Lecture 6 Cancer s Most Deadly Weapon Cell Differentiation The process by which a cell changes from a less specialized type to a more specialized type Differentiation dramatically changes a cells size Profile of a Cancer Cell Summary Self sufficient in growth signals Insensitive to anti growth signals Tissue invasion metastasis Limitless replication potential Sustained angiogenesis Evading apoptosis Typical Cancer Progression Mutation inactivates tumor suppressor gene Cell Proliferates Mutation inactivates DNA repair gene Mutation of proto oncogene creates an oncogene Mutation inactivates several more tumor suppressor genes Cancer Primary and Secondary Cancer The main reason cancer can be difficult to cure is that it can spread to another part of the body from where it started The cancer that is growing where it started in the body is called the primary cancer The place a cancer spreads to and starts growing is called secondary cancer or metastasis In order to spread some cells from the primary cancer must break away travel to another growing part of the and start growing there Cancer Spread and Mortality 90 of Cancer Deaths Occur Because of Where Cancer Ends Up Not Where it Begins Research shows that most metastatic cancers induce prematastic niches or landing pads allowing cancerous cells to colonize a secondary organ When cancer cells travel to a vital organ they often overwhelm the cells and cause it to shut down How Hematologic Cancers Cause Death Hematologic blood cancers kill because the components of the blood are no longer fulfilling their duties The immune system is no longer working effectively The platelet count drops causing hemorrhage Red cells are significantly reduced causing reduced oxygen and the patient has a heart attack How Solid Tumors Cause Death Solid tumors kill in very mechanical ways Ovarian cancer kills you by obstructing your bowel as does colon cancer and most other cancers of the GI tract Lung cancers usually kill by eroding into an artery or obstructing the airway Breast cancers typically kill by metastases in the brain causing increased intracranial pressure More than 40 of cancer patients die from malnutrition not the cancer itself Tumors induce hypermetabolic state and secrete a substance called cachectin that results in weakness and weight loss Most Common Sites of Cancer Metastasis Brain headaches seizures vertigo Lymph nodes lymphadenopathy Respiratory Cough hemoptysis dyspnea Liver Hepatomegaly jaundice Skeletal Pain fractures Vasculogenesis and Angiogenesis there are no pre existing ones existing ones Vasculogenesis Is the term used for the formation of new blood vessels when Angiogenesis The term denotes the formation of new blood vessels from pre Experiments Showing That Tumor growth depends on Angiogenesis Compare size of tumor growing in the lab and in the iris tumor of the iris grew considerably more than the tumor grown in the lab Dr Judah Folkman Pioneer in Tumor Angiogenesis While working for the Navy in 1960 s on blood substitutes he began experimenting with tumors and found that all grew to the same size and stopped Hypothesized that the tumors could not grow beyond a certain size without a blood supply and that tumors must have some mechanism to induce the formation of blood vessels Cancer Cells Produce Angiogenesis Stimulating Molecules Chamber surrounded by filter with tiny pores 1 Place chamber containing cancer cells beneath an animal s skin 2 Blood vessel growth occurs outside chambers Cancer cells produce VEGF will signal signal transduction proteins then activate transcription of cell migration cell proliferation and secretion of matrix metalloproteinases Tumor Angiogenesis When they number only 100 300 the cancer cells have created new fully functioning blood vessels Stages of Angiogenesis Small tumor Genetic mutations cause a cell to become cancerous Pre Angiogenesis Tumors need a fuel supply system for growth more fuel often equals more aggressive growth Chemical signal and growing capillaries Early stage angiogenesis Capillary and other blood vessel growth often promotes rapid tumor development Growing tumor nutrients from blood cancer cells migrate to other parts of the body Advanced Angiogenesis A dense network of blood vessels fuel the growth of the malignant tumor to the point where it can become life threatening Avastin Inhibits Angiogenesis Blood vessel blockers Genentech received federal approval Friday to marker its drug avastin for late stage breast cancer The drug is designed to block the supply of blood to cancerous tumors by attacking Vascular Endothelial Growth Factor VEGF a protein that causes the growth of new blood vessels to cancerous tumors 1 Cancer cells multiply and grow into a tumor The tumor released VEGF in a 2 Capillaries from a network that feeds the tumor oxygen and nutrients and the process called angiogenesis tumor grows larger 3 Cancer cells break off from the tumor and enter the bloodstream allowing the cancer to spread to other parts of the body How Avastin works the drug attaches to VEGF and prevents the protein from working thereby stopping the growth of new blood vessels of the tumor There Are Three Main Ways a Cancer Spreads Local spread Cancer cells in normal cells Through the blood Circulation Cancer cell slips out of capillary into body tissue Through the lymphatic system Will enter that system Lymphatic capillaries pulmonary capillary network blood flow system capillary network lymphatic capillaries lymph flow lymph node lymphatic vessels lymph node Where 10 Cancer Commonly Spread The type and stage of your cancer determines whether it s likely to spread metastasize Some types of cancer have a tendency to spread to certain areas Cancer Type Breast Colon and Rectal Kidney Ovarian Pancreatic Where it s most likely to spread Bones lungs liver brain skin Liver lungs bones Lungs bones liver brain skin Liver lungs Liver lungs bones brain Cancer Type Soft Tissue Stomach Thyroid Prostate Where it s most likely to spread Lungs bones brain Liver lungs brain Lungs liver bones Bones lungs liver Steps Involved in the Metastatic Process The ability to invade differs among cancer cells and tumors Blood flow patterns often dictate where cancers will spread to Relatively few cancer cells survive the voyage through the blood stream Cancer cells are able to invade because Decreased adhesiveness Activated motility Protease production 1 Cancer cells invade surrounding tissues and vessels 2 Cancer
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