The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells.

The skeleton is a common destination for many cancer metastases including breast and prostate cancer. There are many characteristics of bone that make it an ideal environment for cancer cell migration and colonization. Metaphyseal bone, found at the ends of long bone, in ribs, and in vertebrae, is comprised of trabecular bone interspersed with marrow and rich vasculature. The specialized microvasculature is adapted for the easy passage of cells in and out of the bone marrow. Moreover, the metasphyseal regions of bone are constantly undergoing remodeling, a process that releases growth factors from the matrix. Bone turnover also involves the production of numerous cytokines and chemokines that provide a means of communication between osteoblasts and osteoclasts, but co-incidentally can also attract and support metastatic cells. Once in the marrow, cancer cells can interact directly and indirectly with osteoblasts and osteclasts, as well as hematopoietic and stromal cells. Cancer cells secrete factors that affect the network of cells in the bone microenvironment as well as interact with other cytokines. Additionally, transient cells of the immune system may join the local mileau to ultimately support cancer cell growth. However, most metastasized cells that enter the bone marrow are transient; a few may remain in a dormant state for many years. Advances in understanding the bone cell-tumor cell interactions are key to controlling, if not preventing metastasis to bone.

Purpose: In vivo studies have focused on the latter stages of the bone metastatic process (osteolysis), whereas little is known about earlier events, e.g., arrival, localization, and initial colonization. Defining these initial steps may potentially identify the critical points susceptible to therapeutic intervention. Experimental Design: MDA-MB-435 human breast cancer cells engineered with green fluorescent protein were injected into the cardiac left ventricle of athymic mice. Femurs were analyzed by fluorescence microscopy, immunohistochemistry, real-time PCR, flow cytometry, and histomorphometry at times ranging from 1hour to 6 weeks. Results: Single cells were found in distal metaphyses at 1 hour postinjection and remained as single cells up to 72 hours. Diaphyseal arrest occurred rarely and few cells remained there after 24 hours. At 1week, numerous foci (2-10 cells) were observed, mostly adjacent to osteoblast-like cells. By 2 weeks, fewer but larger foci (z50 cells) were seen. Most bones had a single large mass at 4 weeks (originating from a colony or coalescing foci) which extended into the diaphysis by 4 to 6 weeks. Little change (<20%) in osteoblast or osteoclast numbers was observed at 2 weeks, but at 4 to 6 weeks, osteoblasts were dramatically reduced (8% of control), whereas osteoclasts were reduced modestly (to f60% of control). Conclusions: Early arrest in metaphysis and minimal retention in diaphysis highlight the importance of the local milieu in determining metastatic potential.These results extend the Seed and Soil hypothesis by demonstrating both intertissue and intratissue differences governing metastatic location. Ours is the first in vivo evidence that tumor cells influence not only osteoclasts, as widely believed, but also eliminate functional osteoblasts, thereby restructuring the bone microenvironment to favor osteolysis.The data may also explain why patients receiving bisphosphonates fail to heal bone despite inhibiting resorption, implying that concurrent strategies that restore osteoblast function are needed to effectively treat osteolytic bone metastases.Breast cancer has a remarkable predilection to colonize bone, with an incidence between 70% and 85% in patients (1-3). At the time of death, metastatic bone disease accounts for the bulk of tumor burden (4). For women with bone metastases, the complications-severe, often intractable pain, pathologic fractures, and hypercalcemia-are catastrophic. Despite its obvious clinical importance, very little is understood about the fundamental mechanisms responsible for breast cancer metastasis to bone. Research progress has been hampered by the dearth of, and technical difficulties inherent in, the current models.Most models of metastasis poorly recapitulate the pathogenesis of breast cancer. The ideal model would involve dissemination from an orthotopic site (i.e., mammary fat pad), colonization, and osteolysis. None of the currently available human breast xenograft models spread to bone following orthotopic implantation and only on...