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    Research Grants Awarded

    The Prognostic And Therapeutic Implications Of Bone Marrow-Derived Progenitor Cells In Breast Cancer Invasion And Metastasis

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Rationale: It has long been recognized that the preferential colonization of lymph nodes and distant organs such as bone and lung by breast tumor cells is in part determined by the local microenvironment. However, the molecular mechanisms and temporal/spatial organization of these events has not yet been detailed, hampering significant progress in development of therapies targeting this most devastating complication of breast cancer. As a result of tumor-associated growth factors and chemokines, our preliminary studies demonstrate that bone marrow (BM)-derived vascular endothelial growth factor receptor 1 (VEGFR1) expressing hematopoietic progenitor cells (HPCs) home to pre-metastatic lymph nodes prior to the arrival of breast cancer cells. Here, the HPCs adhere to pockets of upregulated fibronectin forming ?pre-metastatic niches? and promote adhesion and invasion of breast cancer cells and BM-derived VEGFR2 expressing endothelial progenitor cells (EPCs) to complete metastatic progression. We propose that VEGFR1 signaling by the HPCs at the pre-metastatic sites alters the local chemokine milieu and the expression of adhesion factors, thereby initiating metastasis. This project will augment our previous findings and seeks to explore the functional role of BM-derived VEGFR1+ HPCs in the initiation and VEGFR2+ EPCs for the progression of breast cancer metastasis. Hypothesis: We propose that VEGFR1+ HPCs arrive at sites of future metastatic lymph nodes prior to tumor cells, where they alter the expression of key adhesion and migration molecules thereby promoting invasion and adhesion by circulating tumor cells and VEGFR2+ EPCs. Furthermore, the identification of HPCs in the pre-metastatic lymph nodes and in circulation portends metastatic progression and therefore may serve as a prognostic indicator with therapeutic implications. We anticipate that the studies in this proposal and our future work may reveal novel potential therapeutic targets for the treatment and prevention of metastasis. Specific Aims: We will employ a comprehensive strategy to elucidate the role of VEGFR1 and VEGFR2 in this process, integrating in vivo and in vitro experimental systems: 1) To characterize the temporal and spatial recruitment patterns of BM-derived hematopoietic and endothelial progenitor cells and investigate their functional role and the impact of targeting VEGFR1 and VEGFR2 in breast cancer metastasis. 2) To investigate the prognostic significance of VEGFR1+ hematopoietic and VEGFR2+ endothelial progenitor cells in metastatic progression in patients with breast cancer. Advances: Despite progress in other areas of cancer research, metastasis, the most devastating phase of tumor progression in breast cancer, remains poorly defined. It is now recognized that the stromal microenvironment of distant organs is a key determinant of metastasis, in addition to the intrinsic metastatic propensity of breast tumor cells. Both differentiated cells and immature cells from the BM participate in the creation of a site conducive for metastasis. Our long-term objectives are to elucidate the cellular and molecular mechanisms involved in the regulation and development of the pre-metastatic/metastatic breast cancer microenvironments, and to apply these insights to the clinical detection and treatment of malignant breast disorders. A key aspect of this is to detail more precisely with the molecular regulation and functional contribution of the BM-derived cells that are recruited to pre-metastatic sites such as lymph nodes, promoting the migration and adhesion of disseminating breast tumor cells. This work may reveal targets for novel therapeutic and prognostic strategies to identify, treat and prevent metastatic breast disease.

    Lay Abstract:
    We understand many things about breast cancer. We know that breast cancer is unpredictable and behaves in biologically distinct ways and that primary tumors rarely kill people but metastases do. This project attempts to tackle both arenas. Only by this, can we prevent the formation and spread of tumors in a focused and ultimately individualized approach that is the emerging trend in breast cancer oncology today. It was proposed over a hundred years ago that the ?seed and the soil? needed to be aligned and were crucial to tumor propagation. Contemporary laboratory studies have confirmed this observation identifying distinct subpopulation of tumor cells within a tumor mass with an intrinsic ability to home and spread to pre-determined metastatic sites. Furthermore, work in our laboratory has been shown that particular adult stem cells from the bone marrow bookmark sites both at the invasive front of the tumor and at distant sites very early in the metastatic process. In breast cancer metastasis, we hypothesize that these bone marrow stem cells arrive at future metastatic tissues such as lymph nodes and form a favorable and necessary localized environment for the arrival and attachment of tumor cells. Thus, the presence of bone marrow stem cell clusters in lymph nodes and other tissues may serve as a prognostic indicator of impending metastatic disease. Our question is: if this a critical process, than can it be interrupted? The important step is to characterize this process in model systems and in breast cancer patients, which forms the basis of our proposal. The first part of this project aims to build on prior experiments in our lab and characterize the specific and relative contribution of two bone marrow stem cells, one cell expressing the receptor VEGFR1 that supports the homing site for metastatic tumor cells and the other cell expressing the receptor VEGFR2 that helps build blood vessels to continue the growth of the metastatic lesion using implantable and spontaneous breast tumor models. These represent potential targets for therapy as there are a number of new agents available today that have these receptors as targets. Secondly, this proposal will assess the relative contribution of the host in ?allowing? metastases to occur or not occur- the so called ?metastasis efficiency? genes. Recently, data suggest that perhaps it is not just tumor-related factors that determine the ability of a tumor to metastasize but the presence or absence of specific metastasis efficiency genes in the host. Maybe tumor related factors should not be the sole target when deciding appropriate treatment for a patient with breast cancer as it is today. This would represent a paradigm change. Pre-clinical models are important but if they cannot be applied to people, then they not meaningful. The second specific aim of this proposal is to investigate the relative contribution of these two bone marrow derived cell populations in metastatic progression in women with primary and metastatic breast cancer. If we can understand why some tumors spread and others don?t, then we can direct specific treatment individualized to the specific tumor. For example, if these studies support the concept that bone marrow derived cells that are VEGR1+/R2+ are a critical factor for metastasis in patients with breast cancer then should therapy include (or be heavily weighted) with agents that directly target VEGFR1+/R2+ even prior to surgery for treatment of primary breast cancer? Moreover, if we know that a patient does or does not have a ?metastatic phenotype? should therapy be different? In theory, if a patient does not possess these metastases efficiency genes, should they not receive any therapy at all? That the tumor alone might not be the target/driver of therapy is an innovative concept in breast cancer oncology today. This project attempts to continue elucidating several concepts proposed by our lab, which are now ready to be extended into other model systems and into humans. Accomplishing these goals could potentially alter how we ultimately treat patients with primary and metastatic breast cancer by further individualizing therapy. The ultimate goal is to prevent metastatic progression as a primary and subsequent event for our patients.