Properties of cancer cells
Three important properties-
1) Diminished or unrestricted control of growth
2) Capability of invasion of local tissues
3) Capable of spreading to distant parts of body by metastasis.
Characteristics of cancer cells (Deviations from normal characteristics)
1) Morphological changes
- Round shape, larger than normal
- Altered nuclear : cytoplasmic ratio
- Transformed cells grow over another and form multilayers.
- Can grow without attaching to the surface (in vitro), diminished adhesion
2) Biochemical Changes
- Increased synthesis of DNA and RNA
- Increased rate of glycolysis- both aerobic and anaerobic
- Show alteration of permeability and surface charges
- Alteration of oligosaccharide chains
- Increased activity of Ribonucleotide reductase and decreased catabolism of pyrimidines
- Alteration of isoenzyme pattern to fetal proteins
- Appearance of new antigens and loss of certain antigens
- Changes of glycolipid and glycoprotein constituents on cell surface
- Alteration of the activities of certain enzymes such as proteases
- Alteration in transport properties
- Inappropriate synthesis of certain hormones and growth factors.
Etiology of cancer
Agents causing cancer fall in to three broad groups-
a) Radiant energy
b) Chemical compounds
There may also be familial causes due to mutation in specific genes (e.g. tumor suppressor genes)
a) Radiant energy
- UV Rays
Mechanism of carcinogenesis by radiations- Damage to DNA is the basic mechanism
- UV Rays cause the formation of pyrimidine dimers, apurinic or apyrimidinic sites, single or double strand breaks or by causing cross linking of strands.
- X-rays and Y-Rays, apart from causing direct damage to DNA, cause generation of free radicals also.The resultant free radicals interact with DNA and other macromolecules, leading to molecular damage contributing to carcinogenic effect of radiant energy.
b) Chemical Compounds
A wide variety of chemicals are carcinogenic. Some of these are direct reacting and majority occurs as procarcinogens which are converted in the body to ultimate carcinogenic chemicals. These chemicals gain entry in to the body through diet, environment (occupation, life style) or through drugs used for a therapeutic cause.
Examples of chemical carcinogens
|1.||Polycyclic aromatic hydrocarbons||Benzo(α) pyrene, Dimethyl benzanthracene|
|2.||Aromatic amines||2-Acetyl amino fluorine,N-Methyl-4 amino azo benzene|
|3.||Nitrosamines||Dimethylnitrosamine, Diethyl nitrosamine|
|4.||Drugs||Alkylating agents, diethyl stibestrol|
|5.||Naturally occurring compounds||Dactinomycin, Aflatoxin B|
|6.||Inorganic compounds||Arsenic, asbestos, beryllium, cadmium, chromium, nickel, vinyl chloride, β- propiolactone etc.|
Mechanism of action of chemical carcinogens
- Some may be direct acting- β- propiolactone, methyl cholanthrene; these agents interact directly with the target molecule.
- Some require metabolic activation- Aromatic hydrocarbons, aromatic amines etc.
Metabolic activation- The process whereby one or more enzyme catalyzed reactions convert procarcinogens to active carcinogens is called metabolic activation. Any intermediate compounds formed are called proximate carcinogens. The sequence can be displayed as follows-
Procarcinogen—–> Proximate Carcinogen—–>Ultimate carcinogen
The Procarcinogen in itself is not a chemically reactive species, whereas the ultimate carcinogen is highly reactive. The procarcinogens are electrophiles (molecules deficient in electrons), which readily attack nucleophilic (electron rich) groups in DNA, RNA and proteins.
The metabolism of procarcinogens involves action by mono-oxygenases (cytochrome P450) and transferases. The activities of these enzymes are affected by a number of factors- such as species, age, gender and genetic variations. The variations in activities of these enzymes help explain the often appreciable differences in carcinogenicity of chemicals among different species and different individuals of the same species.
Damage to DNA- can be by
1) Covalent binding- The carcinogens and their derivatives bind covalently to cellular molecules such as DNA, RNA and proteins.
2) These agents interact with the purines, pyrimidines or Phospho diester groups of DNA. Most common site of attack is guanine.
The covalent interactions of direct or ultimate carcinogens with DNA can result in several types of DNA damage. This damage can be repaired by the repair system. The unrepaired damage leads to mutations.
c) Viral Oncogenesis
The Oncogenic viruses contain DNA or RNA as a genome.
i) DNA Viruses
Many DNA viruses cause tumor in animals. The DNA viruses causing cancers in human are-
- Epstein- Barr virus-causes Burkitt’s lymphoma and nasopharyngeal carcinoma.
- Hepatitis B Virus– is probably the major etiological agent for many primary liver cancers.
- Human Papilloma virus (HPV)- Multiple warts and cervical cancer.
Mechanism of action of DNA viruses
- DNA viruses bind tightly to the DNA and alter the gene expression.
- The viral proteins show co-operative effect suggesting that alteration of more than one reaction takes place for malignant transformation.
ii) RNA Viruses (Retro viruses)
- These viruses convert their RNA genome in to DNA with the help of reverse transcriptase enzyme,
- The resultant DNA is integrated in to the DNA of normal cells causing malignant transformation by various mechanisms.