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CONCEPT: OVERVIEW OF CANCER Cancer is a disease which is primarily caused from misregulated cell division, which form There are two types of tumors - Benign tumors remain confined to its original location - Malignant tumors invade surrounding tissues and spread throughout the body (metastasis) There are three main of cancers - Carcinomas are cancers of epithelial cells (90%) - Leukemias/lymphomas are cancers of blood and immune system (7%) - Sarcomas are cancers of connective tissue (very rare) Benign Malignant Cancer is caused by many Carcinogens are substances that cause cancer (Ex: tobacco associated with 30% of all cancers) - Epidemiology is a field which studies diseases in human populations identifies carcinogens Cancer is not caused by a single mutation, but a number of mutations - Tumor initiation is when a genetic alteration leads to abnormal cell proliferation and replication - Tumor progression occurs as the tumor cells gain more mutations Mutations are found within two of genes Page 2
- Oncogenes are genes that when mutated cause cell growth - Proto-oncogenes can easily become an oncogene through additional mutations - Tumor suppressors are genes that normally suppress cell growth Tumor cells present with certain They are genetically unstable because they accumulate mutations at a rapid rate They lose contact inhibition which is a trait cells have to tell them to stop dividing when touching other cells - Also called anchorage-independent growth They undergo angiogenesis which allows them to form new blood vessels within the tumor They have defects in apoptosis pathways Page 3
PRACTICE: 1. Which of the following is not a characteristic of tumor cells? a. Undergo angiogenesis b. Are genetically unstable c. Perfectly control apoptosis d. Loose contact inhibition 2. Which of the following genes normally suppress tumor growth, but when mutated allow for tumor growth? a. Carcinogens b. Oncogene c. Tumor suppressors d. Proto-oncogenes Page 4
CONCEPT: ONCOGENES AND TUMOR SUPPRESSORS Mutations give cancer cells certain properties: 1. Self-sufficiency to grow without growth signals 2. Insensitivity to anti-growth signals 3. Apoptosis evasion 4. Unlimited replication 5. Angiogenesis 6. Invasion and metastasis in other tissues 7. Genetic instability Oncogenes are genes that become overexpressed and support cancer Proto oncogenes are the normal (not mutated) versions of oncogenes - Become oncogenes through mutations, or through gene amplification Activity gain results in cell proliferation, cell survival, and tumor development Oncogenes are generally - Growth factors - Receptors that stimulate growth-signaling pathways - GTP binding proteins - Protein kinases (receptor or non-receptor) - Transcription factors - Regulators of the cell cycle or apoptosis Ras is an oncogene GTPase that is mutated in 20% of cancers Page 5
Tumor suppressors are genes that when mutated result in activity loss and to cancer Activity loss results in cell proliferation, cell survival, and tumor development The transcription factor p53 is a great example of a tumor suppressor - Normally p53 responds to DNA damage and helps the cell repair itself - When mutated, the cell can t respond properly to DNA damage - leads to genetic instability Retinoblastoma is a tumor suppressor that regulates the cell - Mutated form can be inherited Page 6
PRACTICE: 1. True or False: Tumor suppressors are mutated genes that results in higher amounts of gene activity. a. True b. False 2. Which of the following properties is not one given to cancer by gene mutations? a. Ability to evade apoptosis b. Unlimited replication c. Self-sufficiency from growth signals d. Genetic Stability Page 7
CONCEPT: CARCINOGENS Cancer begins with in the DNA of a cell Carcinogens are substances that induce DNA damage which can lead to cancer - Tumor initiators are carcinogens that damage DNA directly - Tumor promoters don t cause mutations, but promote cancer is already mutated DNA Carcinogen DNA Damage DNA Repair deficiency Increased in damaged DNA Cancer DNA damage includes - Loss of DNA damage repair systems - Telomere shortening - Viral genome integration Environmental factors can induce DNA damage - Tobacco - Viral exposure (HPV, HBV, HCV, etc..) - Diet and lifestyle choices Page 8
PRACTICE: 1. True or False: All carcinogens act by directly damaging DNA. a. True b. False 2. Which of the following is not a type of DNA damage? a. Loss of DNA repair and accumulation of mutations b. Shortening of telomeres c. Epigenetic modifications leading to gene suppression d. Integration of a viral genome Page 9
CONCEPT: TUMOR VIRUSES There are many oncogenic viruses that cause Some viruses integrate into the host cell genome, which can be harmful Other viruses have proteins which interfere with normal cell functions - Block tumor suppressor activities - Interfere with cell cycle control (increase) and apoptotic (decrease) mechanisms - Overtake the cell replicative machinery to replicate its genome Virus Hepatitis B/C Papillomavirus Herpesviruses Retroviruses Cancer Liver cancer Cervical cancer and head, neck, throat cancer Kaposi s Sarcoma Kaposi s Sarcoma (AIDS) HPV E6 protein HPV E7 protein p53 Rb p53 tumor suppressor destruction Rb tumor suppressor inhibition Page 10
PRACTICE: 1. True or False: Many viruses can cause cancer. a. True b. False 2. Which of the following viruses can cause head, neck, and throat cancer? a. Hepatitis B b. Human Papillomavirus c. Herpesvirus d. Retroviruses Page 11
CONCEPT: METASTASIS Metastasis describes the ability of cancer cells to enter the bloodstream and travel to distant parts of the body Very few cells traveling through the bloodstream - First, the cells travel to the lymph nodes and then eventually travel to more distant tissues Rho GTPase is important for metastasis, but no one is sure what exactly it does The tumor microenvironment describes the environmental components the tumor lives in - The environment influences growth, invasion into nearby tissues, and metastasis - Also supports angiogenesis which is the growth of blood vessels - Tumors without a blood supply will die due to a lack of oxygen and nutrients Page 12
PRACTICE: 1. True or False: Many cells do not survive traveling through the blood stream. a. True b. False 2. Angiogenesis does what for cancer cells? a. Stimulates the production of more growth factors b. Provides a blood supply to the tumor cells c. Blocks apoptosis d. Stimulates an increased rate of DNA replication Page 13
CONCEPT: CANCER TREATMENTS There are many different types of cancer treatments Therapy type Traditional Therapies Surgery Radiation Chemotherapy Immunotherapy Passive Active Anti-angiogenic Molecular targeting Function Remove the tumor Kill tumor by damaging DNA Kill tumor by damaging DNA Uses antibodies against tumors to kill them Stimulates patients own immune system to kill the tumor Destroys blood vessels that support tumor growth Uses small molecules to target specific cancer causing genes Cancer cells can develop resistance against the Multidrug resistance is when cancer cells exposed to one treatment, develop resistance to multiple treatments - Mdr1 gene, which is an ABC Transporter, becomes amplified - The Mdr1 protein transports cancer killing chemicals out of the cell making them insensitive Page 14
PRACTICE: 1. Which of the following therapies targets cancer cells by introducing antibodies into the tumor? a. Chemotherapy b. Surgery c. Passive immunotherapy d. Anti-angiogenic drugs 2. Which of the following therapies targets cancer cells by destroying blood vessels that support tumor growth? a. Chemotherapy b. Surgery c. Passive immunotherapy d. Anti-angiogenic drugs Page 15