They
remain small or in situ, possibly for years, until the angiogenic switch terminates this stage
of vascular quiescence.

29. • The molecular basis of the angiogenic switch involves
-increased production of angiogenic factors (VEGF and basic FGF)
and/or
-loss of angiogenic inhibitors (angiostatin, endostatin, and vasculostatin).
• in normal cells, p53 can stimulate expression of anti-angiogenic molecules
(thrombospondin-1) and repress expression of pro-angiogenic molecules (VEGF).
Thus, loss of p53 in tumor cells not only removes the cell cycle checkpoints but
also provides a more permissive environment for angiogenesis.

30. Ability to invade and metastasize
Invasion of Extracellular Matrix:
 Dissociation of cells from one another- downregulation of E-cadherin expression
reduces the ability of cells to adhere to each other and facilitates their detachment from
the primary tumor and their advance into the surrounding tissues.
 local degradation of the basement membrane and interstitial connective tissue- Tumor
cells may either secrete proteolytic enzymes themselves or induce stromal cells like
fibroblasts and inflammatory cells to elaborate proteases (matrix metalloproteinases,
cathepsin D, and urokinase plasminogen activator)

31. • changes in attachment of tumor cells to ECM proteins- cleavage of the basement
membrane proteins collagen IV and laminin by MMP2 or MMP9 generates novel
sites that bind to receptors on tumor cells and stimulate migration.
• Locomotion is the final step of invasion, propelling tumor cells through the degraded
basement membranes and zones of matrix proteolysis. Such movement seems to be
potentiated and directed by tumor cell–derived cytokines.

32. Vascular Dissemination and Homing of Tumor Cells:
• Once in the circulation, tumor cells are vulnerable to destruction. So, tumor cells tend to aggregate in clumps. This is
favored by homotypic adhesions among tumor cells as well as heterotypic adhesion between tumor cells and blood cells,
particularly platelets. Formation of platelet-tumor aggregates may enhance tumor cell survival and implantability.
• Tumor cells may also bind and activate coagulation factors, resulting in the formation of emboli. Arrest and extravasation
of tumor emboli at distant sites involves adhesion to the endothelium, followed by egress through the basement
membrane.
Organ tropism (prostatic carcinoma preferentially spreads to bone, bronchogenic carcinomas tend to involve the adrenals and
the brain etc.) may be related to the following mechanisms:
• Tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target
organ.
• In some cases, the target tissue may be a non permissive environment e.g. Well vascularized, skeletal muscles are rarely
the site of metastases.

33. Molecular genetics of Metastasis:
Why do only some tumors metastasize?
Several competing theories have been proposed to explain how the metastatic
phenotype arises:
• The clonal evolution model suggest that, as mutations accumulate in genetically
unstable cancer cells and the tumor become heterogeneous, a subset of tumor cell
subclones develop the right combination of gene products to complete all the steps
involved in metastasis.
• Metastasis is caused by the gene expression pattern of most cells of the primary
tumor, referred to as a metastatic signature; This signature may involve not only
properties intrinsic to the cancer cells but also the characteristics of their
microenvironment, such as the components of the stroma, the presence of
infiltrating immune cells, and angiogenesis.

34. Evasion of apoptosis
apoptosis represents a barrier that must be surmounted for cancer to occur.
In the adult, cell death by apoptosis is a physiologic response to several pathologic
conditions that might contribute to malignancy if the cells remained viable.

35. (1) Reduced CD95 level.
(2) Inactivation of death-induced signaling complex by
FLICE protein (caspase 8; apoptosis- related cysteine
peptidase).
(3) Reduced egress of cytochrome c from mitochondrion
as a result of up- regulation of BCL2.
(4) Reduced levels of pro-apoptotic BAX resulting from
loss of p53.
(5) Loss of apoptotic peptidase activating factor 1
(6) Up-regulation of inhibitors of apoptosis (IAP) FADD,
Fas-associated via death domain.

36. Defects in DNA repair
 Although humans literally swim in environmental agents that are mutagenic (e.g.,
chemicals, radiation, sunlight), cancers are relatively rare outcomes of these encounters.
This state of affairs results from the ability of normal cells to repair DNA damage and the
death of cells with unrepairable damage.
 Defects in three types of DNA-repair systems contribute to different types of cancers —
mismatch repair,
nucleotide excision repair, and
recombination repair

37. Defect in DNA mismatch repair gene:
Ex. HNPCC
• When a strand of DNA is being replicated, these genes act as “spell checkers.” For
example, if there is an erroneous pairing of G with T rather than the normal A with T, the
mismatch-repair genes correct the defect. Without these “proofreaders,” errors gradually
accumulate randomly in the genome, and some of these errors may involve proto-oncogenes
and tumor suppressor genes.
• Each affected individual inherits one defective copy of a DNA mismatch-repair gene and
acquires the second hit in colonic epithelial cells. Thus, DNA-repair genes behave like
tumor suppressor genes in their mode of inheritance, but in contrast to tumor suppressor
genes (and oncogenes), they affect cell growth only indirectly—by allowing mutations in
other genes during the process of normal cell division.
Defect in nucleotide excision repair gene:
Ex. Xeroderma Pigmentosum
• UV radiation causes cross-linking of pyrimidine residues, preventing normal DNA
replication. Such DNA damage is repaired by the nucleotide excision repair system.
Several proteins are involved in nucleotide excision repair, and an inherited loss of any one
can give rise to xeroderma pigmentosum.

38. Defects in DNA Repair by Homologous Recombination:
Homologous recombination is a type of genetic recombination in
which nucleotide sequences are exchanged between two similar or identical molecules
of DNA. It is most widely used by cells to accurately repair harmful breaks.
• The gene mutated in ataxia-telangiectasia, ATM, is important in recognizing and
responding to DNA damage caused by ionizing radiation.
• Persons with Bloom syndrome have a defective gene which is located on
chromosome 15 and encodes a helicase that participates in DNA repair by
homologous recombination.

40. Oncogenes
Growth
factors
Growth factor
receptors
Signal
transduction
proteins
Nuclear
regulatory
proteins
Cell cycle
regulators

42. Proto-oncogenes
Proto-oncogenes are a group of genes that cause normal cells to become
cancerous when they are mutated (Adamson, 1987; Weinstein & Joe, 2006).
Mutations in proto-oncogenes are typically dominant in nature, and the
mutated version of a proto-oncogene is called an oncogene. Often, proto-oncogenes
encode proteins that function to stimulate cell division, inhibit
cell differentiation, and halt cell death. All of these processes are important
for normal human development and for the maintenance of tissues and
organs. Oncogenes, however, typically exhibit increased production of these
proteins, thus leading to increased cell division, decreased cell
differentiation, and inhibition of cell death; taken together, these phenotypes
define cancer cells. Thus, oncogenes are currently a major molecular target
for anti-cancer drug design

45. From Good to Bad: How Proto-Oncogenes Become Oncogenes
Today, more than 40 different human proto-oncogenes are known. But what
types of mutations convert these proto-oncogenes into oncogenes? The
answer is simple: Oncogenes arise as a result of mutations that increase the
expression level or activity of a proto-oncogene. Underlying genetic
mechanisms associated with oncogene activation include the following:
Point mutations, deletions, or insertions that lead to a hyperactive gene
product
Point mutations, deletions, or insertions in the promoter region of a proto-oncogene
that lead to increased transcription
Gene amplification events leading to extra chromosomal copies of a proto-oncogene
Chromosomal translocation events that relocate a proto-oncogene to a new
chromosomal site that leads to higher expression
Chromosomal translocations that lead to a fusion between a proto-oncogene
and a second gene, which produces a fusion protein with oncogenic activity

46. Oncogenes Were First Identified in Cancer-Causing Retroviruses
Evidence that viruses could cause cancer first came from a series
of studies by Peyton Rous beginning in 1911. He excised
fibrosarcomas (connective tissue tumors) from chickens, ground
them up, and removed cells and debris by centrifugation. After
passing the supernatant through filters with very small pores, which
retained even the smallest bacteria, Rous injected the filtrate into
chicks. Most of the injected chicks developed sarcomas. The
transforming agent in the filtrate eventually was shown to be
a virus, called Rous sarcoma virus (RSV). Some 50 years later, in
1966, Rous was awarded the Nobel prize for his pioneering work.
The long delay in recognizing the importance of his discovery was
due to the absence of any obvious molecular mechanism by
which a virus could cause cancer, either in birds or in humans

47. Growth Factors
 Normally cell require stimulation by GFs to undergo proliferation.
 Mostly these GFs are secreted by one cell type and act on a neighboring cell
to stimulate proliferation. (paracrine action)
 Cancer cells acquire the ability to synthesize their own GFs generating an
autocrine loop.
 Examples: - Glioblastomas secrete PDGF
- Sarcomas secrete TGF-α

48. Growth Factor Receptors
 Several oncogenes that encode growth factor receptors have been found.
Ex. Transmembrane proteins with an external ligand-binding domain and a cytoplasmic
tyrosine kinase domain.
 In the normal forms of these receptors, the kinase is transiently activated.
 The oncogenic versions of these receptors, kinase is constitutively activated. Resulting
in continuous mitogenic signals to the cell, even in the absence of growth factor in the
environment

49. Examples of Growth Factor receptor oncogenes and associated cancer:
• RET - dominantly inherited MEN types 2A and 2B and familial medullary thyroid carcinoma
• receptor tyrosine kinase c-KIT - gastrointestinal stromal tumors
• ERBB1 - squamous cell carcinomas of the lung, glioblastomas, head and neck tumors.

50. Signal-Transducing Proteins
 signal-transducing proteins plays an important role in signaling cascades downstream of
growth factor receptors, resulting in mitogenesis.
 RAS is a signal transducing oncoprotein belonging to family of GTP-binding proteins (G
proteins). Point mutation of RAS family genes (HRAS, KRAS, NRAS) is the single
most common abnormality of proto-oncogenes in human tumors.
KRAS- colon and pancreas
HRAS- bladder tumors
NRAS- hematopoietic tumors.
 In CML and some acute lymphoblastic leukemias, the ABL gene is translocated from its
normal habitat on chromosome 9 to chromosome 22. The resultant chimeric gene
encodes a constitutively active, oncogenic BCR-ABL tyrosine kinase.

52. Nuclear Regulatory Proteins
(Transcription Factors)
 all signal transduction pathways converge to the nucleus where stimulation of
nuclear transcription factors allow them for DNA binding. Binding of these proteins
to specific sequences in the genomic DNA activates transcription of genes.
 Growth autonomy may thus occur as a consequence of mutations affecting genes
that regulate transcription.

53. Example:
• MYC is a nuclear regulatory protein with very broad range of activity which includes
histone acetylation, reduced cell adhesion, increased telomerase activity and other changes
in cellular metabolism that enable a high rate of cell division.

54. Cell Cycle Regulators
(Cyclins and Cyclin-Dependent Kinases)
The ultimate outcome of all growth-promoting stimuli is the entry
of quiescent cells into the cell cycle. Cancers may grow
autonomously if the genes that drive the cell cycle become
dysregulated by mutations or amplification.

56. Example of cell cycle regulator genes and associated cancers:
• Overexpression of cyclin D genes - cancer of breast, esophagus, liver, and a subset
of lymphomas.
• Amplification of the CDK4 gene - melanomas, sarcomas, and glioblastomas.
While cyclins arouse the CDKs, their inhibitors (CDKIs) silence the CDKs and exert
negative control over the cell cycle. The CDKIs are frequently mutated or otherwise
silenced in many human malignancies.
• Germline mutations of p16 - melanoma.
• Somatically acquired deletion or inactivation of p16 - pancreatic carcinomas,
glioblastomas, esophageal cancers, acute lymphoblastic leukemias, non-small-cell
lung carcinomas, soft-tissue sarcomas, and bladder cancers.

57. Table : from wikipedia.com

58. Tumor suppressor gene
Cell surface
Inner aspect
of plasma
membrane
Cytoskeleton Cytosol Nucleus

59. Cell surface
 TGF-β receptors I and II are involved in regulation of cellular process by binding to
serine-threonine kinase complex .
 TGF-β signaling activate transcription of genes, including the CDKIs p21 and
p15/INK4b. In addition, TGF-β signaling leads to repression of CDK2, CDK4, and
cyclins A and E.
 these changes result in decreased phosphorylation of RB and cell cycle arrest.
 TGF-β type II receptor mutations - cancers of the colon, stomach, and endometrium.
 TGF-β pathway mutation - In 100% of pancreatic cancers and 83% of colon cancers

60. Inner aspect of plasma membrane
 protein product of the NF1 gene (Neurofibromin), contains a GTPase-activating
domain, which regulates signal transduction through RAS proteins.
 Neurofibromin facilitates conversion of RAS from an active to an inactive state. With
loss of neurofibromin function, RAS is trapped in an active, signal-emitting state.
 Individuals who inherit one mutant allele of the NF1 gene develop numerous benign
neurofibromas and optic nerve gliomas as a result of inactivation of the second copy
of the gene. This condition is called neurofibromatosis type 1.

61. Cytoskeleton
 The product of the NF2 gene, called neurofibromin 2 or merlin are related to the family
of membrane cytoskeleton-associated proteins.
 Cells lacking this protein are not capable of establishing stable cell-to-cell junctions and
are insensitive to normal growth arrest signals generated by cell-to-cell contact.
 Germline mutations in the NF2 gene predispose to the development of
neurofibromatosis type 2. Individuals with mutations in NF2 develop benign bilateral
schwannomas of the acoustic nerve.

62. Cytosol
PTEN (Phosphatase and tensin homologue)
 PTEN acts as a tumor suppressor by serving as a brake on the prosurvival/pro-growth
PI3K/AKT pathway.
 mutated In - Cowden syndrome, an autosomal dominant disorder marked by
frequent benign growths, such as tumors of the skin appendages, and an increased
incidence of epithelial cancers, particularly of the breast, endometrium, and
thyroid.
APC/β-Catenin Pathway:
 Adenomatous polyposis coli genes (APC) down-regulate growth-promoting
signals.
 Germ-line mutations at the APC (5q21) loci are associated with familial
adenomatous polyposis and colon cancer.

64. Nucleus
 RB protein, the product of the RB gene, is a ubiquitously expressed nuclear
phosphoprotein that plays a key role in regulating the cell cycle.
 germline loss or mutations of the RB gene - retinoblastomas and osteosarcomas.
 Somatically acquired RB mutations - glioblastomas, small-cell carcinomas of
lung, breast cancers, and bladder carcinomas.

66. • The p53 gene is located on chromosome 17p13.1, and it is the most common target for
genetic alteration in human tumors.
• p53 acts as a “molecular policeman” that prevents the propagation of genetically
damaged cells.

68. In order for cells to start dividing uncontrollably, genes that regulate cell
growth must be damaged. Proto-oncogenes are genes that promote cell
growth and mitosis, whereas tumor suppressor genes discourage cell growth,
or temporarily halt cell division to carry outDNA repair. Typically, a series of
several mutations to these genes is required before a normal cell transforms
into a cancer cell. This concept is sometimes termed "oncoevolution."
Mutations to these genes provide the signals for tumor cells to start dividing
uncontrollably. But the uncontrolled cell division that characterizes cancer
also requires that the dividing cell duplicates all its cellular components to
create two daughter cells. The activation of anaerobic glycolysis
(the Warburg effect), which is not necessarily induced by mutations in proto-oncogenes
and tumor suppressor genes, provides most of the building blocks
required to duplicate the cellular components of a dividing cell and,
therefore, is also essential for carcinogenesis

69. • different cell types that are critical to tumour growth. In particular
endothelial progenitor cells are a very important cell population in
tumour blood vessel growth.The hypothesis that endothelial
progenitor cells are important in tumour growth, angiogenesis and
metastasis has been supported by a recent publication in Cancer
Research (August 2010 This novel finding meant that investigators
were able to track endothelial progenitor cells from the bone
marrow to the blood to the tumour-stroma and vasculature
Cell types
involved in
cancer growth
• One of the first oncogenes to be defined in cancer research is
the ras oncogene. Mutations in the Ras family of proto-oncogenes
(comprising H-Ras, N-Ras and K-Ras) are very common,
being found in 20% to 30% of all human tumours. Ras was originally
identified in the Harvey sarcoma virus genome, and researchers
were surprised that not only is this gene present in the human
genome but also, when ligated to a stimulating control element, it
could induce cancers in cell line cultures.
Oncogenes

70. •Discussed before Proto-oncogenes
•Discussed before
Tumor
suppressor
genes

71. •mutations in both types of genes are required for cancer to
occur. For example, a mutation limited to one oncogene
would be suppressed by normal mitosis control and tumor
suppressor genes. A mutation to only one tumor suppressor
gene would not cause cancer either, due to the presence
of many "backup" genes that duplicate its functions. It is
only when enough proto-oncogenes have mutated into
oncogenes, and enough tumor suppressor genes
deactivated or damaged, that the signals for cell growth
overwhelm the signals to regulate it, that cell growth
quickly spirals out of control. Often, because these genes
regulate the processes that prevent most damage to
genes themselves, the rate of mutations increases as one
gets older, because DNA damage forms a feedback loop
Multiple
mutations

72. • Many mutagens are also carcinogens, but some
carcinogens are not mutagens. Examples of
carcinogens that are not mutagens
include alcohol and estrogen. These are thought to
promote cancers through their stimulating effect on
the rate of cell mitosis. Faster rates of mitosis
increasingly leave fewer opportunities for repair
enzymes to repair damaged DNA during DNA
replication, increasing the likelihood of a genetic
mistake. A mistake made during mitosis can lead to
the daughter cells' receiving the wrong number
ofchromosomes, which leads to aneuploidy and
may lead to cancer.
Non-mutagenic
carcinogens

73. Role of infection
bacterial viral Helminthiasis

74. Bacterial
Heliobacter pylori is known to cause MALT lymphoma. Other types of bacteria have
been implicated in other cancers.

75. Viral
12% of human cancers can be attributed to a viral infectionThe
mode of virally induced tumors can be divided into two, acutely
transforming or slowly transforming.
Viruses that are known to cause cancer such as HPV (cervical
cancer), Hepatitis B (liver cancer), and EBV (a type
of lymphoma), are all DNA viruses. It is thought that when the
virus infects a cell, it inserts a part of its own DNA near the cell
growth genes, causing cell division. The group of changed cells
that are formed from the first cell dividing all have the same viral
DNA near the cell growth genes. The group of changed cells are
now special because one of the normal controls on growth has
been lost.

76. Helminthiasis
Certain parasitic worms are known to be carcinogenic.These
include:
Clonorchis sinensis (the organism causing Clonorchiasis)
and Opisthorchis viverrini (causing Opisthorchiasis) are
associated with cholangiocarcinoma.
Schistosoma species (the organisms causing Schistosomiasis) is
associated with bladder cancer.

82. References
www.wikipedia.com
Molecular basis of cancer *Dr pranhash
Bhavsar ppt
www.slideshare.com
www.ncbi.nlm.nih.gov
www.learningobjects.weslyan.edu/cancer/
molecular_basis
www.nature.com/scitable