PATHOPHYSIOLOGY OF TISSUE GROWTH.

1. PATHOPHYSIOLOGY OF TISSUE GROWTH. Proffessor Yu.I. Bondarenko

3. Definition of tumor • Tumor− typical pathological process, whichischaracterized with anunlimited (uncontrolled, independent and endless) icreased tissuelgrowth and cellular anaplasia

4. Pathophysiologicalcharacteristic oftumor • Unlimition of growth • Unregulationof growth • Anaplasia oftumor cells

5. Pathophysiologicalchracteristic • Universal and obligatory property of benign and malignant neoplasms – is their capacity for unlimited growth. • In base of the growth lies uncontrolled surplus proliferation of cellular elements. • Neoplastic cells mitoses speed does not exceed the one of normal cells – embryonic bone marrow cells, bowels epithelium and other. • Tumor cells differ from normal not by the cell division speed, but character of proliferation.

6. Pathophysiologicalchracteristic • Neoplastic cells acquire ability to cell-fission boundless. • Growth unlimitation carries the fact, that the tumor cells are not able to exhaust division resources. • In each cell there is genetic program, which limits its division amount. • Tumor cells do not have limiting program. They lost it owing to somatic mutation.

7. Pathophysiologicalchracteristic • Tumor cells fiss to death of the organism. • Tumor can be carried into the other biological kind of organism (that is from mouse to mouse, from rat to rat etc.). • Tumor living and growth to organism-recipient’s death.

8. Pathophysiologicalchracteristic • Transfer of neoplastic cells from one organism to the other is called transplantation. • Tumor cells can also be carried into culture medium, where its can also fiss endlessly for a long time. • Cultivation of tumor in culture medium is called explantation. • Neoplasms, which support artificially, are called neoplastic strains.

9. Methods oftumorcultivation • 1. Transplantation • 2. Explantation Transplantionstains 1. Erlich сarcinomain mise 2. Crocer сarcinomain mise 3. SаrcomaM-1 inrats 4. CarcinomaBraun-Pirsinrabbit Explantationstains 1. Cells ofHeLa- cervix cancer

10. Pathophysiologicalchracteristic • Tumor cells have autonomous growth. • Cultural growth is controlled at two levels – organismal and tissue ones. • Organismal level of control is realized with aid nervous and endocrine systems. • Tissual level – with aid biologically active substances - mitogenes and keylones.

11. Pathophysiologicalchracteristic • Autonomy of tumor cells develops gradually. • The first tumor cell gets partially hormonal regulated (hormone dependent tumor). • Later it is perfectly irresponsible for hormones (hormone independent tumor).

12. Pathophysiologicalchracteristic • The third characteristic feature of tumorcells – is anaplasia. • Structural and biochemical organization simplification of tumor cells, coming back to embryonic state. • Neoplastic cells lose a capacity to differentiation and can not form the specific tissue complexes.

13. Pathophysiologicalchracteristic • Tumor arises from one mutational maternal cell. • Mutated cells differ from their general ancestor by much parameters. • These distinctions concern of cell structure, its organelles, metabolism, specific properties and functions. • There are following kinds of anaplasia: morphological, biochemical, physical and chemical, functional, immunological.

14. Kinds ofcellular аnаplasia • 1.Моrphological • 2. Biochemical • 3. Physic-chemical • 4. Functional • 5. Immunological

15. Characteristic of the anaplasia • The essence of morphological anaplasia is in appearance of atypic cellular and tissue. • In base of cellular atypism lie polymorphism of cell,nuclear size increase, polynuclear state, nuclear hyperchromatosis, nucleoles amount increase, mitochondrial changes – decrease of its amount,crests disappearance. • Tissuel atypism – changes of sizes and shapes of tissue structures, sometimes is the total loss of morphological tissue signs.

16. Morphologicalanaplasia • Polymorphismof cells • Increase of relation nucleus /cytoplasma • Multinucleonic • Hyperchromatosis of nucleuses • Increase of quantity nucleoles • Changes of cell оrganels

17. Changes of mitochondrias • Decrease ofamount • Decreaseof sizes • Thinningof mitochondriale membranes • Decreaseofamount crest • Thinning of mitochondriale crest

18. 1. Dysfermentosis 2. Unification of isoenzymic spectr 3. Activation ofnucleonicacids synthesis 4. ActivationDNA-polymerase 5. Increase ofprotein synthesis 6. Decrease of protein catabolism Biochemical аnaplasiaFeatures ofproteinmetabolism

19. Chracteristic of the anaplasia • Biochemical anaplasia– is the tumor cells metabolism peculiarities. • It is characterized genetic system changes. • Enzymic spectrum of tumorcells changed. • All cells get alike by enzymic admission (unification of isoenzymic spectrum). • The most typical biochemical feature of neoplasticcells concern proteins and carbohydrates metabolism. • Proteins metabolism peculiarities are: synthesis activation of nucleinic acids, DNA-polymerase inactivation, increase of proteins synthesis and decrease of proteins disintegration

20. Biochemical аnaplasiaEnergy supply • 1. Activation ofanaerobic glycolysis • 2. Present of aerobicglycolysis • 3. Activationof glycolicenzymes - pyruvatkinase - hexokinase - fruitkinase • 4. Inhibition ofKrebs cycle

21. Chracteristic of the anaplasia • Carbohydrates metabolismand energetic of tumor cells is also differ of norm. • The main energy sources in normal cells are anaerobic and aerobic carbohydrates disintegration, that is glycolysis and Krebs cycle. • Neoplastic cell also receives the energy owing to glycolysis and Krebs cycle. However glycolysis role in tumor cell is more, than in normal one. • The tumor cells energetic supply include: anaerobic glycolysis activation, aerobic glycolysis presence, oppression of Krebs cycle by powerful glycolytic enzymes system.

22. Physic-Chemical аnaplasia • Acidosis • Intracellularhydration • Accumulation of potassium • Increaseof electroconductivity • Decreaseof colloid viscosity • Increaseofmembranes charge • Decrease ofsurfasetension

23. Chracteristic of the anaplasia Physical and chemical peculiarities of neoplastic cells: 1. Acidosis owing to lactic acid accumulation; 2. Intracellular hydration; 3. Raised electroconductivity; 4. Colloid viscosity decrease; 5. Membranes surface-tension decrease; 6. Negative membranes charge increase.

24. Chracteristic of the anaplasia Functional anaplasiadisplays in loss or perversion of tumor cells function. • In neoplastic thyroid cells, for example, a surplus amount of hormones thyroxine and triiodothyronine can be synthesized, thyrotoxicosis arises. • In other cases separate functions of tumor cells fall out, for example, bilirubin does not get conjugated in hepatome. • In very malignant neoplastic cells functions are totally lost. Sometimes such cells begin doing the functions, which are not specific for them (bronchus cancer synthesizes the gastrointestinal hormones).

25. Chracteristic of the anaplasia • Immunological anaplasia – is change of tumor cell antigen properties. • In tumor cells antigen admission is changed. • There is antigen simplification, antigen divergence and antigen reversion. • Antigen simplification – is the general number of neoplastic cells antigens decreased. For example, the cells of normal tissue synthesize up to 7 typical antigens, while same tissue tumor cells synthesize only 2-3 antigens.

26. Chracteristic of the anaplasia • The idea of antigen divergence is in the fact of neoplastic cells starting to synthesize heterologous antigens. For example, hepatoma (liver tumor) begins synthesizing organospecific spleen antigens, or other organs antigens. • Antigen reversion means neoplastic embryonic antigens synthesis. For example, human liver cancer synthesizes a special embryonic protein, which is -fetoprotein.

27. Immunological аnaplasia • Antigensimplification • Antigendivergence • Antigenreversion

28. Tumor etiology • Tumors are caused by carcinogens, which include such groups: chemical, physical and biological. • Chemical carcinogenesis.The first clinical supervisions in this direction had been done by Pott. He described scrotum, internal thighs surfaces and stomach cancer in young chimney-sweepers. • Yamagiva and Ichikawa proved a carcinogenousof chemical matters in experiment at first. They drifted carbonic resin onto the rabbit ear for fifteenth months. This process was followed with skin cancer in rabbit. In 1930-1932 pure carcinogenes were extracted out of carbonic resin, including benzoapyrene, dibenzanthracene, methylcholanthrene.

29. Tumor etiology • Chemical carcinogenes. • The main groups are: polycyclic aromatic hydrocarbons, aromatic amines and amides, nitrosamines and nitrosamides. • Substances, that contain three or more benzoic cycles belong to the first group. More than 200 of them are known. But the only one of them, which is 3,4-benzopyrene is carcinogenic for a human. • Carcinogenes of this group, are usually of antropogenous origin. They are in tobacco smoke, car-petroleum gases, blast-furnaces smoke, chemical productions wastes, overfried food. They cause cancer or sarcoma by their injection way. Polycyclic aromatic hydrocarbons exude from organism by kidneys, skin, mammal glands, therefore are followed with the neoplasms of these organs.

30. Chemicalcarcinogens • 1. Polycyclicaromatic hydrocarbons 3,4-benzopyrine 1,2,5,6-dibenzoantracene 9,10-dimethyl-1,2- benzoantracene 20- methylcholantren • 2. Aromatic аmines andamides monoаzоbenzol 2-аminofluoren 2-naphtylamine chlornaphthisine benzidine

31. 3. Nitrosaminesand nitrosamides • N,N-dimethylnitrosamine N-nitrosopyrolidine N-nitrosomethylаniline N-nitrosomorpholine N-methyl- N-nitrosourine

32. Tumor etiology • Aromatic aminesand amides. • Monoazobenzene; • Benzidine; • Chlornaphthisine • These substances are usually used for natural or synthetic fabrics colouring, polygraphy, cosmetics production, colour-photography processes, medications or eather insecticides synthesis that is followed with neoplastic growth attached to skin or gastrointestinal contacts. Tumors are usually located in liver, urinary cyst, bowels, kidneys.

33. Tumor etiology • Nitrosamines and nitrosamides cause neoplastic processes in 40 animals species. • Their carcinogenous effects upon the humans are not proved, however the experimental data are of the great attention. • Nitrosamines and thear productions in man digestive channal transfer in nitrogen.

34. Tumor etiology • Almost all of carcinogenic matters are not active. But they acquire carcinogenic properties due to their entering the organism. them. • Carcinogenes react with purine bases of DNA obligatorily. • The most frequent target – is guanine, which gets methylated or eather alkylated by cancerogenes. • Changed guanine is unable to bind with cytosine, but gets associated with thymine. The sequence of bases in DNA molecule gets disturbed. In a result arises gene mutation.

35. Tumor etiology • Physical carcinogenesis.To physical factors belong ionizing and ultraviolet rays. • The ionizing rays cause genetical and chromosomal mutations. • They cause neoplastic growth almost in all of organs.In skin, bones, lungs, thyroid, mammal gland neoplasms arise in case of external irradiation. In case of ionizing radionuclides entering inside, the tumor arises at their local accumulation. For example barium, calcium, strontium radionuclides cause the bone neoplasms. Caesium, thorium radionuclides, able to cause liver, bone marrow, stomach, thick bowel tumors.

36. Tumor etiology Viral carcinogenesis. • Tumors can be caused by viruses. • There are some neoplasms examples of viral origin: Rauss sarcoma in chicken, Shope papilloma in rabbits, mammal gland cancer in rats, which arises in case of Bittner milk factor. • Viruses, which cause neoplastic growth, are called oncogenous. They belong to the group of retroviruses. • Not many human tumors, which get caused by viruses are known. They are Burkitt’s lymphoma (Central Africa), nasopharyngeal cancer (China), cervix cancer

37. Tumor pathogenesis • Conception of oncogenA special theory was formulated in the end of last century,due to the foundation of contemporary knowledge, which united all of known carcinogenesis forms (chemical, physical, biological) into a single universal mechanism. It had been called as conception of oncogen. • Appearance of neoplastic growth is related to genetic system somatic cells changes. Tumor is a hereditary phenomenon at the cell level. There are many causes of cancer and all of them get DNA damaged. This damage must be located in that area DNA, where cellular oncogenes are situated. These genes are the usual components of the cell genome. They control growth and cells differentiation.

38. Tumor pathogenesis • Cellular oncogenes are also called as cancer genes. • Carcinogenic agents damage either oncogenes or genes-repressors, which are serial located. • In effect of chemical, physical and viral factors, their activity gets raised sharply and they turn the normal cell into the neoplastic one. • Cellular oncogenes activative mechanisms: viral transduction, chromosomal mutation, genetic material insertion, genetic amplification, point mutations.

39. Tumor pathogenesis • Viral transduction. Retroviruses are the cause of cellular DNA damage due to the transforming genes invasion, they are called viral oncogenes and have cellular origin. • The cellular DNA areas, which were seized by virus into the own genome occasionally. Now more than 20 viral oncogenes are known. All of them have cell twins. • Cell twins (cell oncogenes) are situated in different chromosomes. Examples are: Raus sarcoma virus in hens is located in 20-th chromosome, Molone sarcoma virus in mice – in 8-th chromosome, Rorru-Donal virus in cats – in 5-th chromosome, sarcoma virus in hairy moukeys – in 22-th chromosome

40. Tumor pathogenesis • Viral oncogenes differ from their cell predecessors. • Viral oncogene preserves an ability to stimulate cells growth and differentiation, but at the same time loses genes-repressors and becomes uncontrolled. • Therefore a recurrent entrance into the infected cell DNA is followed unrestricted cell division. • Cell oncogen itself gets changed also in its seizure by retrovirus process. It consists of exones (encoding areas) and intrones (unencoding areas) in the cell. It combines exones only (encoding areas) in virus genome. Therefore it is very active.

41. Formation ofcarcinogenes Precarcinogene ↓ Proximal ↓ carcinogene ↓ Finalcarcinogene

42. VIRAL carcinogenesis • ANIMALS: • 1. Rausssarcomainhen - 1910 • 2. Shope fibroma in rabbits - 1932 • 3. Shope papillomain rabbits - 1934 • 4. Bіttnermilk factor - 1936 • PEOPLE: • 1. Burkittlymphoma– Central Аfrica • 2. Nasopharyngealcancer –Chine • 3. Cervixcancer

43. Activation ofprotooncogene • Pointmutations • Chromosomaltranslocation • Viraltransduction • Insertion ofgeneticmaterial • Amplification of genes

44. Mechanisms of oncogene activation • Point mutations.All cell oncogenes activation mechanisms, which were characterized earlier, obligatorily related to cell DNA changes. Eventually, all of them are of mutational origin. Now it is admitted, that point mutations are a major carcinogenesis mechanism.

45. Mechanisms of oncogene activation • Chromosomal aberration. • Translocatons are observedin human neoplastic growth cells more often. • Translocation is one of the cell oncogenes activation ways majority. • Chromosomes breaking takes place close to the cellular oncogenes frequently. They get activated after the breaking. • Such tumor example is Berkit lymphoma. Mutual translocation between 8 and 14 chromosomes is typical for such lymphoma.

46. Mechanisms of oncogene activation • Insertion of genetic material. Neoplastic growth arises not only, in case of viral oncogene injury into the cell DNA. • Cell oncogene activation is also possible, when any heterologous (viral) genetic material encroaches into the cell DNA close to it . It is not suppose to keep oncogene. • Any viral DNA is able to activate cell oncogene, due to its incorporation into the cell DNA beside the oncogene.

47. Mechanisms of oncogene activation • Amplification of cell oncogene.Usually, cell oncogenes are represented by one copy. • Amount of copies can increase as a result of spontaneous DNA replication anomalies. Such phenomenon is named amplification. • DNA copies amount augmentation causes their summary expression augmentation. • Supplementary RNA and oncoalbumen amount gets synthesized on supplementary DNA matrices. • Amplification is typical for some human tumors. Neuroblastoma and thick bowels carcinoma arises due to such mechanism.

48. Stages of carcinogenesis Neoplastic growth beginning and development in multistage process. The main three stages are: transformation, promotion and progression. • Transformation.The first stage is followed with the cell oncogene activation. • The cell acquires unusual property, which is called immortalisation. This is a potential unlimited division, immortality ability. However, the presence of active oncogene is a readiness to division only. • A cell with active oncogene can resist in latent (condition) for years. It does not display itself with anything.

49. Stages of carcinogenesis • Promotion.Supplementary influences upon immortalisated cell, are necessary to exit it out of the latent state, for giving a push to irrepressible division. • Provoking factors, which are supplementary doses of chemical cancerogenes or x-rays, retroviral superinfection. They are named promotors.

50. Stages of carcinogenesis • Progressionis the very last and the most protracted stage of neoplastic growth development. • The clearest determination of this notion Fulds has given: “Progression is a neoplasm development in a way of constant, irreversible, qualitative changes of its one or a few signs". • Progression is not just quantitative tumor growth, but native change of its biological properties. • One of the major Fuld’s principles is an independent progression of separate neoplastic signs. • Its essence is the following: each tumor sign (morphological anaplasia degree, hormones dependence degree, invasive growth capacity, metastasing ability) evolutionizes irrespectively to the other signs, however to the malignisation side always.