Chapter 080. Cancer Cell Biology and Angiogenesis (Part 12)

Figure 80-6Oncogene signaling pathways are activated during tumor progression and promote metastatic potential.This figure shows a cancer cell that has undergone epithelial to mesenchymal transition (EMT) under the influence of several environmental signals. Critical components include activated transforming growth factor beta (TGF-β) and the hepatocyte growth factor (HGF)/c-Met pathways, as well as changes in the expression of adhesion molecules that mediate cell-cell and cellextracellular matrix interactions. Important changes in gene expression are mediated by the Snail and Twist family of transcriptional repressors (whose expression is induced by the oncogenic pathways), leading to reduced expression of E-cadherin, a key component...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 12) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 12)Figure 80-6 Oncogene signaling pathways are activated during tumor progressionand promote metastatic potential. This figure shows a cancer cell that has undergone epithelial tomesenchymal transition (EMT) under the influence of several environmentalsignals. Critical components include activated transforming growth factor beta(TGF-β) and the hepatocyte growth factor (HGF)/c-Met pathways, as well aschanges in the expression of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. Important changes in gene expression aremediated by the Snail and Twist family of transcriptional repressors (whoseexpression is induced by the oncogenic pathways), leading to reduced expressionof E-cadherin, a key component of adherens junctions between epithelial cells.This, in conjunction with upregulation of N-cadherin, a change in the pattern ofexpression of integrins (which mediate cell-extracellular matrix associations thatare important for cell motility), and a switch in intermediate filament expressionfrom cytokeratin to vimentin, results in the phenotypic change from adherenthighly organized epithelial cells to motile and invasive cells with a fibroblast ormesenchymal morphology. EMT is thought to be an important step leading tometastasis in some human cancers. Host stromal cells, including tumor-associatedfibroblasts and macrophages, play an important role in modulating tumor cellbehavior through secretion of growth factors and proangiogenic cytokines, andmatrix metalloproteinases that degrade the basement membrane. VEGF-A, -C, and -D are produced by tumor cells and stromal cells inresponse to hypoxia or oncogenic signals, and induce production of new bloodvessels and lymphatic channels through which tumor cells metastasize to lymphnodes or tissues. The metastatic phenotype may be a characteristic of all cells constitutingthe primary tumor; however, it is likely that variants with metastatic potential arisedue to genetic and epigenetic events that characterize tumor progression (Fig. 80-6). A number of candidate metastasis-suppressor genes have been identified. The loss of function of these genes enhances metastasis, and although themolecular mechanisms are in many cases uncertain, one common theme is anenhancing of the ability of the metastatic tumor cells to overcome the manyapoptosis signals they encounter during the metastatic process. Gene expression profiling is being used to study the metastatic process withthe goal of identifying signatures characteristic of primary tumors that have a highpropensity to metastasize, leading to a more rational basis for the use of adjuvantchemotherapy. Bone metastases are extremely painful, cause fractures of weight-bearingbones, can lead to hypercalcemia, and are a major cause of morbidity for cancerpatients. Osteoclasts and their monocyte–derived precursors express the surfacereceptor RANK (receptor activator of NFκB), which is required for terminaldifferentiation and activation of osteoclasts. Osteoblasts and other stromal cells express RANK ligand, as both amembrane-bound and soluble cytokine. Osteoprotegerin (OPG), a soluble receptorfor RANK ligand produced by stromal cells, acts as a decoy receptor to inhibitRANK activation. The relative balance of RANK ligand and OPG determines the activationstate of RANK on osteoclasts. Many tumors increase osteoclast activity bysecretion of substances such as parathyroid hormone (PTH), PTH-related peptide,interleukin (IL)-1, or Mip1, that perturb the homeostatic balance of boneremodeling by increasing RANK signaling. One example is multiple myeloma, where tumor cell–stromal cellinteractions activate osteoclasts and inhibit osteoblasts, leading to the developmentof multiple lytic bone lesions. Inhibition of RANK ligand by IV administration ofrecombinant OPG or the extracellular domain of RANK linked to animmunoglobulin Fc-receptor (RANK-Fc) can prevent further bone destruction.Bisphosphonates are also effective inhibitors of osteoclast function that are used inthe treatment of cancer patients with bone metastases.[newpage]