Biochemistry of cancer cells- Lecture-1

“International Union Against cancer” has defined Cancer as a disturbance of growth, characterized by excessive proliferation of cells without apparent relation to the physiological demands of the organ involved.

Properties of cancer cells

Three important properties-

1) Diminished or unrestricted control of growth

2) The capability of invasion of local tissues

3) Capable of spreading to distant parts of the 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
• The appearance of new antigens and loss of certain antigens
• Changes of glycolipid  and glycoprotein constituents on the 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 into three broad groups-

a) Radiant energy

b) Chemical compounds

c) Viruses

There may also be familial causes due to mutation in specific genes (e.g. tumor suppressor genes)

a) Radiant energy

• UV Rays
• X-Rays
• Y-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 the generation of free radicals also. The resultant free radicals interact with DNA and other macromolecules, leading to molecular damage contributing to the carcinogenic effect of radiant energy.

b) Chemical Compounds

A wide variety of chemicals are carcinogenic. Some of these are direct reacting and the majority occurs as procarcinogens which are converted in the body to ultimate carcinogenic chemicals. These chemicals gain entry into the body through diet, environment (occupation, lifestyle) or through drugs used for a therapeutic cause.

Examples of chemical carcinogens

S.No.	Class	Compound
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, diethylstilbestrol
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 the 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.  The most common site of the 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. 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 tumors 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 Papillomavirus (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 (Retroviruses)

• These viruses convert their RNA genome into DNA with the help of reverse transcriptase enzyme,
• The resultant DNA is integrated into the DNA of normal cells causing malignant transformation by various mechanisms.