An Introduction to Cancer

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.

What is cancer? Abnormal cell growth (neoplasia)‏ Malignant as opposed to benign Benign: slow growth, non-invasive, no metastasis Malignant: rapid growth, invasive, potential for metastasis

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 Activated anti- cell death signalling Sustained angiogenesis Activated VEGF signalling Invasion and metastasis Loss of cell-to-cell interactions, etc.

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 --> B[a]P --> lung cancer a component of cigarette smoke benzo[a]pyrene (BaP) UV and ionizing radiation --> skin cancer What do these agents have in common?

Mutagens Viruses: insertional mutagenesis Chemicals: DNA adducts 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

Smoking and Cancer About one-third of all cancer cases in the United States are directly attributable to cigarette smoking. Smoke contains many mutagenic chemicals, and places them in direct contact with lung tissues. damages genes of epithelial cells lining the lungs

Tobacco Reduces Life Expectancy

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 “The guardian of the genome” 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

Chromosomal Instability

Tumor-Suppressor Genes Tumor suppressor genes encode proteins that turn off cell division in healthy cells. Cancer may be initiated by the inappropriate activation of proteins that regulate the cell cycle, or by the inactivation of proteins that normally suppress cell division.

Cancer and the Cell Cycle Cells control proliferation at several checkpoints. All these controls must be inactivated for cancer to be initiated. Induction of most cancers involves mutations of several genes. explains why most cancers occur in people over 40 more time for individual cells to accumulate multiple mutations

The Cell Cycle and Cancer

Cancer Cancer is a growth disorder of cells. uncontrolled and invasive growth results in tumor may metastasize can be caused by mutagenic chemicals or possibly viruses cell division never stops in a cancerous line, and are thus essentially immortal

Causes of Cancer Sarcomas - arise in connective tissue or muscle Carcinomas - arise in epithelial tissue Carcinogens are agents thought to cause cancer. Ames test Carcinogenic chemicals are all mutagenic.

The Stages of the Cell Cycle 1. Click on picture for cell cycle animation – will go to www.cancerquest.org) 2. Use alt-tab keys to go between website and power point presentation. 3. Click on blank space to proceed to next slide.)

Cancer and the Cell Cycle Oncogenes - genes that when introduced into normal cells cause them to become cancerous Originally discovered by transfection - nuclear DNA from tumor cells is isolated and cleaved into random fragments, and tested for ability to induce cancer

Cancer and the Cell Cycle Proto-oncogenes are genes encoding proteins that stimulate cell division. Mutated proto-oncogenes become cancer-causing genes (oncogenes). Mutated alleles of many oncogenes are genetically dominant.

There are several factors that regulate the cell cycle and assure a cell divides correctly. 1.Before a cell divides, the DNA is checked to make sure it has replicated correctly. (If DNA does not copy itself correctly, a gene mutation occurs. DNA replication animation:click on DNA picture

2. Chemical Signals tell a cell when to start and stop dividing. (Target cells animation: click on go sign)

Neighboring cells communicate with dividing cells to regulate their growth also. (Normal contact inhibition animation: click on petri dish)

Cancer is a disease of the cell cycle Cancer is a disease of the cell cycle. Some of the body’s cells divide uncontrollably and tumors form. Tumors in Liver Tumor in Colon

DNA mutations disrupt the cell cycle. Mutations may be caused by: 1. radiation 2. smoking 3. Pollutants 4. chemicals 5. viruses

While normal cells will stop dividing if there is a mutation in the DNA, cancer cells will continue to divide with mutation.

Due to DNA mutations, cancer cells ignore the chemical signals that start and stop the cell cycle. 2 animations of cancer cells dividing: click on picture

Due to DNA mutations, cancer cells cannot communicate with neighboring cells. Cells continue to grow and form tumors. Skin cancer (cancer cells dividing: click on picture.)

SUMMARY Normal Cell Division DNA is replicated properly. 2. Chemical signals start and stop the cell cycle. 3. Cells communicate with each other so they don’t become overcrowded. Cancer Cells Mutations occur in the DNA when it is replicated. 2. Chemical signals that start and stop the cell cycle are ignored. 3. Cells do not communicate with each other and tumors form.

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? Cancer treatments include drugs that can stop cancer cells from dividing.

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

Curing Cancer Preventing start of cancer receiving signal to divide mutations that increase number of receptors on cell surface amplify the division signal relay switch passage of signal into the cell’s interior relay switch stuck in “ON” position

Curing Cancer amplifying the signal releasing the brake amplification of signal within cytoplasm releasing the brake used to restrain cell division checking readiness ensures DNA is undamaged and ready to divide stepping on the gas restore telomerase inhibitor

Potential Cancer Therapy Targets

Curing Cancer Preventing the spread of cancer tumor growth metastasis angiogenesis inhibitors metastasis cells break off and migrate