Chapter 080. Cancer Cell Biology and Angiogenesis (Part 1)

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Harrison's Internal Medicine Chapter 80. Cancer Cell Biology and Angiogenesis Cancer Cell Biology and Angiogenesis: Introduction Two characteristic features define a cancer: unregulated cell growth and tissue invasion/metastasis. Unregulated cell growth without invasion is a feature of benign neoplasms, or new growths. Cancer is a synonym for malignant neoplasm. Cancers of epithelial tissues are called carcinomas; cancers of nonepithelial (mesenchymal) tissues are called sarcomas. Cancers arising from hematopoietic or lymphoid cells are called leukemias or lymphomas. Cancer is a genetic disease. The malignant phenotype often requires mutations in several different genes that regulate cell proliferation, survival, DNA repair, motility, invasion,...

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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 1) Harrison's Internal Medicine > Chapter 80. Cancer Cell Biology and Angiogenesis Cancer Cell Biology and Angiogenesis: Introduction Two characteristic features define a cancer: unregulated cell growth and tissue invasion/metastasis. Unregulated cell growth without invasion is a feature of benign neoplasms, or new growths. Cancer is a synonym for malignant neoplasm. Cancers of epithelial tissues are called carcinomas; cancers of nonepithelial (mesenchymal) tissues are called sarcomas. Cancers arising from hematopoietic or lymphoid cells are called leukemias or lymphomas.
Cancer is a genetic disease. The malignant phenotype often requires mutations in several different genes that regulate cell proliferation, survival, DNA repair, motility, invasion, and angiogenesis (Table 80-1). Cancer-causing mutations often activate signal transduction pathways leading to aberrant cell proliferation and perturbations of tissue-specific differentiation programs. The normal cell has protective mechanisms that lead to the repair of DNA damage that occurs during DNA synthesis and mitosis and in response to environmental mutagens; these repair pathways are often abnormal in cancer cells. When a normal cell has sustained too much damage to repair, the cell activates a suicide pathway to prevent damage to the organ. These cell death pathways are also commonly altered in cancer cells, leading to the survival of damaged cells that would normally die. Cancer cells often exist under conditions of low oxygen tension (hypoxia) and nutrient deprivation, and selective pressure leads to the outgrowth of neoplastic variants that can survive under these conditions through the upregulation of a series of hypoxia-inducible genes (see below). The acquisition of novel phenotypic characteristics includes those that facilitate invasion and metastasis, such as the ability to break through basement membranes, migrate through the extracellular matrix and into the vascular compartment, and generate new blood vessels to support colonization in remote sites. The accumulation of genetic lesions may lead through an identifiable progression of altered phenotypes as is noted in colon cancer: hyperplasia →adenoma
→dysplasia →carcinoma in situ →invasive carcinoma. Premalignant changes have also been identified in prostate, breast, and pancreatic cancers. Table 80-1 Phenotypic Characteristics of Malignant Cells Deregulated cell proliferation: Loss of negative regulators (suppressor oncogenes, i.e., Rb, p53), and increased positive regulators (oncogenes, i.e., Ras, Myc). Leads to aberrant cell cycle control and includes loss of normal checkpoint responses. Failure to differentiate: Arrest at a stage prior to terminal differentiation. May retain stem cell properties. (Frequently observed in leukemias due to transcriptional repression of developmental programs by the gene products of chromosomal translocations.) Loss of normal apoptosis pathways: Inactivation of p53, increases in Bcl-2 family members. This defect enhances the survival of cells with oncogenic mutations and genetic instability and allows clonal expansion and diversification within the tumor without activation of physiologic cell death pathways. Genetic instability: Defects in DNA repair pathways leading to either
single or oligo-nucleotide mutations, (as in microsatellite instability, MIN) or more commonly chromosomal instability (CIN) leading to aneuploidy. Caused by loss of function of p53, BRCA1/2, mismatch repair genes, and others. Loss of replicative senescence: Normal cells stop dividing after 25–50 population doublings. Arrest is mediated by the Rb, p16 INK4a, and p53 pathways. Further replication leads to telomere loss, with crisis. Surviving cells often harbor gross chromosomal abnormalities. Increased angiogenesis: Due to increased gene expression of proangiogenic factors (VEGF, FGF, IL-8) by tumor or stromal cells, or loss of negative regulators (endostatin, tumstatin, thrombospondin). Invasion: Loss of cell-cell contacts (gap junctions, cadherens) and increased production of matrix metalloproteinases (MMPs). Often takes the form of epithelial-to-mesenchymal transition (EMT) with anchored epithelial cells becoming more like motile fibroblasts. Metastasis: Spread of tumor cells to lymph nodes or distant tissue sites.
Limited by the ability of tumor cells to survive in a foreign environment. Evasion of the immune system: Downregulation of MHC class I and II molecules; induction of T cell tolerance; inhibition of normal dendritic cell and/or T cell function; antigenic loss variants and clonal heterogeneity. Note: VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; IL, interleukin.