Etiology of cancer: Carcinogenic agents

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 Aspergillusflavus 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 2. Autonomy.(Self-government; freedom to act or 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,suchas 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.