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It is the ability to metastasize that makes cancer a fatal disease. Of the 555,500 cancer-related deaths expected this year in the United States, the vast majority are due to the development of metastatic disease rather than the primary tumor (Jemal et al., 2002). Although treatment is available for patients with metastatic cancer, options are limited and responses can be quite variable. Furthermore,...
Bone is the second most common site of metastases in human cancer. At least two-thirds of the approximately 553,400 Americans who die from cancer each year have bone metastases (Greenlee et al., 2001). Prostate, breast, and lung cancers account for at least 80% of the skeletal metastases. Tumors arising in the prostate and breast are particularly prone to disseminate to bone; up to 85% of patients...
Animal models are important tools to investigate the pathogenesis and develop treatment strategies for bone metastases as they occur in humans. However, there are few spontaneous models of bone metastasis despite the fact that rodents (rats and mice) and other animals, such as dogs and cats, often spontaneously develop cancer. Therefore, most experimental models of bone metastasis in rodents require...
Multiple myeloma (MM) is a severely debilitating, incurable, and uniformly fatal neoplastic disease of B cell origin (Barker et al., 1993). Although much effort has been directed at devising effective treatments for these patients, their prognosis and survival have been relatively unchanged over the last 30 years, except for a subgroup of patients undergoing successful autologous or allogeneic stem...
Increasingly it is recognized that the extracellular matrix (ECM) plays a critical role in the normal development and differentiated phenotype of cells and tissues (Lee et al, 1999; Bokel et al, 2002). Engagement of ECM molecules by cells through surface receptors, including integrins, results in the activation of signaling pathways along with specific changes in gene expression. Intracellular signals...
Skeletal metastasis is a common event in many advanced-stage cancer patients, with half of the common primary tumors eventually metastasizing to bone (Rubens, 2000). In most cases, it is the metastasis rather than the primary tumor that is responsible for the cancer-associated mortality (Chambers et al., 2002). Certain solid tumors such as cancer of the prostate, breast, and lung preferentially metastasize...
In normal adult human bone, the skeleton is renewed on a continuous basis in a dynamic, highly regulated process known as the bone remodeling sequence. The synthesis of new bone by osteoblasts is consequent to the critical primary step of excavation of old bone (resorption or osteolysis) by large multinucleated osteoclasts. These processes are tightly coupled such that, in normal bone homeostasis,...
The degradation of stromal and epithelial extracellular matrices (ECM) is partly mediated by a family of zinc-dependent endopeptidases, the matrix metalloproteinases (MMPs), which have the potential to cleave virtually all structural ECM components and thus are major mediators of extracellular proteolysis in normal and pathological conditions. In humans, the MMP family comprises at least 25 closely...
Since their isolation in 1988, endothelins have emerged as modulators of many functions including vasomotor tone, hormone production and cell proliferation. Endothelins and their receptors are expressed by many tissues, thus, it is no surprise that endothelins play an important role in the normal physiological functions and pathological states. Abundant evidence implicates a role for endothelins in...
Bone abundantly stores a variety of growth factors and thus provides migrating cancer cells with fertile soil. Osteoclastic bone resorption releases these growth factors providing fertile environment, which allows colonizing cancer cells to proliferate and survive. Consequently, cancer cells produce a variety of factors that in turn influence bone metabolism. This intimate partnership between cancer...
Cancer is not a single cell disease but involves complex interaction between cancer cells and their microenvironment (Ingber, 2002; Liotta and Kohn, 2001; Quaranta, 2002; Shekhar et al., 2003; Sung and Chung, 2002). It has been widely recognized that the growth, survival and invasion of cancer cells require the participation of vascular endothelial component of the host (Folkman, 2001; Monsky et al...
Cancer cell metastasis is a complex process involving several well-characterized steps. To metastasize successfully, tumor cells must first detach from a primary mass, enter the blood circulation or lymphatics. Subsequently, tumors must home to a particular organ, adhere to the endothelium lining the capillaries of that organ, exit the circulation where they must adhere to organ-specific extra-cellular...
Carcinoma of the prostate (CaP) is the most common malignancy in older men in the United States. In 2002, more than 200,000 cases of CaP were diagnosed and an estimated 32,000 Americans died of this cancer (Jemal et al., 2002). Most of the devastating effects of prostate cancer can be attributed to its tendency to metastasize to bone. At the time of clinical presentation, 8% of Caucasian-Americans...
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