Cancer Biology Lecture 5 (2024/2025) PDF

CANCER BIOLOGY WHAT CAUSES CANCER? Dr. HAYTHAM MOHAMED First Semester Lecture ACADEMIC YEAR 2024/2025  TUMOR INVASION Tumor-Host ANGIOGENESIS AND Interactions...

CANCER BIOLOGY WHAT CAUSES CANCER? Dr. HAYTHAM MOHAMED First Semester Lecture ACADEMIC YEAR 2024/2025  TUMOR INVASION Tumor-Host ANGIOGENESIS AND Interactions METASTASIS Previously Objectives 1 2 3 STUDYING CHEMICALS MECHANISMS OF CAUSES OF AND CANCER CHEMICAL CANCER CARCINOGENESIS  STUDYING CAUSES OF CANCER ▪ Hardly a week seems to go by without another new claim appearing in the media about the latest cause of cancer. ▪ Finding what are the possible causes of cancer can be performed through 2 approaches : 1- The Epidemiological Approach (2 types Retrospective and Prospective) 2- The Experimental Approach THE EPIDEMIOLOGICAL APPROACH ▪ Epidemiology, the branch of medical science that investigates the frequency and distribution of diseases in human populations. ▪ By tracking and analyzing who develops what kind of cancer under which conditions, epidemiologists gather clues about the possible origins of the disease. Epidemiological Approach classified into 2 types (Retrospective and Prospective) ▪ Epidemiology, Retrospective studies that assess the past exposures of people who have already developed cancer. ▪ Epidemiology, Prospective studies that follow people into the future to see who will develop cancer. ▪ Dose-response relationship—that is, by showing that the risk of developing cancer increases in direct relationship to the amount of exposure to the agent being investigated THE EXPERIMENTAL APPROACH ▪ To obtain definitive evidence that some- thing causes cancer in humans, an active experiment would need to be performed ▪ Example Ames test ▪ The Ames test is based on the rationale that most carcinogens are mutagens. The ability of chemicals to induce mutations is measured in bacteria that cannot synthesize the amino acid histidine. When the bacteria are placed in a growth medium lacking histidine, the only bacteria that can grow are those that have acquired a mutation allowing them to make histidine. ▪ The number of bacterial colonies that grow is therefore related to the mutagenic potency of the substance being tested. Chemicals studied with the Ames test are first incubated with a liver homogenate because many chemicals become carcinogenic only after they have undergone biochemical modification in the liver Animal Studies to estimate Human Cancer Risks ▪ Animals are often exposed to the maximum tolerated dose (MTD) of a suspected carcinogen, which is defined as the highest dose that can be administered without causing serious weight loss or signs of immediate life-threatening toxicity. ▪ low-dose carcinogen exposures. One problem is the need to obtain a sufficient number of cancer cases to generate statistically reliable results. But how data is expressed ??? ▪ Linear model: a linear dose response relationship exhibiting no threshold. ▪ Threshold model: dose-response relationship in which there is no cancer risk at low doses and a linear dose response relationship exists after a threshold dose is exceeded. ▪ Hormetic model: U-shaped dose- response relationship in which cancer rates decline (beneficial dose) at very low doses of a carcinogen and then begin to rise as the dose is further increased. Humans and Animals Differ in Their Susceptibilities to Some Carcinogens 2-acetylaminofluorene (AAF), which is a potent carcinogen in rats but does not cause cancer in guinea pigs That AAF is actually a “Pre-carcinogen” or Procarcinogens term referring to any substance that can cause cancer only after it has been metabolically activated. Rats, but not guinea pigs, contain the enzyme that catalyzes this metabolic activation. Biochemical analysis of human tissues has revealed that we also contain the activating enzyme ▪ ESTIMATE OF CANCER DEATHS ATTRIBUTABLE TO DIFFERENT ENVIRONMENTAL CAUSES  CHEMICALS AND CANCER ▪ In 1761, a London doctor, John Hill reported that people who routinely use snuff (a powdered form of tobacco that is inhaled) suffered an abnormally high incidence of nasal cancer ▪ 1800s, Bladder cancer arising in workers who were exposed to 2-naphthylamine in the clothing dye industry was the first human cancer to be linked to a specific chemical. ▪ In the late 1800s, Asbestos is the second most lethal commercial product (after tobacco) in causing cancer deaths. In addition to triggering the development of lung cancer, microscopic fibers of inhaled asbestos penetrate through the lung and enter the chest cavity, where they cause a rare type of cancer known as mesothelioma ▪ Several dozen chemical carcinogens were identified as significant workplace hazards during the twentieth century ▪ Some Medications and Hormones Can Cause Cancer MECHANISMS OF CHEMICAL CARCINOGENESIS 1. Carcinogenic polycyclic aromatic hydrocarbons EX: chemicals that occur naturally in coal, crude oil, and gasoline. They result from burning coal, oil, gas, wood, garbage, and tobacco. Ex: benzopyrene 2. Carcinogenic aromatic, organic molecules that possess an amino group (—NH2) EX: Compounds were once employed in the manufacturing of dyes, 2 naphthylamine and 4 aminobiphenyl 3. Carcinogenic alkylating agents ▪ Molecules that readily undergo reactions in which they attach adding an alkyl group to the guanine base EX: Vinyl chloride, Several drugs and drugs used in cancer chemotherapy. 4. Carcinogenic N-nitroso compounds are organic chemicals that contain a nitroso group (N=O)joined to a nitrogen atom. EX: Nitrates and nitrites 5. Carcinogenic natural products are a structurally diverse group of cancer- causing molecules produced by biological organisms EX: Aflatoxin 6. Inorganic substances (compounds without carbon and hydrogen) are carcinogenic. Ex: Asbestos Some Carcinogens Need to Be Activated by Metabolic Reactions Occurring in the Liver The activation of pre-carcinogens is generally carried out by liver proteins that are members of the cytochrome P450 enzyme family One function of these liver enzymes is to catalyze the oxidation of ingested foreign chemicals, such as drugs and pollutants, with the aim of making molecules less toxic and easier to excrete from the body. P450 oxidizes foreign chemicals to make them more water soluble, thereby facilitating their excretion in the urine. Occasionally, however, oxidation reactions catalyzed by cytochrome P450 accidentally convert substances into carcinogens, a phenomenon known as carcinogen activation. Many Carcinogens Are Electrophilic Molecules That React Directly with DNA Carcinogens when metabolized in the liver, they are converted into highly unstable compounds with electron-deficient atoms. Such molecules are said to be electrophilic (“electron-loving”) because they readily react with substances possessing atoms that are rich in electrons. DNA, RNA, and proteins all have electron-rich atoms, making each a potential target for electrophilic carcinogens.  After entering the body, metabolic reactions catalyzed by cytochrome P450 in the liver convert benzo[a]pyrene into activated derivatives containing an epoxide group. Epoxide tend to react with atoms that are electron rich, such as the amino nitrogen found in the DNA base guanine. Epoxide: three-membered ring consisting of an oxygen atom covalently bonded to two carbon atoms; the two carbons are electron-deficient and therefore tend to react with atoms that are electron-rich. Reaction of the epoxide group with guanine causes the benzo[a]pyrene to become covalently bonded to DNA, thereby forming a DNA carcinogen complex called a DNA adduct DNA adduct complex formed by the covalent linkage of a chemical carcinogen to DNA.  Epoxide formation is also involved in the activation of other classes of chemical carcinogens. For example, aflatoxin and vinyl chloride Some carcinogens are activated by reactions that create other types of electrophilic groups, such as positively charged nitrogen atoms or carbon atoms or free radicals. Like epoxides, these electrophilic groups also attack electron-rich atoms in DNA. Tobacco -Tobacco smoke contains more than 4000 different chemicals, more than 40 of which are carcinogenic when administered to animals -The carcinogens benzo[a]pyrene and 2- naphthylamine are examples of the numerous potent carcinogens in tobacco smoke that cause mutations by forming chemical linkages to DNA. - Secondhand smoke increases the concentration of the angiogenesis stimulator VEGF in the bloodstream ▪ Alcohol Acts Synergistically with Tobacco to Increase Cancer Risk  Food Contains Carcinogens as Well as Anticarcinogens Particular attention has been paid to artificial additives and pesticides, although the potential hazards from such substances are probably overemphasized. ▪ In fact, probably every fruit and vegetable sold at the grocery store contains natural plant chemicals that can cause cancer in animals, and the overall concentration of these molecules is thousands of times higher than the concentration of the synthetic pesticides that are present as contaminants. Despite that people who eat lots of fruits and vegetables have a decreased risk of developing cancer specially stomach and colon cancers. due to the presence of many anticancer compounds. This is due to the presence of many anti-cancer agents in vegetables and fruits. Examples: Lycopene in tomatoes, epigallocatechin (EGCG) in green tea, Resveratrol in the skin of red grapes, and sulfides in garlic are among the numerous natural substances currently being investigated for possible anticarcinogenic activity. Aflatoxin—does pose a significant cancer risk. Aflatoxin is a toxic chemical produced by the mold Aspergillus, which grows on grains and nuts stored under humid conditions. Contamination of food with aflatoxin is prevalent in certain areas of Africa and Asia, where its presence correlates with high rates of liver cancer. Total dose of only 0.0001 gram of aflatoxin given to rats spread out over 16 months is sufficient to cause every single animal to develop liver cancer Food preservation techniques are another potential source of carcinogenic chemicals. - High salt intake can damage the stomach lining, stimulate cell proliferation, and trigger an inflammatory response that makes the stomach lining more susceptible to other carcinogens. - High rates of stomach cancer are common in countries where large amounts of smoked, cured, and pickled foods are consumed - Nitrate and nitrite are not very carcinogenic either, but they can be converted both in cured meats and in the stomach to N-nitroso compounds which is carcinogenic Red Meat, Saturated Fat, Excess Calories, and Obesity May All Contribute to Cancer Risk - In the case of meat consumption and colon cancer, additional evidence has tended to support the idea that eating red meat (but not poultry or fish) contributes to colon cancer, perhaps through the large amount of saturated fat it contains. - High-fat diets are known to cause the liver to secrete large amounts of bile acids into the intestines. One of these bile acids, lithocholic acid, can produce DNA damage and has been found to induce colon cancer when injected into animals. - Animal studies have revealed that cancer rates go up as the number of calories in the diet is increased, so the elevated cancer rates seen in people who eat high-fat diets may be caused by the consumption of excess calories. - In fact, some studies suggest that up to one third of all cancers of the colon, breast, kidney, and digestive tract are linked to obesity and lack of exercise. Grilling meat at high temperatures over an open flame causes fat droppings on the hot fire to create smoke containing polycyclic aromatic hydrocarbons, which are carcinogenic chemicals that adhere to the surface of the meat. Carcinogenic aromatic amines are also produced under such conditions or even by regular cooking methods when meats are cooked at high temperatures or for a long time. Diet Appears to Be an Important Factor in Determining Cancer Risk but Is Difficult to Study Summary of Main Concepts Next Lecture CHEMICALS AND CANCER END OF LECTURE 5