Cancer

Cancer - 03.30.11 Cancer Biology 1 Outline 1.How do cancer...

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Unformatted text preview: 03.30.11 Cancer Biology 1 Outline 1.How do cancer cells differ from normal cells? 2.Tumor progression 3.Molecular basis for cancer 2 Cancer is the second leading cause of death in the U.S. Cancer accounts for nearly one ­quarter of deaths in the United States, exceeded only by heart diseases. In 2004, there were 553,888 cancer deaths in the US. Cancer may be derived from many tissues Epithelial cells ConnecIve Issue Muscle Issue Epithelial cells: carcinomas 80 ­90% ConnecIve Issues: sarcomas 1% Blood and lymphaIc systems: leukemias, lymphomas Neuronal system: neuroblastoma, reInoblastoma, etc. The most common types of cancer involve epithelial cells. These compose 80 ­90% of cancers. A cancer like this would be called Carcinoma. There are also cancer that evolve from transformaIon of non ­epithelial cells. There are three main groups: Cancer of the connecIve Issues: Sarcoma (1%) Cancer of the blood and lymphaIc system: Leukemia, Lymphoma, Myeloma Cancer of the neuroectodermal system system: Neuroblastoma, Re?noblastoma Cells within a tissue are normally highly organized and tightly regulated e.g. intesIne e.g. skin Cancer: an aberration of normal development Cancer cells exhibit behaviors found in normal cells during development differentiation, and homeostasis Cancer cells exhibit behaviors found in normal cells during development & differen?a?on. However, in cancer cells these proper?es are separated from normal developmental controls & combined in unique & troublesome ways. Cancer: an aberration of normal development Cancer cells exhibit behaviors found in normal cells during development differentiation, and homeostasis However, cancer cells put together suites Of cell behaviors in problematic ways And do so out of normal regulatory controls Cancer cells exhibit behaviors found in normal cells during development & differen?a?on. However, in cancer cells these proper?es are separated from normal developmental controls & combined in unique & troublesome ways. Properties of Cancer Cells Most normal cells have a limited potential to divide senescent cells In what ways cancer cells differ from normal cells? 1. Cancer cells are "immortalized" ­ i.e. conInue to divide indefinitely without differenIaIng ­ a normal property of body's stem cells Normal stem cells can divide indefinitely, but under tight control Differen?ated cells Self ­renewing stem cell In what ways cancer cells differ from normal cells? 1. Cancer cells are "immortalized" ­ i.e. conInue to divide indefinitely without differenIaIng ­ a normal property of body's stem cells Properties of Cancer Cells Cancer cells are "immortalized”,just like stem cells, but w/o control Differen?ated cells Self ­renewing stem cell In what ways cancer cells differ from normal cells? 1. Cancer cells are "immortalized" ­ i.e. conInue to divide indefinitely without differenIaIng ­ a normal property of body's stem cells Cancer cell Most Normal cells differentiate 3. Cancer cells fail to form differenIated Issues like epidermal sheets, or specific blood cells But stem cells do NOT differentiate 3. Cancer cells fail to form differenIated Issues like epidermal sheets, or specific blood cells Like normal stem cells cancer cells do not differentiate tumor 3. Cancer cells fail to form differenIated Issues like epidermal sheets. Most normal cells stop proliferating under contact inhibition in vitro Figure 20 ­29 Molecular Biology of the Cell (© Garland Science 2008) 2. Cancer cells not under contact inhibiIon Normal cells stop dividing when come into contact with neighbors. Normal blastocyst stage embryonic cells share this property. in vivo Cancer cells do not exhibit contact inhibition Figure 20 ­29 Molecular Biology of the Cell (© Garland Science 2008) 2. Cancer cells not under contact inhibiIon However cells of early embryos also lack contact inhibition - thus cancer cells exhibit properties off embryonic cells Cancer cells exhibit altered cell adhesion and cytoskeletal organization Normal “Transformed” These changes in cell shape and behavior are shared by many migrating cells,including those that migrate into wound sites Late stage cancer cells are invasive normal ?ssue invasive tumor Figure 20 ­17 Molecular Biology of the Cell (© Garland Science 2008) 5. Cancer cells are invasive Normal cells can be invasive at the right time and place 5. Normal cells can also be invasive (inflammatory response, EMT). A neutrophil penetrates through blood vessels and the extra ­cellular matrix as part of an inflammatory response Normal cells that are starved for O2 Induce Angiogenesis Can’t breathe! Send Blood vessels Consequences 1. Nutrients and oxygen are supplied to the tissue Cancer Cells also Induce Angiogenesis Consequences 1. Nutrients and oxygen are supplied to the tumor 2. New blood vessels provide as easy way out Normal cells may undergo apoptosis As part of a developmental program 4. Cancer cells do not undergo normal programmed cell death. when cells become “dangerous” (e.g. DNA damage) Properties of Cancer Cells Cancer cells escape apoptosis Blue cells = breast cancer cells Yellow cells = apopto?c cells Dave McCarthy and Annie Cavanagh 4. Cancer cells do not undergo normal programmed cell death. Properties of Cancer Cells • Immortalized • Do not differentiate • Fail to exhibit contact inhibition • Invasive • Escape apoptosis Cancer develops through gradual changes in cell morphology and properties Figure 20-9 Molecular Biology of the Cell (© Garland Science 2008) Tumor progression, from over ­proliferaIon, to –”taking over” the Issue and eventually ­ invasion through the basal lamina Tumor Progression Tumor = abnormal growth of solid tissue Benign- self contained Malignantinvasive Tumor progression: Hyperplasia: cells divide in an uncontrolled manner Dysplasia: more abnormal growth. Cells and Issues don’t look normal anymore. They sIll “Respect” the boundary of their Issue (e.g. basal lamina) UnIl now, these abnormaliIes are defined as a benign tumor. A benign tumor is not too problemaIc, as it is self ­contained and can be removed surgically. In the majority of the cases it does not cause death. SomeImes, benign tumors can put pressure on organs and Issues and cause problems. The big problem, however, is that one of those cells can acquire the ability to penetrate and becomes malignant. Carcinoma in situ: high risk of malignancy Malignancy In many cases (especially from the clinical prospecIve) only cells at this stage and on will be defined as cancer. From our prospecIve, as cell biologists, we are interested also in the early stages as they lead to cancer. Metastasis: cell penetrate the blood vessels and sefle in foreign Issues. As the tumor is growing is needs more nutrients and oxygen and then it signals to starts angiogenesis. The forming blood vessels not only supply what the cells need but provide a way to “get out”. Metastasis is a difficult and dangerous process both for the tumor cell and the host Cellular changes required for metastasis All cancers have a genetic basis and are diseases caused by mutations in normal signaling pathways • Random mutations (mistakes during DNA replication) • Inherited mutations (pre-disposition) • Viral infections • Environmental factors (chemical; physical) Other factors that can cause mutaIons are radia?on (e.g. sun screen) and viral infec?on. Cancer from viral infecIon is common in animals and less in humans. However there are cancers that are caused by viral infecIons, wither indirectly, like in HIV, where the body defense mechanism is compromised, or directly: human papilloma virus causes carcinoma of the uterine cervix. That being said, the fact that viruses do cause cancer in animals was the basis for our understanding on the cellular and molecular mechanisms that are involved in human cancers Inherited mutations may predispose individuals towards cancer e.g., Familial adenomatous polyposis (FAP) Cancer results from a series of mutations, each cumulatively altering the cell Hypothetical progression of colon cancer • Mutations in 4 key genes • Progressive changes in cancerous tumor cells Carcinogens are chemical agents that contribute to tumor formation Figure 20-20b Molecular Biology of the Cell (© Garland Science 2008) Carcinogens contribute to cancer. We need to remember that the data are based on staIsIcal correlaIon (it is hard to prove that someone who smoked 60 cigarefes a day for 30 year dies because of that, but staIsIcal analysis in a populaIon, together with known biological carcinogenic effects of specific chemicals (e.g. in cigarefes) do not allow us to give the benefit of the doubt. Tumors evolve by repeated rounds of mutation and proliferation AccumulaIon of mutaIons The fact that cancer is a multi-step process is reflected in correlation between age and incidence of cancers Figure 20 ­7 Molecular Biology of the Cell (© Garland Science 2008) This mulI ­step process and accumulaIon of mutaIons in Ime is reflected in correlaIon between old age and incidence of cancers Especially late in the process, Cancer cells also accumulate chromosomal abnormalities Karyotype from breast cancer cell • Total of 48 chromosomes (instead of 46) • Multiple chromosomal translocations Two classes of genes are mutated in cancer: 1. Oncogenes 2. Tumor suppressor genes Oncogenes Proto-oncogene: a normal cellular gene that can become an oncogene, upon DNA damage Following this discovery, many genes from infecIous viruses that can transform animal (not human) cells , were found in animal (and human) normal cells. We disInguish between them as oncogenes (e.g. v ­src) and proto ­oncogenes (c ­src). Oncogenes result from rare dominant mutations that lock signaling machinery in the ON state Examples of oncogenic mutations Mutations that cause ligandindependent receptor activation (dimerization) The molecular basis of cancer. When v ­src was introduced to chicken, the cells became cancerous, although there was sIll a normal, endogenous copy of c ­src. This is also true for proto=oncogenes that become oncgones due to mutaIons and not because of viruses. Thus, a cellular Oncogene is dominant. One mutated copy is enough. If a proto ­oncogene has a normal, cellular role and when it is mutated into an oncogene, it can promote cancer, what would you expect its cellular role is? AffecIng funcIons that are criIcal for cell proliferaIon and survival, but funcIons that are normally under control. In a cell that carries an oncogene, the same “normal” funcIon lost its control. Oncogenes result from rare dominant mutations that lock signaling machinery in the ON state Examples of oncogenic mutations Mutations that lock Ras into the GTP-bound form 40 Tumor suppressor inactivation result from rare recessive mutations that lock signaling machinery in the OFF state Examples of oncogenic mutations Mutations that inactivate the Retinoblastoma protein (Rb) Tumor suppressor inactivation result from rare recessive mutations that lock signaling machinery in the OFF state Examples of oncogenic mutations Mutations that inactivate p53 Also promotes cell death ...
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