Cancer pathophysiology dietetics-1

pathophysiology of cancer

1. CANCER PATHOPHYSIOLOGY Radhika D Prabhu MS124129

2. 0UTLINE- Pathophysiology Genetics- Cancer genes Environmental Carcinogenesis: Chemical Physical Viral Dietary

3. What is Cancer? Neoplasia means ‘ new growth ’ Neoplasm means ‘ tumour/ cancer ’ A neoplasm is : A bnormal mass of tissue which grows in an uncoordinated manner even after cessation of the stimuli which evoked the change. Cancer results from a series of molecular events that fundamentally alter the normal properties of cells. As long as these cells remain in their original location, they are considered benign and if they become invasive, they are considered malignant.

4. TYPES

5. COMMON CANCERS : GLOBAL * Related to Infection All the three common cancers above ( both developed & Developing) are also leading causes of cancer death. 15 % of all cancers – infection related ( 3 times more in developing countries)

6. All tumors, benign and malignant, have two basic components clonal neoplastic cells that constitute their parenchyma reactive stroma made up of connective tissue, blood vessels, and variable numbers of macrophages and lymphocytes

7. An important hallmark of many cancers is resistance to apoptosis, which contributes to the ability of the cells to divide uncontrollably When normal cells become old/damaged, they go through apoptosis (programmed cell death) Normal cell division C ell damage – no repair A poptosis Cancer cell division Uncontrolled growth Fourth or later mutation Third mutation Second mutation First mutation Tumors are clonal (one parent) But have different mutations  different shapes & features. Each new mutation adds a new feature.

8. How apoptosis happens…….

9. Genetics of Cancer Four kinds of normal genes : Genes that promote growth (proto-oncogenes) Genes that inhibit growth (tumor-suppressor genes) Genes that regulate apoptosis (apoptotic genes) Genes involved in DNA repair (DNA repair genes)

10. ONCOGENES

11. Normal Cancer Proto-oncogenes Cell growth and proliferation Tumor suppressor genes + - Mutated or “activated” oncogenes Malignant transformation Loss or mutation of Tumor suppressor genes What are the genes responsible for cancer cell growth? ++

12. “Cancer genes” contribute: Autonomous growth Insensitivity to growth-inhibitory signals Evasion of apoptosis Defects in DNA repair Limitless replication Sustained angiogenesis Invasion and metastasis Heredity - 5%

13. AUTONOMOUS GROWTH Growth factors may be made by cell itself! Receptors may be over expressed or always on Signal-transducing proteins may always be on Nuclear transcription factors may always be expressed Cyclins may be overactive In cancer cells… Cell divides on its own!!!

14. INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS Tumor-suppressor genes/ anti-oncogenes : normal genes whose products act as “brakes” on the cell cycle. Mutation cause loss of these brakes!

15. EVASION OF APOPTOSIS

16. DEFECTS IN DNA REPAIR Normal cells have ability to repair DNA damage Thus, prevent mutations in genes But if mutations are not repaired, results in cancer.

17. LIMITLESS REPLICATION Normal human cells: Telomeres keep getting shorter…leading to cell cycle arrest In cancer cells: Length of telomeres – regulated by enzyme TELOMERASE Stem cells and cancer cells use telomerase to maintain telomere length and keep replicating!

18. SUSTAINED ANGIOGENESIS Tumor cells need blood too! Can’t grow >1-2 mm without new vessels Tumor cells eventually stimulate angiogenesis Tumor vessels are abnormal

19. INVASION AND METASTASIS Abnormal cells proliferate and spread (metastasize) to other parts of the body Invasion - direct migration and penetration into neighboring tissues Metastasis - cancer cells penetrate into lymphatic system and blood vessels

20. CARCINOGENESIS Carcinogens: Substances known to cause cancer or produce an increase in incidence of cancer. Unidentified ‘environmental’ agents play a role in 95% of cancers

21. PHYSICAL CARCINOGENESIS CHEMICAL CARCINOGENESIS MICROBIAL CARCINOGENESIS

22. Physical Carcinogenesis-Radiation Properties of radiation carcinogens : Result in mutations following a long period of latency after the initial exposure (10-20 yrs ) May enhance the effect of other carcinogens 2 types : Ionizing radiation Ultraviolet rays

23. Ionizing radiation Ex- X-rays, alpha, beta & gamma rays, radioactive isotopes Mechanism of action : Directly alter cellular DNA Dislodge ions from water & other molecules  free radicals  damage Causes chromosome breakage, translocations Occasionally, point mutations genetic damage and carcinogenesis. Examples : Unprotected miners: lung cancer Atomic bomb survivors: leukemia, other cancers Therapeutic head/neck radiation: thyroid cancer

24. UV Rays UV rays derived from the sun cause an increased incidence of squamous cell carcinoma, basal cell carcinoma, and possibly melanoma of the skin. The degree of risk depends on the type of UV rays, the intensity of exposure , and the quantity of the light-absorbing “ protective mantle ” of melanin in the skin.

25. Chemical Carcinogenesis 2 Types: Proximate/direct acting: act locally without metabolic change. Indirect acting: carcinogenic only after being metabolised into active compounds ( procarcinogen ultimate carcinogen)

26. Some Chemical Carcinogens DIRECT-ACTING CARCINOGENS PROCARCINOGENS THAT REQUIRE METABOLIC ACTIVATION 1- Alkylating Agents: β- Propiolactone , Dimethyl sulfate, Diepoxybutane , Anticancer drugs ( cyclophosphamide , chlorambucil , nitrosoureas 1-Polycyclic and Heterocyclic Aromatic Hydrocarbons: Benz[ a ] anthracene , Benzo [ a ] pyrene , Dibenz [ a,h ] anthracene , 3-Methylcholanthrene, 7,12-Dimethylbenz[ a ] anthracene . 3- Natural Plant and Microbial Products: Aflatoxin B 1: Griseofulvin , Cycasin , Safrole , Betel nuts. 2- Acylating Agents: 1-Acetyl-imidazole, Dimethylcarbamyl chloride 2-Aromatic Amines, Amides, Azo Dyes: 2-Naphthylamine ( β- naphthylamine ), Benzidine , 2-Acetylaminofluorene, Dimethylaminoazobenzene (butter yellow) 4- Others: Nitrosamine and amides, Vinyl chloride, nickel, chromium, Insecticides, fungicides, Polychlorinated biphenyls.

27. MICROBIAL CARCINOGENESIS Oncogenic DNA viruses: Human Papilloma Virus Epstein-Barr Virus Hepatitis B Virus Oncogenic RNA virus: Human T-cell Leukemia virus Type 1 Bacteria: Helicobacter pylori

28. ONCOGENIC DNA VIRUSES- PATHOGENESIS Genomes of oncogenic DNA viruses integrate & form stable associations with host genome . The virus is unable to complete its replicative cycle because viral genes essential for completion of replication are interrupted during integration of viral DNA. Thus, the virus can remain in a latent state for years.

29. HUMAN PAPILLOMA VIRUS 70 genetically distinct types identified Low risk types- HPV 6, 11  genital warts High risk types- 16,18, 31,33,35,51  Ca cervix, severe dysplasia and CIS Cervical cancer Anogenital cancer Oral cancer Laryngeal cancer

30. Infection with high-risk HPV types simulates : loss of tumor suppressor genes activates cyclins inhibits apoptosis combats cellular senescence

31. EPSTEIN-BARR VIRUS Burkitt lymphoma Post-transplant lymphoproliferative disease Primary CNS lymphoma in AIDS patient Subsets of Hodgkin lymphoma Nasopharyngeal carcinoma

32. Hepatitis B and Hepatitis C Viruses

33. HELICOBACTER PYLORI Gastric lymphoma Gastric carcinoma Mucosal Associated Lymphoid Tumor (MALT)

34. Oncogenic RNA Virus HTLV-1 causes a T-cell leukemia

35. Dietary Causes Energy Balance: Cancers of breast ,endometrium, gall bladder and kidney Meat: Digestive tract cancers Sugars: Simple sugars,colorectal cancer Fat: Breast cancer, prostate cancer Vitamins and minerals: Lung cancer: oro -pharyngeal, oesophageal cancers Alcohol,tobacco : Mouth,throat,pharynx and oesophagus Nitrates: stomach, colorectal Aflatoxins : liver cancer

36. Other Causes Stress Hormones: Estrogens Age Physical Activity Immune Factors