Cancer

Learning Objectives The students will be able to: Identify the 3 most prevalent cancers for a person of their gender Define cancer Explain why cancer is a genetic disease even though its heritability is rather low Compare the functions of oncogenes and tumor suppressor genes Explain why tumor suppressors are often the 1st genes mutated in a developing cancer List the Six Hallmarks of Cancer Describe the advantages of using modern, targeted cancer therapies

US Mortality, 2003 No. of deaths % of all deaths Rank Cause of Death 1. Heart Diseases 685,089 28.0 2. Cancer 556,902 22.7 3. Cerebrovascular diseases 157,689 6.4 4. Chronic lower respiratory diseases 126,382 5.2 5. Accidents (Unintentional injuries) 109,277 4.5 6. Diabetes mellitus 74,219 3.0 7. Influenza and pneumonia 65,163 2.7 8. Alzheimer disease 63,457 2.6 Nephritis 42,453 1.7 10. Septicemia 34,069 1.4

2006 Estimated US Cancer Cases* Men 720,280 Women 679,510 Prostate 33% Lung & bronchus 13% Colon & rectum 10% Urinary bladder 6% Melanoma of skin 5% Non-Hodgkin 4% lymphoma Kidney 3% Oral cavity 3% Leukemia 3% Pancreas 2% All Other Sites 18% 31% Breast 12% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Non-Hodgkin lymphoma 4% Melanoma of skin 3% Thyroid 3% Ovary 2% Urinary bladder 2% Pancreas 22% All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2006.

2006 Estimated US Cancer Deaths* Men 291,270 Women 273,560 Lung & bronchus 31% Colon & rectum 10% Prostate 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4% bile duct Esophagus 4% Non-Hodgkin 3% lymphoma Urinary bladder 3% Kidney 3% All other sites 23% 26% Lung & bronchus 15% Breast 10% Colon & rectum 6% Pancreas 6% Ovary 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Multiple myeloma 2% Brain/ONS 23% All other sites ONS=Other nervous system. Source: American Cancer Society, 2006.

Cancer Cancer is one of the most common diseases in the developed world: 1 in 4 deaths are due to cancer 1 in 17 deaths are due to lung cancer Prostate cancer is the most common cancer in men Breast cancer is the most common cancer in women There are over 100 different forms of cancer What is cancer video https://www.youtube.com/watch?v=SGaQ0WwZ_0I

Terminology A factor which brings about a mutation is called a mutagen. A mutagen is mutagenic. Any agent that causes cancer is called a carcinogen and is described as carcinogenic. So some mutagens are carcinogenic.

Carcinogens Ionising radiation – X Rays, UV light Chemicals – tar from cigarettes Virus infection – papilloma virus can be responsible for cervical cancer. Hereditary predisposition – Some families are more susceptible to getting certain cancers. Remember you can’t inherit cancer its just that you maybe more susceptible to getting it.

Is cancer a heritable disease? There are heritable cancer syndromes The majority of cancers, however, are not familial Cancer is a genetic disease, but the majority of mutations that lead to cancer are somatic

What causes the mutations that lead to cancer? Viruses: HPV --> cervical cancer Bacteria: H. pylori --> gastric cancer Chemicals --> Chemical in tar--> lung cancer UV and ionizing radiation --> skin cancer What do these agents have in common?

Mutagens Viruses: insertional mutagenesis Chemicals: DNA adducts (a segment of DNA bound to a cancer causing chemical) UV and ionizing radiation: single and double strand DNA breaks

What types of genes get mutated in cancer? Oncogenes are activated Normal function: cell growth, gene transcription Tumor suppressor genes are inactivated Normal function: DNA repair, cell cycle control, cell death

Tumor suppressors “Guardian(s) of the genome” Often involved in maintaining genomic integrity (DNA repair, chromosome segregation)‏ Mutations in tumor suppressor genes lead to the “mutator phenotype”—mutation rates increase Often the 1st mutation in a developing cancer

p53—a classic tumor suppressor Senses genomic damage Halts the cell cycle and initiates DNA repair If the DNA is irreparable, p53 will initiate the cell death process

Rb—a classic tumor suppressor Rb binds to a protein called E2F1 E2F1 initiates the G1/S cell cycle transition When bound to Rb, E2F1 can't function Thus, Rb is a crucial cell cycle checkpoint

HER2/neu—an oncogene A growth factor receptor 25-30% of breast cancers over-express HER2/neu Which hallmark of cancer does this lead to? Herceptin is used as a treatment

Phenotype of a cancer cell The Six Hallmarks of Cancer Self-sufficient growth signals Constitutively activated growth factor signalling Resistance to anti-growth signals Inactivated cell cycle checkpoint Immortality Inactivated cell death pathway

Phenotype of a cancer cell (cont'd)‏ The Six Hallmarks of Cancer Resistance to cell death (apoptosis: programed cell death) Activated anti- cell death signalling Sustained angiogenesis Activated Blood vessel formation Invasion and metastasis Loss of cell-to-cell interactions, etc.

The Development of Cancer Within every nucleus of every one of the human body's 30 trillion cells exists DNA, the substance that contains the information needed to make and control every cell within the body. Here is a close-up view of a tiny fragment of DNA.

1. DNA of a normal cell This piece of DNA is an exact copy of the DNA from which it came. When the parent cell divided to create two cells, the cell's DNA also divided, creating two identical copies of the original DNA.

2. Mutation of DNA Change in the sequence of DNA This DNA has suffered a mutation, either through mis-copying (when its parent cell divided), or through the damaging effects of exposure to radiation or a chemical carcinogen.

3. Genetically altered cell Sometimes a genetic mutation will cause a cell and its descendants to reproduce even though replacement cells are not needed.

4. Spread and second mutation The genetically altered cells have, over time, reproduced unchecked, crowding out the surrounding normal cells. After about a million divisions, there's a good chance that one of the new cells will have mutated further. This cell, now carrying two mutant genes, could have an altered appearance and be even more prone to reproduce unchecked.

5. Third mutation Over time and after many cell divisions, a third mutation may arise. If the mutation gives the cell some further advantage, that cell will grow more vigorously than its predecessors and thus speed up the growth of the tumour.

6. Fourth mutation The new type of cells grow rapidly, allowing for more opportunities for mutations. The next mutation paves the way for the development of an even more aggressive cancer. At this point the tumour is still contained.

7. Breaking through the membrane The newer, wilder cells created by another mutation are able to push their way through the epithelial tissue's basement membrane, which is a meshwork of protein that normally creates a barrier. The invasive cells in this tumour are no longer contained. At this point the cancer is still too small to be detected.

8. Angiogenesis Angiogenesis takes place. Angiogenesis is the recruitment of blood vessels from the network of neighbouring vessels. With the new blood supply, however, the growth of the tumour accelerates; it soon contains thousand million cells and, now the size of a small grape, is large enough to be detected as a lump

9.Invasion and dispersal The tumour has now invaded the tissue beyond the basement membrane.

10. Tumour cells travel - metastasis What makes most tumours so lethal is their ability to metastasize -- that is, establish new tumour sites at other locations throughout the body forming secondary tumours. .

11. Metastasis To form a secondary tumour, a tumour cell needs to leave the vessel system and invade tissue. The cell must attach itself to a vessel's wall. Once this is done, it can work its way through the vessel and enter the tissue.

What can cancer therapies target? Classic cancer therapies target rapidly dividing cells Target the DNA Ionizing radiation Chemotherapy Many side effects Hair loss Weakened immune system Problems with GI tract

What can cancer therapies target? A person's immune system will not target tumor cells because they appear to be “self” Some new therapies focus on activating one's immune system against a cancer

What can cancer therapies target? Modern, targeted therapies attack specific proteins that are abnormally expressed in a tumor May block over-expressed growth factor receptors --> Herceptin Generally, there are few side effects since these therapies are specifically targeted to cancer cells

Types Of Cancers Classification of cancers Carcinomas : a cancer arising in the epithelial tissue of the skin or of the lining of the internal organs. Sarcomas: a malignant tumor of connective or other non- epithelial tissue Lymphomas: cancer of the lymph nodes Leukemias: cancer of white blood cells

Colon And Rectal Cancers Third most common cancer in men and women with over 148,610 new cases diagnosed in 2006 Risk factors: over 50 years old, obese, family history of colon or rectum cancer or polyps, diets high in fats, low in fiber, smoking, high alcohol consumption, lack of exercise 90% of colorectal cancers are preventable Treatment: radiation, surgery, and possible chemotherapy Prevention: regular exercise, a diet heavy in fruits and plant-origin foods, a health weight, and moderation in alcohol consumption

Prostate Cancer Most common cancer in American men, excluding skin cancer In 2006, 234,460 new cases diagnosed 1 in 3 men will be diagnosed in their lifetime Prostate is a muscular, walnut-sized gland the surrounds part of the urethra. Its primary function is to produce seminal fluid. Symptoms: nonspecific, weak or interrupted urine flow, difficulty starting or stopping urination Risk factors: age, race, nationality, family history, diet, lifestyle, and vasectomy Prevention: diet high in lycopenes, vitamin E

Skin Cancer Long term effects of sun exposure can result in skin cancer Malignant melanoma, deadliest form of skin cancer Sun give off 3 types of harmful rays: UVA UVB UVC Prevention: limit exposure to harmful UV rays, drink more fluids than usual, apply cool compresses to skin, moisturize skin

Types of Ultraviolet Rays Figure 16.7

Skin Cancer – cont. What to look for – The ABCD rule Asymmetry – half of mole does not look like the other half Border irregularity – the edges are uneven Color – pigmentation is not uniform Diameter – greater than 6mm

Testicular Cancer Affects nearly 8,250 young men in 2006 Men between the ages 15-35 are at the greatest risk Important to practice regular testicular self exams Lance Armstrong Foundation “LiveStrong” campaign to raise awareness

Ovarian Cancer Fifth leading cause of cancer death for women, 20,180 new cases diagnosed reported in 2006 Most common symptom is enlargement of the abdomen Risk factors include: family history, age, childbearing, cancer history, fertility drugs, talc use in genital area, genetic predisposition Prevention: diet high in vegetables and low in fat, exercise, sleep, stress management, and weight control

Cervical and Endometrial (Uterine) Cancer 9,710 new cases of cervical cancer, 41,200 cases of endometrial cancer in U.S. in 2006 Pap test – cells are taken from the cervical region Risk factors: Cervical cancer: early age at first intercourse, multiple sex partners, cigarette smoking Endometrial cancer: age, endometrial hyperplasia, overweight, diabetes, and high blood pressure

Other Cancers Pancreatic cancer – “silent” 4% 5-year survival rate Leukemia – cancer of blood forming tissues

Detecting Cancer The earlier the diagnosis the better the prospect for survival Magnetic resonance imaging (MRI) Computerized axial tomography scan (CAT scan) Prostatic ultrasound Regular self-exams, and check ups

New Hope In Cancer Treatments Remove less surrounding tissue during surgery Combine surgery with radiation or chemotherapy Immunotherapy Cancer-fighting vaccines Gene therapy Stem cell research