We have established that developing primary tumors can establish a pre-metastatic niche, which is a distant microenvironment that contributes to effective metastatic progression. We have delineated key components essential to creating this conducive microenvironment including activation of fibroblasts, increased expression of fibronectin and resultant homing of bone marrow-derived cells. The pre-metastatic tissue has an influx of bone marrow-derived cells including VEGFR1 expressing cells, CD11b myeloid cells and myeloid progenitors which provide factors such as matrix metalloproteases to remodel extracellular matrix and pro-growth and survival signals to the colonizing metastatic tumor cells. These sites are created as a systemic response to tumor progression. We have shown that injecting mice with tumor-conditioned media containing tumor-derived exosomes, which are small membrane-bound particles, can induce pre-metastatic niche formation. These microvesicles as well as tumor -secreted chemokines can induce bone marrow-derived cell recruitment to pre-metastatic sites and serve to induce specific pro-vasculogenic phenotype in the bone marrow-derived cells and provide a pro-survival environment for tumor cells. This work was recently published (Nature Medicine 2012). Over the past year, using syngeneic cells lines that have a high spontaneous metastatic rate, we have identified a unique population of bone marrow-derived VEGFR1-expressing cells that are recruited to the pre-metastatic niche in multiple tumor models including E0771 breast carcinoma, 76-9 pediatric rhabdomyosarcoma and B16 melanoma. Previously we have shown that Cd11b myeloid cells expressed VEGFR1 in the pre-metastatic tissue. We have now discovered a subset of these cells are not only myeloid but a unique population that alter the local immune environment favoring immune evasion similar to sanctuary sites in stem cell niches. We are currently investigating the role of VEGFR1 signaling in these cells and the pro-metastatic features of this population.The pre-metastatic niche appears to have similar features to physiological stem cell niches in order to promote distant tumor cell survival. We have found that the localized tumor prior to evidence of metastatic spread is activating the hematopoietic stem cell niche within the bone marrow and inducing proliferation of hematopoietic stem cells and mobilization of these cells into the circulation. We also have evidence that the bone marrow-derived cell mobilization is enhanced in response to surgical resection of the primary tumor. It is likely surgical resection of the primary tumor enhances wound healing responses that include bone marrow-derived cell activation and mobilization and enhanced pre-metastatic niche formation. We have demonstrated this mobilization in mouse models and in patients undergoing tumor lumpectomy for breast adenocarcinoma. Treatments targeting the tumor microenvironment changes at the time of primary tumor resection may provide a novel approach to prevent metastatic recurrence. We plan to submit this work for publication shortly. In addition to investigations into the recruited cell populations, the transcriptional changes in the pre-metastatic niche are also an active area of investigation. We are working with the bioinformatics core facility to perform transcriptional profiling studies in different metastatic sites.
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