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cancer
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I. The Basics A. “Transformation” from a normal to a cancerous state occurs at the level of individual cells. · metastatic cancer cells resemble the primary cancer · cancers are usually clonal in origin (X-inactivation studies in females; unique Ig or TCR rearrangements in lymphoid cancers) · single cell transformation can be observed in culture systems (decreased adherence, anchorage independence for growth, loss of contact inhibition, decreased growth factor requirement, increased nutrient uptake and membrane ruffling) · Implications: Cancer arises at the level of the single cell and therefore must be understood at that level. This is different than other common diseases such as hypertension or diabetes that are due to "systemic" perturbations in physiology. B. Cancer is primarily a genetic disease. · somatic mutations occur in common “sporadic” (non-familial) cancers · inherited germline mutations occur in rare familial cancer syndromes · increases in the mutation rate or genomic instability correlate with increased risk of cancer · selection for mutations in cancer occur at the level of the single cell, not at the level of organismal survival. C. Cells must make critical decisions in a multi-cellular organism. · stem cell renewal; growth / quiescence; differentiation; cell death · adult humans have a remarkable homeostasis of cell number · communication between different cells is critical for this homeostasis · failure at any of these decision points can lead to overgrowth D. The good, the bad, and the ugly. · tumor suppressor genes prevent transformation [good] · oncogenes cause transformation [bad] · loss of genomic integrity causes mutations in both [ugly] II. Oncogenes A. Oncogenes are dominantly acting agents of cellular transformation. Note that a small number of different oncogenes explains a very large number of different types of cancer. This is a great simplification of the problem. B. Independent lines of cancer research identify the same set of oncogenes. 1. Acutely transforming retroviruses · why study tumor viruses? rapid and reliable oncogenesis can be readily quantitated genetically simple: only 4 genes instead of 60,000 · retroviral oncogenes required for transformation but not viral growth · retroviral oncogenes (v-onc) arise from highly conserved cellular proto-oncogenes (c-onc) [examples: v-myc in avian myelocytomatosis virus; v-ras in rat sarcoma virus; v-src in Rous sarcoma virus] Note that Rous sarcoma virus (RSV) is unusual because it has all three essential viral genes (gag, pol, env) and also contains a viral oncogene of cellular origin (src). Some transformation defective (td) mutants of RSV have completely lost the src gene but still replicate.
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