Carcinogens and Carcinogenesis

Transcription

1 Special topics in tumor biochemistry Carcinogens and Carcinogenesis Speaker: Prof. Jiunn-Jye Chuu

2 What Is Cancer? Cancer is the unregulated multiplication of specific cells in the body. Cancer is a group of more than 100 different diseases. If a normal cell begins to grow abnormally and reproduces too rapidly, a mass of abnormal cells eventually becomes a tumor. If cells remain localized at the site of origin and if the cells multiply slowly, the tumor is referred to as a benign tumor.

3 What Is Cancer? Some benign tumors are cysts, warts, and moles. Benign tumors are usually removed surgically and generally are not a threat to life. If all of the cells are removed successfully, the tumor will not regrow. Malignant tumors are composed of cells that grow rapidly, have abnormal properties, and invade normal cells. Malignant cells have altered shapes.

4 What Is Cancer? A pathologist (a physician who specializes in the causes of diseases) can determine whether the cells removed from a tumor are abnormal and to what degree. The cells of most malignant tumors undergo metastasis, a process in which cells detach from the original tumor, enter the lymphatic system and bloodstream, are carried to other organs, and begin to grow there.

5 What Is Cancer? Cancers are medically classified according to the organ or tissue in which the tumor originates. There are four major categories: Carcinomas (e.g., cancer of epithelial tissues, skin, nerves, breasts) Sarcomas (e.g., cancers of connective tissues, bone, muscles, fat, and blood vessels) Leukemias (e.g., cancers of organs and tissues that form blood cells) Lymphomas (similar to leukemias)

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11 THE FOUR BASIC CHARACTERISTICS OF CANCER CELLS The cells of the cancer, at least at its beginning, must have been derived from a single cell that went wrong. The cell must have independent ability to divide continuously and out of control. The cell must be able to separate from its neighbouring cells and move to a new location where a new mass of cells will develop. When a cancer cell divides, it often results in a cell with an abnormal number of chromosomes, either more or less than the normal complement. This characteristic varies strongly with the type of cancer. In some cancers, the cell divisions are perfectly normal.

12 Biology of tumor growth

13 Tumor Growth Curve

14 What is a neoplasm? Lay term of tumor conveys usual connotations ie a new growth or mass Definition revolves around these features: Monoclonal proliferation of cells with specific mutations Excessive and unregulated growth of these cells, often at the expense of surrounding normal tissue

15 NEOPLASIA: new abnormal growth A neoplasm is a abnormal purposeless mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissues, and which persists in the same excessive manner after cessation fo the stimuli which evoked the change Tumor= swelling. Benign tumor -- no infiltration into surrounding tissue. Malignant tumor = cancer Cancer is the common term for all malignant tumors. Cancer derives from the Latin term crab presumably because it adheres to any part that it seizes in an obstinate manner like the crab

16 Benign tumors: fibroadenomas, polyps of the colon, lipomas Source: National Cancer Institute

17 Classification of neoplasms Epithelial tumors Benign forms adenoma, papilloma Malignant forms carcinoma, eg adenocarcinoma, squamous cell carcinoma Mesenchymal tumors Benign forms fibroma, leiomyoma, Malignant forms sarcoma, eg fibrosarcoma, leiomyosarcoma

18 Classification of Neoplasms Tissue Origin Benign Malignant Examples Epithelial Glandular Adenoma Adenocarcinoma Thyroid follicular adenoma Adenocarcinoma of lung Squamous and Polyp, Squamous cell carcinoma Squamous papiloma of skin Transitional papilloma Transitional cell carcinoma Squam. cell carcinoma skin Connective tissue Tissue type + suffix (-oma) Hematopoietic & lymphoreticular Sarcoma Lymphoma Leukemia Osteoma, Osteosarcoma, Hemangioma, Hemangiosarcoma Large cell lymphoma Hodgkin s disease Mylocytic leukemia Neural tissue Neuroma Neurofibroma Sarcoma Blastoma Glioblastoma multiforme Neurofibrosarcoma Mixed tissues of origin Teratoma Teratocarcinoma Teratoma of ovary Teratocarcinoma of testis

19 Cancer Development

20 -Malignant tumors of epithelial cells -well differentiated, moderately differentiated, poorly differentiated -squamous carcinomas - adeno-carcinomas alveolar papillary tubular CARCINOMAS (anaplastic, undifferentiated, large cell, small cell) (hepatocellular carcinoma, cholangiocarcinoma)

21 SARCOMAS Malignant tumors of supporting tissue -chondrosarcomas--cartilage -osteosarcomas--bone -hemagiosarcomas--blood vessel -gliomas (astrocytoma, glioblastoma) -lymphomas -melanomas -rhabdomyosarcomas -leiomyosarcomas -fibrosarcomas -seminoma, teratoma, etc.

22 Classification of Cancer

23 Carcinogenesis Carcinogenesis refers to the process by which a normal cell is transformed into a malignant cell and repeatedly divides to become a cancer. A chemical which can initiate this process is called a chemical carcinogen. Some chemicals which are non-carcinogenic or only weakly carcinogenic can greatly enhance the effectiveness of carcinogenic chemicals. Such "helpers" are called cocarcinogens. They may act by altering uptake or metabolism of carcinogens by cells. Carcinogenesis may take as long as years in humans and in several animal models has been shown to involve two stages, initiation and promotion.

24 Cancer Development (Four Stages) Stage I: Cancer cells can be distinguished from normal cells. Stage II: Cancer cells begin to metastasize and may migrate to nearby lymph nodes. Stage III: Cancer cells have spread throughout the body and tumors may have started to grow in other organs. Stage IV: Often a terminal stage; tumors are found throughout the body and usually are resistant to treatment.

25 The Development of Cancer

26 The Development of Cancer

27 The Development of Cancer Normal Tissue with a few abnormal cells growing and dividing (anaplasia).

28 Causes of Cancer Scientific research indicates that 90% to 95% of all cancers (including breast, lung, stomach, colon, skin, and prostate cancers) are not inherited from parents (except in a few families). It is estimated that only 5 10% of all cancers are hereditary.

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30 Causes of Cancer Most cancer arises as the result of somatic mutations in the genome resulting from: Chance (ie, we don t know) Environmental factors chemical, radiation, viruses Ageing Inherited cancer syndromes- defect in germline DNA

31 Environmental Factors It is difficult to pinpoint a single cause of cancer, but certain environmental factors are strongly associated with the occurrence of particular cancers. Epidemiological studies show that 80% to 90% of cancers are caused by exposure to environmental factors known to increase the risk of cancer.

32 Factors Believed to Contribute to Global Causes of Cancer

33 Environmental Factors Three classes of environmental agents: Ionizing radiation Tumor viruses Chemical carcinogens Ionizing radiation consists of x-rays, UV light, and radioactivity, which damage cells and chromosomes.

34 Chemical Carcinogens Environmental chemicals that can interact with cells to initiate cancer: Cigarette smoke Pesticides Asbestos Heavy metals Benzene Nitrosamines

35 Radiation Ionizing radiation x-rays, gamma rays, radioactive materials such as Radon gas all cause a variety of defects to DNA UV light (non-ionizing) primarily sun-exposure and T-T dimerization skin cancers

36 Tumor Viruses Four tumor viruses have been identified in human cancers: Liver cancer and hepatitis B virus Genital and cervical cancer and human papillomavirus Leukemia and lymphoma and human T-cell leukemialymphoma virus Cancer of the nose in Africans and Epstein-Barr virus

37 Xenoestrogens Chemicals found in the environment that mimic the body s estrogen hormone and may cause breast cancer. Substances that contain xenoestrogens: Pesticides Polychlorinated biphenyls (PCBs) Biphenol-A Gasoline vapor

38 Cancer Risk and Aging Because cancer usually requires a number of mutations, the chances of developing cancer increase as a person gets older because more time has been available for mutations to accumulate. For example, a person 75 years old is a thousand times more likely to develop and die of colon cancer than a person 25 years old. Because people are living longer today than they did 50 or 100 years ago, they have a longer exposure time to the factors that may start gene changes that lead to cancer

39 Genes and Cancer Chemicals (e.g., from smoking), radiation, viruses, and heredity all contribute to the development of cancer by triggering changes in a cell's genes. Chemicals and radiation act by damaging genes, viruses introduce their own genes into cells, and heredity passes on alterations in genes that make a person more susceptible to cancer. Genes are inherited instructions that are regions within DNA molecules. Each gene allows a cell to make a specific product in most cases, a particular kind of protein. Genes are altered, or "mutated," in various ways as part of the mechanism by which cancer arises.

40 Activation of carcinogen Chemical carcinogens: chemicals that cause tumor formation 1. have a very broad range of structures with no obvious unifying features 2. are genotoxic and can be classified into two broad categories based on their action mechanisms: a. Direct-acting carcinogens - react with nitrogen and/or oxygen atoms in DNA example: ethylmethane sulfonate (EMS) b. Indirect-acting carcinogens - become reactive after metabolic activation examples: aflatoxin, benzo[a]pyrene *genotoxic: an agent or process that interacts with cellular DNA, resulting in alteration of DNA structure

41 Carcinogenic hydrocarbons

42 Aromatic amines

43 Metabolic activation of aflatoxin epoxide (procarcinogen) (ultimate carcinogen) Aflatoxin B1, a toxin from a mold (Aspergillus flavus oryzae) that grows on grain and peanuts when they are stored under humid tropical conditions. It is thought to be a contributory cause of liver cancer in the tropics.

44 DNA adduct formation Since most chemical carcinogens react with DNA and are mutagenic, interactions with DNA have been viewed as the most important reactions of these agents. The principal reaction products of the nitrosamines and similar alkylating agents with DNA are N 7 and O 6 guanine derivatives. Reactions also occur with other DNA bases.

45 Examples of carcinogen- DNA adducts N 7 O 6 deoxyguanosine A. N-7 (benzo[a]pyren-6-yl)guanine B. N-(deoxyguanosin-8-yl)-{acetyl}aminobiphenyl C. 8,9-dihydro-8-(N5-formyl- 2, 5, 6 -triamino-4 -oxo-n5-pyrimidyl)-9-hydroxy-aflatoxin B1 D. O 6 -[4-Oxo-4(3-pyridyl)butyl]guanine, a mutagenic lesion formed by the metabolism of the tobacco-specific nitrosamine, NNK E. N-7-methyldeoxyguanosine

46 Activation and action of AAF

47 Activation and action of NMA

48 Oxidation as a cause of cancer Reactive oxygen species, generated naturally or from artificial sources, damage DNA and alter signal transduction. The main source of damaging agents is reactive oxygen species (ROS) but additional contributions are made by reactive nitrogen species (RNS) Nitric oxide (NO ),Nitrogen peroxide (NOO ), Peroxynitrite (ONOO )

49 Oxidation as a cause of cancer

50 Types of DNA damage caused by ROS

51 Types of DNA damage caused by ROS

52 Radiation Carcinogen

53 The energy of Radiation 1. Atomic particles > X-rays > ultraviolet light > visible light > infrared, microwaves and electrical waves 2. Ionising radiation: the forms of radiation can generate ions in the media through with they travel, such as Atomic particles and X- rays.

54 Ionizing radiation Ionising radiation passes through water produces electrons, which in turn generate reactive radicals. Ionising radiation results in chromosom damage involving mainly deletions and rearrangements rather than the point mutations generated by chemical carcinogens and UV light. Cells are most sensitive to ionising radiation during G2/M phases of the cell cycle whereas early S phase is the sensitive period for chemical carcinogens and UV light. The unit of energy release is the gray: Gy; 1 Gy is the release of 1 J/kg tissue. It is suggested that the total lifetime exposure of an average individual is 0.1 Gy.

55 Ionizing radiation

56 Radiobiology Röntgen discovered x-rays in The harmful effects of x- rays were observed soon after their discovery. The first observed effects were the acute ones, such as reddening and blistering of the skin within hours or days after exposure. By 1902, it became apparent that cancer was one of the possible delayed effects of x- ray exposure. High-dose X-ray treatment is suggested that a 3-fold increased risk of leukaemia and a 30% increased risk of other cancers are induced. *Wilhelm Röntgen ( ), a German physicist, received the Nobel Prize in physics in 1901.

57 UV light UVA (>320 nm), UVB ( nm), UVC ( nm). DNA is most sensitive to UV light during early S phase of the cell cycle. UV-induced DNA damage involves the formation of covalent links between adjacent pyrimidine, such as thymine-thymine, cytosine-cytosine and thyminecytosine dimers to cause C T transition.

58 DNA-damaging agents T pyrimidine Transition G puridine Transversion Transversion C pyrimidine Transition A puridine

59 UV-induced formation of pyrimidine dimers

60 DNA-damaging agents

61 Cancer as a Genetic Disease Source: National Cancer Institute