Molecular pathogenesis of cancer

Amr MohammedAhmed Omar Ragheb

Mohammed Osama

Mohammed Youssef Mohammed

Mostafa Hassan

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

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

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.

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.

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

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"

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

Mutation

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

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

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

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

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.

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

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

Blood smear (normal)

Image Credit:

http://lifesci.rutgers.edu/~babiarz/

Sickle cell anemia

Image Credit: http://explore.ecb.org/

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.

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

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.

• 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 .

Flowchart depicting a simplified scheme of

the molecular basis of cancer

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.

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.

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 asmetastasissuppressors.

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

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.

• 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.

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)

• 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.

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.

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.

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.

(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.

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

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.

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.

Oncogenes

Growth factors

Growth factor receptors

Signal transduction

proteins

Nuclear regulatory

proteins

Cell cycle regulators

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

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

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

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 cellto stimulate proliferation. (paracrine action)

Cancer cells acquire the ability to synthesize their own GFs generating anautocrine loop.

Examples: - Glioblastomas secrete PDGF

- Sarcomas secrete TGF-α

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

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.

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.

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.

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.

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.

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.

Table : from wikipedia.com

Tumor suppressor gene

Cell surfaceInner aspect

of plasma membrane

Cytoskeleton Cytosol Nucleus

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

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.

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.

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.

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.

• 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.

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

• 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

•Discussed beforeProto-

oncogenes

•Discussed before Tumor

suppressor genes

• mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogenewould be suppressed by normal mitosis control and tumorsuppressor 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

• 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

Role of infection

bacterial viral Helminthiasis

Bacterial

Heliobacter pylori is known to cause MALT lymphoma. Other types of bacteria have

been implicated in other cancers.

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.

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.

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