Background-Quality of life (QoL) for patients with inflammatory skin disease can be significant, but has been evaluated in just one study in dermatomyositis (DM).
A hallmark of metastasis is organ specificity; however, little is known about the underlying signaling pathways responsible for the colonization and growth of tumor cells in target organs. Since tyrosine kinase receptor activation is frequently associated with prostate cancer progression, we have investigated the role of a common signaling intermediary, activated Ras, in prostate cancer metastasis. Three effector pathways downstream of Ras, Raf/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase, and Ral guanine nucleotide exchange factors (RalGEFs), were assayed for their ability to promote the metastasis of a tumorigenic, nonmetastatic human prostate cancer cell line, DU145. Oncogenic Ras promoted the metastasis of DU145 to multiple organs, including bone and brain. Activation of the Raf/ERK pathway stimulated metastatic colonization of the brain, while activation of the RalGEF pathway led to bone metastases, the most common organ site for prostate cancer metastasis. In addition, loss of RalA in the metastatic PC3 cell line inhibited bone metastasis but did not affect subcutaneous tumor growth. Loss of Ral appeared to suppress expansive growth of prostate cancer cells in bone, whereas homing and initial colonization were less affected. These data extend our understanding of the functional roles of the Ral pathway and begin to identify signaling pathways relevant for organ-specific metastasis.Cancer metastasis is the major determinant of cancer-related death. Metastasis is an inefficient process involving multiple steps that include local tumor cell dissemination, survival in the circulation, arrest in the vasculature, extravasation, and growth in distant organs (5). A hallmark of metastasis is the propensity of many types of cancers to metastasize to specific organs. Most circulating tumor cells passively arrest in capillary beds based upon mechanical constraints, and the organ selectivity for secondary growth of some cancers, such as colon cancer metastasis to liver, correlates with blood flow patterns (28, 41). However, it is clear from other examples, such as the predominant growth of breast and prostate cancer lesions in bone, an organ with relatively low arterial blood flow, that organ-specific factors other than hemodynamics determine metastatic colonization (24, 42).It has been widely accepted that the final outcome of metastasis depends upon multiple interactions between metastatic cells and their host organ microenvironment (10). One type of specific interaction occurs as a result of vascular specialization in individual organs that may lead to the adherence of tumor cells to endothelial cells or other vascular elements (34). In addition, it is well established that after extravasation from the vessels, reciprocal interaction between tumor cells and stromal, parenchymal, and immune cells influences the likelihood of clonal growth (5).The molecular mechanisms that determine metastatic competence and secondary organ specificity are poorly defined.Experimental and clinical studies ...
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