2Genetic damage lies at the heart of carcinogenesis. Three classes of carcinogenic agents induce such damage.These include:Chemical carcinogens.Radiation carcinogens, andViral oncogenes
31-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...
4Chemical carcinogens may be: a-Direct acting carcinogens:Definition: require no metabolic conversion to become carcinogenic.Eg. anticancer drugs.Patients receiving such therapy areat an increased risk of developinganother cancer (leukemia).
5b-Indirect acting carcinogens: ProcarcinogensDefinition: require metabolic activation to be carcinogenicEg.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.
62-Radiation carcinogenesis Ultraviolet rays:Derived from the sun can cause skin cancersEg.1-Squamous cell carcinoma2- Basal cell carcinoma3-Malignant melanoma
7Ionizing radiation:Electromagnetic and particulate radiations are oncogenicEg.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..
8The carcinogenic effect of: ultraviolet rays lies in its ability to damage DNAionizing radiation lies in their ability to induce mutations.
93-Viral oncogenesSome of DNA and RNA viruses have been linked with human cancerE.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.
10CARCINOGENESIS Cancer is a genetic disease. (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.
11The principal targets of gene damage Three classes of normal regulatory genes:1- the growth promoting oncogenes2- the growth inhibitory cancer suppressor genes3-genes that regulate programmed cell death or apoptosis
12In addition, a disability in DNA repair genes can predispose to widespread mutations in the genome and hence to neoplastic transformation.
13The 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
14Cancer 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.[12. Autonomy.(Self-government; freedom to act or function independently)3. Lack of differentiation.4. Metastasis.
15Oncogenes 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.g1-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.
16Cancer 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
17Genes 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.
18Persons 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 tumoure.g. familial retinoblastoma.