Carcinogenesis

Carcinogenesis

“Take benefit of five before five: Your youth before your old age, your health before your sickness, your wealth before your poverty, your free time before you are preoccupied, and your life before your death”(Narrated by Ibn Abbas and reported by Al Hakim)

Definition Carcinogenesis 

= oncogenesis = tumorigenesisIt is a process by which

normal cells are transformed into cancer cells.

Reprogram a cell to undergo uncontrolled cell division, forming a malignant mass.

Cancer is disease of regulation of tissue growth.

Genes involveDefective proto-oncogenes =

Oncogenes.Tumor suppressor

genes defect.

Proto-oncogeneA proto-oncogene code for proteins

that help to regulate cell growth and differentiation.

Often involved in signal transduction and execution of mitogenic signals, usually through their protein products.

proto-oncogene mutation oncogene (tumor-inducing agent).

The proto-oncogene can become an oncogene by small modification of its original function.

OncogenesAn oncogene is a gene that, when

mutated or expressed at high levels, helps turn a normal cell into a tumor cell.

Activated oncogenes cause cells to survive and proliferate instead of programmed form of death (apoptosis).

Oncogenes require an additional step, such as mutations in another gene, or environmental factors, such as viral infection, to cause cancer.

Cont. oncogeneA oncogene can cause

◦ a loss of regulation◦ increase in protein concentration, caused by

an increase of protein expression (through misregulation) an increase of protein (mRNA) stability, prolonging its

existence and thus its activity in the cell a gene duplication (one type of chromosome abnormality),

resulting in an increased amount of protein in the cell A chromosomal translocation (another type of

chromosome abnormality), causing an increased gene expression in the wrong cell type or at wrong

times the expression of a constitutively active ''hybrid protein''. This type

of aberration in a dividing stem cell in the bone marrow leads to adult leukemia

◦ an increase in protein (enzyme) activity

Tumor suppressor geneAlso called antioncogene

protects a cell from develop into cancer cell.

Tumor-suppressor genes code proteins to dampening or repressive the cell cycle or promote apoptosis, and sometimes do both.

Cont. Tumor suppressor geneThe functions of tumor-suppressor

proteins fall into several categories including the following:◦Repression of genes ◦Coupling the cell cycle to DNA

damage. ◦Involved in cell adhesion prevent

tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis.

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.

1. Polymerase

2. Repressor 3. Promoter4. Operator5. Lactose

Etiology Caused by mutation and

epimutation of the genetic material of normal cells, which upsets the normal balance between proliferation and cell death

MutationDefinition

◦A mutation is a permanent change in the DNA sequence of a gene.

◦alter the amino acid sequence of the protein encoded by the gene.

The sun was hot but the old man did not get his hat

Types of mutationSubstitution

◦CTG GAG CTG GGG◦Example : sickle cell anemia

Insertion◦CTG GAG CTG GTG GAG◦Example : Huntington’s disease

Deletion◦CTG GAG CT AG◦Example : Cri du chat

Frameshift◦The fat cat sat hef atc ats at

Example : Crohn’s Disease

Epimutation Definition

◦Epimutation is abnormal transcriptional repression of active genes and/or abnormal activation of usually repressed genes caused by errors in epigenetic gene repression.

◦Epimutation arises in somatic cells and the germline, and constitutional epimutation may also occur.

◦Epimutation is the first step of tumorigenesis and can be a direct cause of carcinogenesis. 

Mutation and epimutationLarge-scale mutations involve the

deletion or gain of a portion of a chromosome

Small-scale mutations include point mutations, deletions, and insertions

Epimutations include methylations, demethylations, acetylation, phosphorylation or other alterations to histones

Cont. etiologyDNA damages can arise from

exposure to ◦Exogenous agents◦Endogenous agent

Category of cancerNon sporadic cancers (30%), do

have hereditary componentSporadic cancers (70%), have no

hereditary component

Non-sporadic vs sporadic cancer

Non sporadic Sporadic

Hereditary cancer often occur earlier than the sporadic - experts often recommend different screening, at a younger age for people with hereditary cancer in their family.

Occur late than non sporadic

Hereditary cancers are caused in part by gene changes passed on from parents to their children. Other blood relatives may share these same gene changes. 

Sporadic cancers are believed to arise from gene damage acquired from environmental exposures, dietary factors, hormones, normal aging, and other influences. Most acquired gene changes are not shared among relatives or passed on to children.

Individuals who have inherited a gene change may be at a higher risk for more than one type of cancer.

Less risk of having multiple cancer

PathogenesisNormal circumstances, the

balance between proliferation and programmed cell death (apoptosis) maintained by tightly regulating both processes to ensure the integrity of organs and tissues

Cont.The uncontrolled and often rapid

proliferation of cells can lead to benign tumors; some types of these may turn into malignant tumors (cancer).

Cont. Hanahan and Weinberg were summarized the biological

properties of malignant tumor cells as follows:1. Acquisition of self-sufficiency in growth signals, leading to

unchecked growth.2. Loss of sensitivity to anti-growth signals, also leading to

unchecked growth.3. Loss of capacity for apoptosis, in order to allow growth despite

genetic errors and external anti-growth signals.4. Loss of capacity for senescence, leading to limitless replicative

potential (immortality)5. Acquisition of sustained angiogenesis, allowing the tumor to

grow beyond the limitations of passive nutrient diffusion.6. Acquisition of ability to invade neighbouring 

tissues, the defining property of invasive carcinoma.

7. Acquisition of ability to build metastases at distant sites, the classical property ofmalignant tumors (carcinomas or others).

Properties of malignant tumor

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