Molecular Basis of Cancer

Molecular basis of cancer
Dr:Zainab
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 genes are the principal
targets of genetic damage:
• I. Growth promoting protooncogenes(dominant genes,

can transform cells into malignant cells with single
allele is damaged).
• II. Growth inhibiting cancer suppressor genes
(recessive genes, can transform cells into malignant
cells only if both alleles of gene are damaged).
• III. Genes that regulate the apoptosis.
• IV. DNA repair gene, disability of DNA repair genes can
predispose to widespread mutation & neoplastic
transformation.
• •Fortunately, in most if not all instances, no single mutation
is sufficient to transform a normal cell into a cancer cell.
• Carcinogenesis is a multistep process resulting from the
accumulation of multiple mutations.
• •These mutations accumulate independently in different
clonal cells, generating subclones with varying abilities to
grow, invade, metastasize, and resist (or respond to) therapy.
• •Over a period of time tumors not only increase in size but

become more aggressive and acquire greater malignant
potential (tumor progression)
Eight fundamental changes in cell
physiology are considered the
hallmarks of cancer.
• 1.Self-sufficiency in growth signals
• 2.Insensitivity to growth-inhibitory signals
• 3.Altered cellular metabolism
• 4.Evasion of apoptosis
• 5.Limitless replicative potential (immortality)
• 6.Sustained angiogenesis
• 7.Invasion and metastasis
• 8.Evasion of immune surveillance
1. Self-sufficiency in growth signals
• •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.
• •Oncogenes encode proteins called oncoproteins
that promote cell growth, even in the absence of
normal growth-promoting signals.
2. Insensitivity to Growth-Inhibitory
Signals (Tumor Suppressor Gene)
• •All tumor suppressor genes cause inhibition of cell

growth by two pathways: -
• 1. Stimulate antigrowth signal, causing cells to enter

G0 phase.
• 2. Prevent the cell to pass from phase G1to S phase.
• •Disruptionsof tumor suppressor genes make the cells
resistant to inhibition of growth & increase their
proliferation.
P53
• •It is one of most commonly mutated gene in human

cancers
• •Normal p53prevents neoplastic transformationby: -
• I.activation of temporary cell cycle arrest (quiescence),
• II.induction of permanent cell cycle arrest
(senescence),
• III.triggering of programmed cell death (apoptosis).
• •In view of these activities,p53 has been rightfully
called a "guardian of the genome."
P53
• •With homozygous loss of p53,DNA damage goes

unrepaired, mutations become fixed in dividing cells, and
the cell turns onto a one-way street leading to malignant
transformation.
• •More than 70% of malignant human tumor show defect in
functions of TP53.
• •Most of mutations in TP53 are acquired & less commonly
they are inherited mutations like Li-fraumeni syndrome
(patient have many cancers like sarcomas, breast cancer,
leukemia, brain tumors, adrenal tumors).
3. Altered cellular metabolism
• •Even in the presence of sufficient oxygen, cancer cells
demonstrate a distinctive form of cellular metabolism
characterized by high levels of glucose uptake and
increased conversion of glucose to lactose
(fermentation) via the glycolytic pathway. This
phenomenon, called the Warburg effect and also
known as aerobic glycolysis.
• •Aerobic glycolysis provides rapidly dividing tumor
cells with metabolic intermediates that are needed for
the synthesis of cellular components, whereas
mitochondrial oxidative phosphorylation does not.
4. Evasion of apoptosis.
•
• •Normally, there are two pathways that lead to apoptosis: the
extrinsic pathway,which is mediated by TNF-Fas receptor &
inhibited by FLICE protein (FLIP). and the intrinsic pathway (also
known as the mitochondrial pathway),is mediated by BAX, BAK
genes & inhibited by bcl2 gene.
• •Changes in mechanism of apoptosis in malignant tumors are:
• •Decrease level of Fas protein (CD95).
• •Increase level of FLICE protein (FLIP); which inhibits apoptosis by
inhibit activation of caspases.
• •Reduced levels of pro-apoptotic BAX resulting from loss of p53.
• •Increase level of Bcl2 gene which inhibits apoptosis (as in 85% of
B-cell lymphoma).
5. Limitless replicative potential
(immortality)
• •Most of normal human cells have capacity of
50 to 70 doublings, after this, the cells lose the
capacity to divide (due to loss of Telomerase
enzymes which is important in DNA
replication).
• •In malignant tumors, there is increased level
of Telomerase.
6. Sustained Angiogenesis:
• •Most of cancers cannot grow more than 1 to 2 mm in diameter or
thickness unless they are vascularized.
• •Angiogenesis has many effects on tumor growth:

• 1. Supplies nutrients & oxygen.
• 2. Newly formed endothelial cells during angiogenesis, will stimulate the
growth of adjacent tumor cells by secretion of polypeptides (like platelets
growth factor).
• 3. Angiogenesis is also important for development of metastasis.
• •Cells of malignant tumor are the main inducer of angiogenesis by their

production of growth factors (Angiogenetic factors); the most two
important ones are:
• 1-Vascular endothelial growth factor.

• 2-Fibroblast growth factor.
7. Invasion and metastasis
• •The Metastatic pathway of cancer can be divided into two phases:
• 1. Invasion of Extracellular matrix: Include the following steps

• I.Detachment of tumor cells from each other (by losing of E-
cadherin & B-catenin molecules).
• II.Degradation of Extracellular Matrix (by Metalloproteinase).
• III.Attachment of tumor cells to new Extracellular Matrix
components.
• IV. Migration of tumor cells to the vessels (mediated by Cytokines).

• 2. Vascular dissemination & Homing of tumor cells:
• -In circulation, Tumor cells are liable to destruction by host
immune cells.
• •To avoid such destruction, tumor cells are arranged
themselves into small emboli (by adhesion to circulating
leukocytes &platelets).
• -Then tumor cells leave circulation by adhesion to the

endothelial cells & destruction of basement membrane of
vessels, to enter the extracellular matrix of metastatic site.
• -Distribution of metastasis can be predicted by the location of
primary tumor & its vascular & lymphatic drainage e.g. cancer
of breast is expected to involve the lung & bones of thorax.
• -Some cancers have unexpected metastatic pathway e.g.
caner of lung metastasize to the adrenal glands.
8. Evasion of immune surveillance
• •Cancer cells express a variety of antigens that
stimulate the host immune system, which
appears to have an important role in
preventing the development of cancers.
• •Despite the antigenicity of cancer cells, the
immune response to established tumors is
ineffective, due to acquired changes that
allow cancer cells to avoid anti-tumor
responses.
Etiology of cancer: carcinogenic Agents
1. Chemical carcinogens:
*lndirect- Acting Agents: refers to chemicals that require
metabolic conversion to ultimate carcinogen before
they become active, ex: the polycyclic hydrocarbon
present in fossil fuels.
* Direct-Acting Agents:
Direct-acting agents require no metabolic conversion to
Become carcinogenic. Ex: cancer chemotherapeutic
drugs (e.g., alkylating agents)
2. Radiation carcinogensis: can causes
chromosome breakage, Translocation & point
mutation.
3. Viral & microbial carcinogens:
* Oncogenic RNA viruses: ex:
- Human T- cell leukaemia virus-1 (HTLV-1)
cause T- cell leukaemia/ lymphoma.
- * Oncogenic DNA viruses:
- Human papilloma virus (HPV) cause
- (type 1,2.4--- squamous cell papilloma)
- ( type16 &18--- Squamous cell carcinoma of cervix)
- - Epstain- Barr virus (EBV) causes Burkitt
lymphoma, Hodgkins lymphoma & nasopharyngeal
carcinoma.
- - Kaposi sarcoma herpes virus (KSHV).
- - Hepatitis B virus (HBV) caused Hepatocellular
carcinoma .
4. Helicobacter pylori ( H. pylori) can caused
Gastric adenocarcinoma & Marginal zone
Associated Lymphoma (MALT).
Grading & Staging of Cancer
* Grading of cancer: attempts to estimate the
aggressiveness of malignancy based on
cytologic differentiation of tumor cells and
number of mitoses within the tumor.
The cancer classified as Grade I, II, III & IV in
order to increase anaplasia.
Grade I= well differentiated.
Grade II = moderately differentiated.
Grade III = poorly differentiated.
Grade IV = undifferentiated ( anaplastic).
Staging of cancer : is the extent of tumor spread
clinically & histopathologically) based on
- Size of primary tumor.
- Extend to spread to regional lymph nodes.
- Presence or absence of metastasis.
Method of staging:
TNM system: ( T: size of primary Tumor
N: lymph Node involvement
M: distance Metastasis)
Thank you

Molecular Basis of Cancer - Pathology Lecture

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• •Nonlethal genetic damage lies at the heart

• I. Growth promoting protooncogenes(dominant genes,

• •Over a period of time tumors not only increase in size but

• •All tumor suppressor genes cause inhibition of cell

• 1. Stimulate antigrowth signal, causing cells to enter

• •It is one of most commonly mutated gene in human

• •With homozygous loss of p53,DNA damage goes

• •Angiogenesis has many effects on tumor growth:

• •Cells of malignant tumor are the main inducer of angiogenesis by their

• 1-Vascular endothelial growth factor.

• •The Metastatic pathway of cancer can be divided into two phases:

• 1. Invasion of Extracellular matrix: Include the following steps

• IV. Migration of tumor cells to the vessels (mediated by Cytokines).

• -Then tumor cells leave circulation by adhesion to the

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