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). We have also recently shown that the myeloid cells contribute to an immune suppressive microenvironment which can be targeted with CXC2 blocking antibodies (Science Translational Medicine 2014). We are currently investigating the role of tumor conditioned media and tumor derived exosomes in making local changes in the stromal cell compartment that provides the scaffolding for bone marrow-derived cells and are essential component of the pre-metastatic niche. Over the past year, using syngeneic cells lines that have a high spontaneous metastatic rate, we have identified unique changes within the bone marrow microenvironment that lead to mobilization of bone marrow-derived cells that are recruited to the pre-metastatic niche in multiple tumor models including E0771 breast carcinoma, 76-9 and M3-9M pediatric rhabdomyosarcomas and B16 melanoma. Previously we have shown that CD11b myeloid cells expressed VEGFR1 in the pre-metastatic tissue. We have now discovered these cells are hematopoietic progenitor cells that become a unique myeloid 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. We have also been able to manipulate metastatic progression by altering these unique bone marrow-derived cell enriched areas. We have new data demonstrating that the pre-metastatic niche has similar features to physiological stem cell niches in order to promote distant tumor cell survival. We have found that the localized tumor prior to established metastasis 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 have found that there are changes that occur in the bone marrow microenvironment in response to tumor secreted factors that induce the myeloid skewing and expansion of hematopoietic progenitor cells that we have seen during tumor progression. These studies have recently been submitted for publication. Targeting the skewing to prevent the expansion in hematopoietic progenitor cells and myeloid cells may be a way to reset this maladaptive response to a growing tumor and prevent metastatic progression. 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 demonstratedthis 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. In addition to investigations into the recruited bone marrow derived cell populations, we continue to investigate the essential changes in stromal cells including pericytes, vascular cells and fibroblasts as well as the extracellular stroma in the pre-metastatic and metastatic niche. We have identified two critical pathways in pre-metastatic niche formation related to inflammation and stem cell biology. Understanding the activation of these stem cell- and inflammation- related pathways in the metastatic process are an active area of investigation. Using stem cell niche biology to better understand how cancer spreads has begun to allow us to uncover new targets for preventing the necessary cell-cell communication that provides a conducive environment for cancer cell growth.
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