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Etiology of cancer: Carcinogenic agents.  Genetic damage lies at the heart of carcinogenesis.  Three classes of carcinogenic agents induce such damage.

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Presentation on theme: "Etiology of cancer: Carcinogenic agents.  Genetic damage lies at the heart of carcinogenesis.  Three classes of carcinogenic agents induce such damage."— Presentation transcript:

1 Etiology of cancer: Carcinogenic agents

2  Genetic damage lies at the heart of carcinogenesis.  Three classes of carcinogenic agents induce such damage. These include:  Chemical carcinogens.  Radiation carcinogens, and  Viral oncogenes

3 1-Chemical carcinogens  Initiation: refers to the induction of mutations in the genome of cells (alteration in DNA structure).  Promotion: the process of tumour induction in the previously initiated cells by chemicals referred to as promoters, which include various hormones, drugs, others...

4  Chemical carcinogens may be: a-Direct acting carcinogens: Definition: require no metabolic conversion to become carcinogenic. Eg. anticancer drugs. Patients receiving such therapy are at an increased risk of developing another cancer (leukemia).

5 b-Indirect acting carcinogens: Procarcinogens  Definition: require metabolic activation to be carcinogenic  Eg. 1-Aromatic hydrocarbons: present in cigarette smoke may be relevant to the pathogenesis of lung cancer. 2-Azodyes: an aniline dye used in the rubber industries was responsible for bladder cancers in exposed workers. 3-Asbestos: predisposes exposed industrial workers to the development of lung cancer and mesothelioma. 4-Aflatoxin B: produced by the fungus Aspergillus flavus is a potent hepatocarcinogen. 5-Estrogen hormone: increases the risk of endometrial and breast carcinomas.

6 2-Radiation carcinogenesis  Ultraviolet rays: Derived from the sun can cause skin cancers  Eg. 1-Squamous cell carcinoma 2- Basal cell carcinoma 3-Malignant melanoma

7 Ionizing radiation:  Electromagnetic and particulate radiations are oncogenic Eg.  1-Miners of radioactive elements have increased risk of lung cancer.  2-Survivors of the atomic bomb dropped on Hiroshima and Nagasaki showed an increased incidence of leukemia after a latent period of about 7 years.  3-Therapeutic radiation of neck in children has been associated with the later development of thyroid cancer..

8  The carcinogenic effect of:  ultraviolet rays lies in its ability to damage DNA  ionizing radiation lies in their ability to induce mutations.

9 3-Viral oncogenes Some of DNA and RNA viruses have been linked with human cancer E.g.  1-Human T-cell leukemia virus type 1 (HTLV-1): T-cell leukemia/lymphoma.  2-Human papilloma virus: squamous cell carcinoma of the cervix and cancer of anogenital region.  3-Epstein-Barr virus: -Burkitt's lymphoma -Hodgkin's disease - -Nasopharyngeal cancer.  4-Hepatitis B virus: Hepatocellular carcinoma.

10 CARCINOGENESIS ( The molecular basis of cancer)  Cancer is a genetic disease.  The genetic damage or mutation may be: 1- Acquired by the action of environmental agents such as chemicals, radiation or viruses, 2-Inherited in the germ line.

11 The principal targets of gene damage  Three classes of normal regulatory genes:  1- the growth promoting oncogenes  2- the growth inhibitory cancer suppressor genes  3-genes that regulate programmed cell death or apoptosis

12  In addition, a disability in DNA repair genes can predispose to widespread mutations in the genome and hence to neoplastic transformation.

13 The genetic hypothesis of cancer  A tumour mass results from the clonal expansion of a single progenitor cell that has suffered the genetic damage  (i.e. tumours are monoclonal).  N.B. Carcinogenesis is a multistep process

14 Cancer can be defined by the following 4 characters:  1. Clonality. A clone is a group of identical cells that share a common ancestry, meaning they are derived from the same mother cell. [1 [1  2. Autonomy.(Self-government; freedom to act or function independently)governmentfreedomact functionindependently  3. Lack of differentiation.  4. Metastasis.

15 Oncogenes and Cancer:  Oncogens: are genes whose products are associated with neoplastic transformation. It is a mutant form of normal cellular gene.  Growth promoting oncogenes: cancer may arise by the activation of growth promoting genes,  e.g 1-Over expression of growth factor receptor family (C-erb- B2 in the majority of squamous cell carcinoma). 2-Amplification of n-myc (nuclear regulatory protein) in neuroblastoma.

16 Cancer supressor genes:  Cancer may also arise by inactivation of genes that normally suppress cell proliferation (cancer suppressor genes) e.g. TP53 (formerly P53).  Mutations of TP53 are seen in a wide variety of tumours: carcinomas of the breast, colon, and lung.  One function of TP53: to prevent cells damaged by mutagenic agents from proceeding to divide.  So mutant TP53 fails to arrest cell proliferation, hence cells with DNA damage continue to divide and accumulate mutations lead to neoplastic transformation

17  Genes that regulate apoptosis: Accumulation of neoplastic cells may result also from mutations in genes that regulate apoptosis (programmed cell death).  DNA repair genes: While exposure to naturally, occurring DNA- damaging agents,such as ionizing radiation, sunlight, and dietary carcinogens, is common, cancer is relatively a rare outcome of such encounters. This results from the ability of normal cells to repair DNA-damage and thus prevent mutation in genes that regulate cell growth and apoptosis.

18  Persons born with inherited mutations of DNA repair proteins are at a greatly increased risk of developing cancer.  Some malignant tumours are hereditary, and are characterized by inheritance of a single mutant gene that greatly increases the risk of developing a tumour e.g. familial retinoblastoma.

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