Etiology of cancer: Carcinogenic agents

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

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...

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).

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.

2-Radiation carcinogenesis

Ultraviolet rays: Derived from the sun can cause skin

cancers Eg. 1-Squamous cell carcinoma2- Basal cell carcinoma 3-Malignant melanoma

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.

.

The carcinogenic effect of: ultraviolet rays lies in its ability to

damage DNA ionizing radiation lies in their ability

to induce mutations.

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.

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.

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

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

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

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 function independently)

3. Lack of differentiation. 4. Metastasis.

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.

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

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.

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.