Cancer physiology

2021-04-29 01:41 PM

Indirect effects through metabolism (precursor carcinogen): after being introduced into the body, enzymes or intestinal bacteria will transform into carcinogens.

The concept of cancer

Cancer is an infinite proliferation of cells that, despite normal control, have the ability to invade surrounding organs and spread elsewhere.

Today it is known that the nature of cancer is involved in genetic alterations in DNA that disrupt normal cell proliferation. It is caused by a tumour suppressor gene mutation (oncogene) or tumour suppressor gene. Identifying that mutant change to diagnose cancer early, on the other hand, one can use genetic methods to treat cancer (genotherapy)

Carcinogenic factors and mechanism of action

Physical factors

Solar radiation (non-ionizing): The sun's ultraviolet rays can cause skin cancer, melanoma. Sensitivity to sunlight is inversely related to skin pigmentation because melanin effectively filters ultraviolet radiation.

Ionizing radiation: May cause skin cancer and blood cancer. Areas with high levels of radioactivity in the air (in Hiroshima and Nagasaki in Japan) have high rates of acute myeloid cell line cancers due to radiation exposure from the womb as well as exposure to radiologists. with radioactive material, radiotherapy, I131 or P32.vv In contrast, mice with systemic radiation or lymphoma and lymphoma.

Chemical factors

Chemical factors that cause cancer are increasingly discovered (more than 50,000 chemicals have been used in industry and 1,000 new chemicals are added each year). They can be inorganic compounds (arsenic, chromium, nickel, etc.) or polycyclic organic hydro carbides, aromatic amino acids, nitrosamines, dyes, hydrazine, alkylating agents, some antibiotics, some substances. Found in nature such as aflatoxin and even some synthetic steroid endocrinology. The mechanism of action of cancer-causing chemicals can be divided into two groups:

Direct effect in the form they are introduced into the body:

Alkyl core compounds.

Arsenic compounds.

Chromate and amiant are used in mining technology.

Indirect effects through metabolism (precursor carcinogen): after being introduced into the body, enzymes or intestinal bacteria will transform into carcinogens.

Polynuclear aromatic hydrocarbon: In the environment and in life: In kitchen smoke, cigarette smoke, soot, asphalt, tar, explosive engine smoke, etc. Also found in general chemical industry products. oil distillation, distillation, etc.

Aromatic amines: Used in many chemical technologies such as 2-naph-thylamine, 4-nitro biphenyl, benzidine. The frequency and frequency of organ cancer caused by a particular chemical are often species-specific, race-specific, and genetic factors.

Azote-nucleated compounds: Dyes such as orthoaminozotoluene (red), 4-dimethylamino benzene (yellow) can cause visceral cancer in dyers.

Nitrosamines, triazene: are abundant in foods (vegetables, meat, fish, sauces) with high concentrations in dry foods, perennial foods, and synthetic foods. The metabolism is as follows:

NO3 - bacteria / enzymes / NO2.

NO2  + R-CH2NH-R( R-CH2N (NO)-R (alkyl nitrosamine: carcinogen).

This reaction occurs in the stomach, from the nitrates available in food under the action of bacteria and yeast, converted to nitrite, then attached to the R base to become alkyl nitrosamine capable of causing cancer.

Naturally available compounds: aflatoxin in moulds of peanuts (peanuts) and some other grains. Pyrrolizidine in some tea trees used instead of tea in some African tribes has a therapeutic effect but can cause liver cancer in small doses for a long time. Besides, in aromatherapy, the cyclamate in spices can cause cancer of the liver, bladder, stomach, etc.

The role of viruses

The biggest difference between a virus that causes cancer and a virus that causes a simple infection is that a virus that infects when cells divide and grow in your host cell destroys the cells they host while viruses cause. Cancer both dissolves (less) and causes malignant transformation in the cells. This has been demonstrated experimentally and clinically.

Some viruses related to human cancer:

DNA virus

Family Apovavirus (papillomavirus) .

H in Hepadnavirus (hepatitis B virus).

H in herpesvirus (Epstein - Barr virus).

RNA virus

Retrovirus (HIV-1, HIV-2).

Factors associated with cancer occurrence

Genetic

Things differ in their receptivity to cancer-causing chemicals. It is difficult to determine genetic effects in human cancer because it is difficult to separate economic, social and environmental factors. However, the appearance of the Philadelphia chromosome in chronic myelogenous leukaemia, and cancer in twins, is characteristic of family cancer.

In addition, race-related cancers such as Burkitt's lymphoma have a high prevalence among Ugandans, while nasopharyngeal cancer is high in China, despite having migrated to the US for a long time compared to the local population. . In particular, the rate of infection with Epstein - Barr virus of the world's inhabitants is the same 95-97%.

Age, gender

Cancer development of some organs and organs depends on gender and age. Some cancers occur more frequently in men due to occupational or smoking problems. Endocrine can play the role of chemicals that cause endogenous carcinogenesis (a genital endocrine structure is similar to the structure of benzopyrene, cholesterol, etc.).

The older the age, the higher the frequency of mutations (> 10-5), the decreased immune response, the more likely it is to develop cancer. In experiments, the target organ in young animals is more susceptible to cancer-causing factors than in ageing.

Nutrition

Rats fed hungry in quantity but did not lack nutrients, the experimental cancer rate was low due to energy restriction; cells will not fully mitigate even though they are malignant.

The high-fat content of the European diet compared to Asians can affect steroid hormones; therefore, European women are more susceptible to breast cancer than Asian women or due to low-fibre diets, leading to an increase in colon cancer rates among Europeans.

Environment

Habitat (humidity, pollution, climate, etc.), along with living conditions and nutrition are all factors that influence carcinogenesis. For example, nasopharyngeal cancer rates are high in Asia, especially in the fishing areas in the sea or eating dried shrimp, thyroid cancer is common in Switzerland, bronchopulmonary cancer is high in countries with many people. tobacco addiction, etc. Cleaning the environment, changing living conditions, and unfavourable habits contribute to the prevention of cancer development in the community.

Endocrine factors

There are two types of endocrine cancers: prostate cancer that does not develop after testicular removal or estrogenic injection. In experiments, people can cause ovarian tumours, testicular tumours and uterus in mice by injection of estrogenic or sex hormones. Breast cancer that cannot remove the tumour, the ovaries are removed and androgens injected.

Immune factors

Malignant cells carry cancer antigens that stimulate the immune response system to fight them off. However, if the immune system against cancer is reduced like in old age, it will make cancer more likely to appear. The rate of some types of cancer is increased in immunocompromised people. Stimulating the immune system to fight cancer itself is a promising new direction in the near future.

The main hypotheses in the mechanism of carcinogenesis

There are two possibilities of cancer:

Structural mutations cause the oncogene to become super active: a modified allele is called an oncogene (an oncogenes gene); the normal allele is called proto-oncogene (precursor gene).

A structural mutation inactivates the suppressor gene: the suppressor gene is also known as the carcinogenicity inhibitor gene.

Recently, some authors have also demonstrated an epigenetic change. for example, the excessive methylation of the CpG islands in the promoter in the p53 gene also favours cancer development).

Cancer-causing virus theory

The oncogenes virus theory originates from the studies of viruses by Kellerman and Bang, Rous.vv. Most of the experimental oncogene viruses belong to the type of RNA virus, these RNAs are very similar to cell RNA. host. Todaro and Huebner discovered that the RNA virus genome is located in the nucleus of the host cell and when it acts like a virus, it will damage the cell's DNA synthesis and combine the viral RNA with the nucleus acid of the cell. the host forms a new nuclear acid, a new genome capable of indefinitely proliferating uncontrolled body forming malignant cells. Some cancers have evidence of a virus in humans. Experimental research shows that control of immunity has a more direct role on the virus than to the antigen to cancer. Mice that do not have a thymus or use anti-lymphocyte serum do not always develop tumours, while the rate of cancer is very high when using mice infected with the DNA of the polyomavirus. The immune response in most tumours is less effective.

Some human tumours have a well-known role of the virus, such as cervical cancer and liver cancer, which can cause many deaths around the world. Viral antigens on the cell surface are probably targets of the immune system but have demonstrated evidence of genetic alteration (mutation, gene amplification, gene fragmentation, gene transfer). Some cancer cell antigens are generally not present in normal organisms (TATAs- Tumour Associated Transplantation Antigens), others may be present in normal humans but have individual tumour specificity (TSTAs-Tumor). Specific Transplantation Antigens), for example, CD10 antigen on pro-B cell.

Genetic mutation theory due to physical and chemical factors

This transformation includes:

Variation of number and structure of chromosomes.

Genetic modification by altering the structure of the DNA creates mutant genes.

Mutagenicity of several causes: mutations can occur due to the effects of environmental agents and mutations naturally occur during cell replication. In humans, it occurs at a low frequency but can increase when many endogenous and exogenous factors interfere.

Effects of ionizing radiation (X-rays): When X-rays are illuminated on an organization, the mutation frequency increases to 150 times, causing DNA mutations, chromosomal structural disturbances. The mechanism by which X-rays can separate electrons from atoms thereby altering the charge and leading to structural changes in DNA due to chemical reactions.

Non-ionizing radiation: Does not change the charges of the atoms but can cause electrons to jump from ring to ring and lead to the change of neighbouring base pairs. For example, ultraviolet rays cause covalent-bound pyrimidine bases (thymine and cytosine) to form pyrimidine pairs, which will not accurately pair with purines during DNA replication.

Chemicals: Many chemicals that cause mutations in both genes and chromosomes directly and indirectly (acridine can attach itself to bases distort the double helix structure of DNA and cause DNA mutation.

Chemicals act on artificial acids to create unsustainable chromosomes, creating mutations immediately or a few generations later.

The chemical acts through inhibition of the enzyme catalase, capable of preventing or limiting genetic mutations.

Oncogene and proto - oncogene

Proto- oncogene

Genes are normally responsible for controlling cell reproduction and differentiation. Thus, the product of proto-oncogene regulates the normal growth and division of cells. These proteins heal wounds, stimulate the growth of tissues and organs in the fetal stage and in adulthood may stop working. In fact, proto-oncogene is involved almost all molecules involved in the cell signalling system such as secretory proteins, transmembrane receptors, regulatory genes, etc.

Oncogene

A proto-oncogene is activated into an oncogene by various pathways such as the insertion of promoters, enhancers, chromosome transposition, gene amplification, and point mutation.

Figure: How to convert a proto-oncogene into an oncogene.

 

Proto-oncogenes

Oncogene

Cancer is caused by a virus

Protein kinase

abl

Pre-B cell blood cancer

Protein kinase

Erl -B

Red blood cell cancer, fibroids

Protein kinase

src

Sarcoma

Table: Relationship between proto-oncogene and oncogene in some cancers.

Mechanism of action of oncogene

Acts as intracellular metabolic products involved in growth control. For example, the src protein acts as tyrosine kinase, ras protein as an adenyl cyclase activator. These products all influence the cell division control involved in the phosphorylation of participating proteins (cdk1 phosphorylation at Thr 161 stem.

Grow factors: Erythropoietin, IL-1, IL-2, EGF, etc.

Mimic is the activity of receptors with certain growth factors.

Nowadays, growth factors and oncogenes have been shown to have mutual effects on a number of pathways.

Genes that inhibit cancer

Concept

A gene that inhibits carcinogenesis is a gene that regulates cell division by slowing cell division, correcting DNA errors, and ordering cells to die (apoptosis). When the gene is mutated (acquired mutation) or absent (inherited), cells can proliferate uncontrollably, leading to cancer. Its discovery helps to understand the molecular mechanisms of malignant transformation of the cell. In addition, it is possible that the p53 gene is blocked by excessive methylation in the promoter, which also favours cancer development.

Currently, about 30 genes have been identified that inhibit carcinogenesis, including BCRA1, BCRA2, and p53.vv The p53 gene encodes protein 53.

Gen p53

The p53 gene is located on chromosome 17, the product of the gene with a TLPT 53kDa, p53 binds to different proteins of the virus to form inactive complexes, so the virus can inhibit p53 to cause cancer. . p53 binds to specific fragments in ds DNA: (1) causes DNA to break during cell growth and division (2) prevents irregular amplification (3) prevents DNA mutation (4) introduce the cell to programmed destruction. Programmed death (apoptosis occurs normally in the fetus, development, and adulthood.) Damage to apoptosis can lead to the inappropriateness of cell survival and development into cancerous cells. This cell death inhibition is caused by mutations of the p53 gene that can lead to cancer. In addition, p53 can synthesize p21, a protein that inhibits the cyclin-dependent protein kinase (cdk).

P53 mutations are more likely to be found in some human cancers such as colon cancer (70%), breast cancer 40%), lung cancer 50%)

Genes that recognize damaged DNA and repair genes for damaged DNA

When these genes are disabled or mutated, they also cause cancer, meaning that under normal operation these genes are responsible for inhibiting cancer growth through their products, enzymes or proteins active.
 

 

MOST VIEW

Pathophysiology of cardiogenic shock

Urine formation: Reabsorbed glomerular filtration

Air in and out of the lungs: pressure causes the movement of air

Mechanism of urine concentration: osmotic pressure changes in different segments of the renal tubule

Absorption and excretion of potassium through the kidneys

Nephron: The functional unit of the kidney

Estimated renal plasma flow: PAH clearance

Prothrombin activation: initiates blood clotting

Pulmonary capillary dynamics: capillary fluid exchange and pulmonary interstitial fluid dynamics

Graphical analysis of high-volume heart failure

Red blood cells: differentiation and synthesis

Calculate the glomerular filtration rate (GFR): the forces that cause the filtration process

Ammonia buffering system: excretes excess H + and creates new HCO3

Concentrated urine formation: urea contributes to increased osmotic pressure in the renal medullary

Reduced sodium chloride, dilates arterioles, increases Renin release.

Extracellular fluid distribution between interstitial space and blood vessels

The proximal tubule reabsorption: active and passive reabsorption

Origin of lymphocytes: the body's resistance to infection

Pathophysiology of fever

Acidosis causes a decrease in HCO3- / H + in renal tubular fluid: compensation mechanism of the kidney

The endocrine regulates tubular reabsorption

Sodium channel blockers: decrease the reabsorption of sodium in the manifold

Self-regulation of glomerular filtration rate and renal blood flow

Physiological anatomy of the kidneys and urinary system

The myogenic mechanism itself regulates renal blood flow and glomerular filtration rate