BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E. S. Severin - 2004

SECTION 16. ONCOGENESIS

Tumors represent a group of genetic diseases characterized by uncontrolled cellular proliferation. According to their capacity to spread throughout the body, they are divided into two groups: benign, or localized tumors, which do not invade neighboring Tissues; and malignant tumors, capable of growing into (invading) specific tissues and migrating to other PARTS OF THE body to form secondary tumors (metastases).

Over 100 Different types of Cancer have been described, although five of them account for more than 50% of all diagnosed cases. These include lung, breast, colorectal, prostate, and uterine/ovarian cancers (Fig. 16-1).

Class="center">Fig. 16-1. Mortality rates from various types of cancer among men and women.

Tumors are also classified According to the tissues and Cell types of origin: carcinomas are tumors arising from ectodermal and endodermal Cells; sarcomas originate from mesodermal cells; and hemoblastoses (leukemias and lymphomas) develop from stem Cells of the hematopoietic and lymphatic tissues.

Following cardiovascular diseases, cancer ranks as the second leading cause of human mortality. The most thoroughly studied causes of cancer in humans include radiation, chemical carcinogens, and Viruses.

Research into viruses as a potential cause of oncological diseases led to the formulation of the oncogene theory, which provided insight into the mechanisms by which various agents trigger the Transformation of a normal cell into a tumor cell.

I. Physical, Chemical, and Biological Agents Inducing Tumor Formation

Approximately 80% of human cancer cases result from exposure to environmental factors, which encompass lifestyle, dietary habits, diseases that increase tumor risk, and hereditary genomic alterations.

Agents that stimulate tumor formation (carcinogens) can be divided into three major groups: radiations, chemical compounds, and viruses.

A. Radiations

It has been established that UV, X-rays, and gamma rays exert mutagenic and carcinogenic effects. They damage DNA through several mechanisms. Radiation exposure can cause the removal of nitrogenous bases from polynucleotide chains, resulting in The formation of apurinic or apyrimidinic sites, as well as single- and double-strand breaks or cross-links. UV radiation induces the formation of thymine dimers (see Section 4). Along with direct effects, X-rays and gamma rays induce the generation of free radicals in tissues (O₂^2-, OH^-, OH^•, O₂, etc.), which attack DNA and other macromolecules, damaging the genetic apparatus and disrupting template-directed synthesis within The Cell.

For instance, in Australia and New Zealand, where solar UV intensity is high, a portion of the population develops carcinomas and melanomas. An increased incidence of leukemia has been noted among the residents of Japan following the atomic bombings. Furthermore, a higher frequency of Lung Cancer is observed in miners working with radioactive ores.

B. Chemical Carcinogenesis

A vast number of chemically diverse substances exhibit carcinogenic activity, with their main groups presented in Table 16-1.

Table 16-1. Principal Chemical Carcinogens

In the Liver, most of these substances act as procarcinogens—compounds that do not directly interact with the cellular genetic apparatus. Following additional metabolic modification, they are converted into ultimate carcinogens capable of reacting with nucleic acid and protein molecules, disrupting cellular regulatory mechanisms, and driving tumor growth. The transformation of cells under METABOLISM/18.html">The Influence of carcinogens is termed chemical carcinogenesis.

It has been established that detoxification Enzymes involved in procarcinogen metabolism display striking polymorphism. Certain isoforms of these Proteins exhibit low activity. In individuals with such enzyme variants, procarcinogens undergo metabolic conversion and elimination more slowly, failing to be converted into active carcinogens in time. This phenomenon explains interindividual differences in susceptibility to tobacco smoke carcinogens and the predisposition of smokers to lung cancer.

In resting cells, DNA is double-stranded, and nitrogenous bases are shielded from damaging agents. However, during Replication, polynucleotide chains become highly sensitive to carcinogens, and cells that have sustained damage may face various fates (Fig. 16-2).

Fig. 16-2. Consequences of cellular DNA damage by carcinogens.

Polycyclic aromatic hydrocarbons (PAHs) are components of incomplete coal and petroleum combustion products, oil pyrolysis products, and substances found in charred meat, and are also generated during tobacco smoking. They can bind to purine bases (particularly guanine) only after enzymatic activation by Monooxygenases (see Section 12), which operate with the participation of various cytochrome P₄₅₀ isoforms. These enzymes catalyze the formation of epoxides, which are subsequently converted into diols by epoxide hydrolase. Primary or secondary epoxides, possessing high chemical reactivity, can interact with nucleophilic groups in the DNA molecule (Fig. 16-3).

Fig. 16-3. Formation of carcinogens from PAHs by xenobiotic-detoxifying enzymes. A and B are two different metabolic pathways for benzo(a)pyrene transformation. Pathway B leads to a non-reactive product, whereas pathway A converts benzo(a)pyrene into a carcinogen capable of binding to guanine and adenine residues in the DNA molecule.

PAHs were the first compounds whose carcinogenicity was experimentally proven in the early 20th century, when benzanthracene, benzo(a)pyrene, 7,12-dimethylbenzanthracene, and Other Compounds containing condensed aromatic rings were isolated from coal tar. Observations linking human exposure to certain substances with The Development of cancer had been described much earlier. For instance, as early as 1775, a report emerged noting that chimney sweeps in London had a remarkably high incidence of scrotal cancer, which was attributed to their continuous exposure to coal tar and soot. Around the same time, a correlation was discovered between The Use of snuff and nasal cancer, and between smoking and lip or lung cancer.

Aromatic amines. Aromatic amines include substances used in The production of aniline Dyes and within the rubber industry. Exposure to these compounds leads to the development of Bladder cancer in workers employed in these industries. One representative of this group is 2-naphthylamine, which undergoes chemical modification primarily in the liver (Fig. 16-4).

Fig. 16-4. Metabolism of 2-naphthylamine.

The carcinogen 2-amino-1-naphthol is formed during the hydroxylation of 2-naphthylamine. However, in the liver, it rapidly interacts with PAPS, turning into a neutral product that is excreted in the urine. In the bladder, some of these conjugates are cleaved by Hydrolases present in trace amounts in the urine. This regenerates 2-amino-1-naphthol—a carcinogen that, upon repeated human exposure to naphthylamine, induces the development of bladder cancer.

Nitrosamines appear in the body As a result of the interaction between secondary aliphatic amines and nitrites. Secondary amines and nitrites are constant components of food, meaning nitrosamines are synthesized during the baking or roasting of meat and fish. At one time, nitrites were widely used as meat and fish preservatives; they are also naturally formed in green plants.

The metabolism of nitrosamines by the microsomal oxidation system leads to the Formation of the methyldiazonium ion, which can methylate cellular DNA, thereby inducing malignant tumors of the Lungs, Stomach, Esophagus, liver, and Kidneys (Fig. 16-5).

Fig. 16-5. DNA Methylation by metabolic products of nitrosamines: dimethylnitrosamine and N-methylnitrosourea.

The primary product of the interaction between nitrosamines and cellular DNA is N₇-methylguanine-DNA, whereas the minor product of this interaction—O₆-methylguanine-DNA—possesses the highest carcinogenicity.

Alkylating and acylating agents, by interacting with the nucleophilic amino and hydroxyl groups of DNA, can damage Gene Structure and induce tumor formation. Compounds such as vinyl chloride (used in the production of plastics and packaging Materials) and certain medications utilized in tumor therapy or as immunosuppressants (cyclophosphamide, busulfan, diethylstilbestrol) can be regarded as risk factors. Pharmaceutical agents belonging to this group of compounds are capable of causing secondary tumors in a small percentage of patients.

B. DNA- and Introduction/7.html">RNA-containing Viruses

Data on The Role of viruses in tumor development were obtained at the beginning of the 20th century. For example, in 1908, avian leukosis was successfully induced using a cell-free extract from tumor cells, and in 1910, F. Rous described the first oncogenic virus capable of initiating Sarcoma in chickens. In 1968, the Russian scientist L. A. Zilber formulated the viral-genetic theory of tumor origin driven by Oncogenic Viruses. Although viral carcinogenesis was initially described only in birds and animals, recent data confirm the involvement of viruses in the development of certain human cancers. Thus, the DNA-containing Epstein-Barr virus causes Burkitt's lymphoma, papillomavirus DNA leads to Skin and genital cancers, and the RNA-containing HUMAN IMMUNODEFICIENCY VIRUS gives rise to sarcomas.

DNA-containing viruses partially, and sometimes fully, integrate into the human cellular genome and express viral genes, resulting in proteins produced in The Nucleus that disrupt Cell Cycle regulation. In addition to those mentioned above, DNA-containing oncoviruses include herpesvirus, adenovirus, papovavirus, and varicella-zoster virus. Typically, these viruses cause infectious diseases and only lead to malignant transformation in about one in a million cases. On the other hand, the DNA-containing hepatitis B virus is responsible for liver cancer, which claims the lives of approximately 500,000 people worldwide each year. Moreover, patient infection usually occurs 20–25 years before the onset of the tumor.

RNA-containing viruses, upon entering human cells, synthesize DNA using Reverse Transcriptase and either partially or fully incorporate it into the eukaryotic genome in the form of a provirus (latent virus).

In 1976, utilizing Recombinant DNA technology, The Genome STRUCTURE OF THE Rous sarcoma virus was deciphered (Fig. 16-6). Along with three genes commonly found in all viruses, a gene responsible for malignant transformation was discovered. It was named the src-oncogene because it was isolated from sarcoma cells. It has been demonstrated that when the src gene is integrated into the genome of normal cells growing in culture, they lose contact inhibition and acquire all The properties of transformed cells.

Fig. 16-6. Genome structure of the Rous sarcoma virus. LTR — long terminal repeats containing promoters to which RNA polymerase binds; gag, pol, env — genes encoding viral proteins; src — gene encoding Tyrosine protein kinase (Tyr-PK) with a Molecular Weight of 60 kD (pp60), which causes the disruption of contact inhibition (the cessation of Cell Division upon physical contact between cells) and cell transformation. Reverse transcriptase is an enzyme that synthesizes DNA using an RNA template. Due to The activity of this enzyme, the genetic material of the virus in host cells is converted into double-stranded circular DNA and can integrate into The Human Genome.

G. Hereditary predisposition

Hereditary alterations in the genome play a crucial role in carcinogenesis. For instance, in children, a predisposition to retinoblastoma (a malignant tumor of the retina) is inherited as an autosomal dominant trait, and approximately 40% of cases are familial in nature. A predisposition to familial adenomatous polyposis of the colon is inherited in a similar manner, and virtually all such patients develop adenocarcinomas in adulthood.

Chromosomal DNA instability can be associated with DNA Repair enzyme defects. This impairment is observed in patients with xeroderma pigmentosum, which is frequently accompanied by the development of skin carcinomas in areas exposed to UV radiation.