We have established that during primary tumor growth there is a formation of a niche environment in distant tissue sites that promote metastatic progression. This pre-metastatic tissue has an influx of bone marrow-derived cells including VEGFR1 expressing cells, CD11b myeloid cells and myeloid progenitors cells, which provide factors such as matrix metalloproteases to remodel extracellular matrix and pro-growth and survival signals such as VEGF and arginase to support the colonizing disseminated tumor cells. These sites are created as a systemic response to tumor progression. 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 hematopoietic stem and progenitor 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 (Giles et al Cancer Research 2016). We are currently investigating the role of VEGFR1 signaling in these cells and the pro-metastatic features of this population, which is lost in immunocompromised mice. These cells play a role in regulating tumor specific T cells that can be inhibited by immune suppressive myeloid cells derived from mobilized hematopoietic stem and progenitor cells from the bone marrow. 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 (Giles et al Cancer Research 2016). 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 have on-going investigations examining the small molecular inhibitor PLX3397 that targets CSF1R found on myeloid cells, cKit and FLT3-ITD which we have determined that when the drug is given in the adjuvant setting can limit metastatic progression in tumor bearing hosts. In addition to investigations into the recruited hematopoietic progenitor bone marrow derived cell populations that become immune suppressive cells in pre-metastatic sites, we continue to investigate the essential changes in stromal cells including pericytes, vascular cells and fibroblasts as well as the extracellular matrix in the pre-metastatic and metastatic niche. We have established several lineage tracing models to better track and characterize these stromal cell populations as well as genetically manipulate key genes within specific cell populations. Using these models we can interrogate the function of specific proteins to these cells and their role in the metastatic process. A specific transcription factor KLF4 we have discovered is critical to mediating this stromal cell plasticity. These stromal cells that become activated create a distinct extracellular matrix that support disseminated tumor cell survival. We are currently investigating the role of tumor conditioned media and tumor derived exosomes in making local changes in the stromal cell compartment and matrix that provides the scaffolding for bone marrow-derived cells and are essential component of the pre-metastatic niche. We have identified two critical cellular pathways in pre-metastatic niche formation related to inflammation and stem cell biology including hematopoietic cells and stromal cell populations. 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 disseminated cancer cell growth.
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