Cancer Biology and Metastasis Lecture Notes PDF

Cancer Biology and Metastasis BMS 532 MOLECULAR BIOLOGY AND GENETICS BLOCK 4 LECTURE 7  Objectives 1. Define the following terms or concepts: gain of function, loss of function, protooncogene, oncogene, tumor suppressor gene, fusion gene/protein, hyperplasia, dysplasia, anaplasticity, b...

Cancer Biology and Metastasis BMS 532 MOLECULAR BIOLOGY AND GENETICS BLOCK 4 LECTURE 7  Objectives 1. Define the following terms or concepts: gain of function, loss of function, protooncogene, oncogene, tumor suppressor gene, fusion gene/protein, hyperplasia, dysplasia, anaplasticity, benign, malignant, contact inhibition, intravasation, extravasation, carcinoma, sarcoma, and leukemia/lymphoma 2. Explain the difference between sporadic and inherited forms of cancer 3. Compare and contrast the features of benign and malignant growths 4. Explain the process of malignant transformation and list the key features of malignancy 5. Explain the difference between reversible and irreversible stages of cancer development/progression 6. Explain the process of metastasis with emphasis on the order and activity of the steps involved in the process and Explain the role of vascular permeability to the permissibility of metastasis 7. List the typical cancer stages (0 through IV) with emphasis on the general corresponding features of each stage LO1 Principles of Cancer 1. Exhibit Malignancy 85% = Carcinoma ◦ Epithelial cells 2. Altered Heritability 10% = Leukemia/Lymphoma 3. Autonomous Growth ◦ Blood/lymph cells 4. Invasion and Interference 5% = Sarcoma ◦ Muscle, Bone, Blood Vessels, or Cartilage LO1, LO2 Cancer Development Most Cancer is NOT inherited or predetermined Most cancers develop due to somatic changes over time with NO INHERITED PREDISPOSITION ◦ Or at least no identified family history or known germline mutations ◦ 0nly 5 to 10% of most cancers are considered familial or inherited though familial clustering can increase that to nearly 35% ◦ Regardless of the differentiation between familial clustering and inherited, THE MAJORITY OF CANCER IS DEVELOPED SOMATICALLY AND SPORADICALLY LO1, LO4 Cancer Cells Abnormal cells in which the normal processes regulating cell division are altered ◦ Callback to Cell Division Regulation (CDKs) Typically around 4 to 7 unique events are required to transition a normal cell through premalignancy into an invasive cancer The events precipitating cancer can be unique and varied even within cancers of the same “type” though the hallmarks demonstrate that there are unifying themes 5 LO1, LO3, LO4 Abnormal Cell Growth: Differentiating Benign from Malignant BENIGN MALIGNANT NONinvasive Invasive through the basement membrane Highly differentiated or TERMINALLY differentiated Poorly differentiated Reduced or low number of cellular Increased or high number of cellular divisions divisions SLOW growth RAPID growth NONmetastatic Potentially Metastatic Can be “CURED” with surgery alone or Often requires aggressive medical left untreated interventions LO1, LO4 Malignancy Multi-tiered process ◦ Initiation ◦ Hyperplasia/Dysplasia ◦ Not interchangeable concepts but often go hand-in-hand ◦ Hyperplasia = excess growth; Dysplasia = abnormal structure or cell type ◦ Can be growing to abnormal levels without having an altered appearance and can have an altered appearance without excess growth (which comes first isn’t always clear especially once malignancy is apparent) ◦ Development of Anaplasticity ◦ 3rd stage after hyperplasia and dysplasia; represents truly abnormal cells ◦ Loss of normal function; enables cell to spread to distant locations ◦ Invasion ◦ Into surrounding tissues/structures though most commonly begins with invasion through basement membrane ◦ Metastasis LO1, LO4, LO5 Carcinogenesis The process of cellular transition leading to malignancy Reversible Stages ◦ Initiation ◦ Promotion (mild hyperplasia or dysplasia) Irreversible Stages ◦ Progression (early and late; significant dysplasia with anaplasticity) ◦ Invasion ◦ Metastasis 8 LO1, LO4 Subversion of the Norms… 1. Growth Stimulation Dependence 2. Contact Inhibition 3. Balance between losses and gains (controlled aging and death balanced with new life) 4. Properly response to stop signals and death signals *Each of these correspond with features of cancer hallmarks; cells must overcome these features to truly become malignant This is simply another way to look at a few of the hallmarks we have already discussed! 9 LO1, LO6 Process of Metastasis 1. Adhesion to Basement Membrane 2. Invasion through Basement Membrane 3. Passage Through Extracellular Matrix 4. INTRAVASATION 5. Travel (Tumor cell embolus) 6. Adhesion to vessel epithelium 7. EXTRAVASATION 8. Passage Through Extracellular Matrix 9. Adhesion to Basement Membrane 10. Growth at secondary location 10 LO7 Cancer Stages Cancer stages can be cancer specific The higher the stage, the more severe the changes and disease Metastatic spread can begin earlier with some evidence of “invisible metastasis” occurring early for some cancer subtypes Examples ◦ Renal carcinoma is invasive earlier ◦ Ovarian Cancer is metastatic earlier due to involvement of/spread to the uterus The Hallmarks of Cancer Perspective on the Molecular Biology of Cancer A FEW KEY FEATURES OF MOLECULAR BIOLOGY AS DEFINED BY THE HALLMARKS  Objectives 1. Define the following terms or concepts: gain of function, loss of function, protooncogene, oncogene, tumor suppressor gene, fusion gene/protein, hyperplasia, dysplasia, anaplasticity, benign, malignant, contact inhibition, intravasation, extravasation, carcinoma, sarcoma, and leukemia/lymphoma 8. Link specific molecular changes to their corresponding hallmarks: ◦ Self-sufficiency in growth signaling ◦ Insensitivity to anti-growth signals ◦ Limitless replicative potential ◦ Genomic instability and chromosomal rearrangements 9. Explain the relationship between growth signaling and cancer development and progression 10. Explain the relationship between telomere length, telomerase, and cancer development and progression 11. Explain the role of chromosomal rearrangements in cancer development or progression LO1, LO8, LO9, Self-Sufficiency in Growth Signals: LO11 i.e. oncogenic potential of a cell Protooncogene ◦ A normal gene capable of oncogenic transformation of a cell when overexpressed or mutated Oncogene ◦ A gene that has a role in or contributes to malignant transformation of a cell Turning a protooncogene into and oncogene… DNA mutation Chromosomal Translocation Gene Amplification **All result in continuous activation or stimulation of growth signaling rendering the proteins less responsive to regulatory controls LO1, LO8, LO9 Protooncogenes and Oncogenes in Signaling Pathways Nearly all of the proteins that convey or promote a signal are encoded by protooncogenes ◦ ALL known protooncogenes encode for signal transducing proteins These are the “GO” signals in growth Turning on growth signaling without the need for growth factors or stimuli for growth enables the cell to grow without needing to be told (self-sufficiency in growth signaling) These same pathways can enable the cell to overcome signals telling them to stop growing (insensitivity to antigrowth signals) 15 LO1, LO8, LO9 Protooncogenes and Oncogenes in Signaling Pathways Distinguishing oncogenic potential from other types of mutation: ◦ Introduction of an oncogene via transfection into a cultured, nonmalignant cell will result in ◦ Formation of foci/loss of contact inhibition ◦ Reductions in the need for growth factors ◦ Anchorage independent growth in soft agar ◦ Transfected cells will also gain the ability to form tumors in athymic or severe immunocompromised mice Inherited mutations are possible but malignant progression requires additional mutations typically in regulatory genes before dysregulated growth will occur 16 LO1, LO8, LO11 Limitless Replicative Potential: Telomeres and Telomerase End replication problem leads to telomere shortening over cellular lifespan ◦ Hayflick Limit: limits on cellular lifespan; determined by critically short telomere Providing a cell with limitless replicative potential requires maintenance of telomere length and restoration of telomeres Telomerase activity is present in most malignant cells and tissues (>90%) and is repressed in most normal tissues Activation of telomerase is a critical step in achieving immortalization of the cell Lengths of telomeres in cancer can eventually exceed the lengths of even germline cells depending on the level of activity of telomerase LO1, LO8, Genomic Instability: LO11 Telomeres and Bridge-Fusion-Breakage Cycle Telomerase Activation Telomerase Activation Artandi, NEJM 355: 1195-1197, 2006 18  Check-in Questions Evaluation of cervical cells indicates dysplasia without any accompanying hyperplasia. There is no evidence of infection with any form of HPV and the dysplasia is highly localized to one region of the cervix. A scientist uses the cells in an experimental therapy that uses gene editing that readily reverses the dysplastic phenotype. Based on this information, in which stage of carcinogenesis were the cells most likely discovered? A. Initiation B. Progression C. Invasion D. Anaplastic growth E. None of these A cancer has been identified as being stage IV with metastatic lesions in multiple tissues. Which of the following best describes the expected appearance of the vasculature at or near a metastatic lesion? A. Capillary bed intact with limited permeability B. Capillary bed intact with complete basement membranes C. Capillary bed altered with limited permeability D. Capillary bed altered with incomplete basement membranes E. Capillary bed altered with small intercellular clefts