Our preliminary data and recent reports have established that bone marrow-derived cells (BMDCs) are key constituents of solid tumors. Cells of myeloid lineage predominate compared to other BMDCs that infiltrate tumor tissues, and their infiltration is thought to be in response to angiogenic growth factors produced by the tumors. However, the kinetics of the recruitment of myeloid BMDC subsets to tumors and their role in tumor relapse after cytotoxic therapy are largely unknown. The proposed research aims to fill this gap. Our research plan is guided by three principal hypotheses. First, we hypothesize that myeloid BMDCs infiltration facilitates tumor growth and angiogenesis.
We aim to determine the tissue distribution of myeloid BMDC subsets (myeloid precursor cells/mural cells, monocytes/macrophages and granulocytes/neutrophils) and their role in tumor angiogenesis and growth (Aim 1). Second, we hypothesize that the myeloid cells are mobilized into blood circulation and recruited to tumor tissue, at least in part, by the combined effect of two angiogenic factors produced by the tumor: VEGF and SDF-1. We will quantify the kinetics of myeloid cells' recruitment to tumors, and evaluate the effect of VEGF and/or SDF-1 blockade in this process (Aim 2). Finally, more than half of the cancer patients are treated by radiotherapy, but in many cases tumors relapse. We hypothesize that myeloid BMDCs contribute in a critical manner to tumor relapse after radiotherapy. We will determine the tissue distribution, phenotype, and establish the function of the myeloid BMDC subsets during relapse after radiotherapy; subsequently, we will test a clinically relevant treatment strategy to inhibit their participation in tumor relapse after treatment (Aim 3). Using state-of-the-art fluorescence microscopy and other complementary approaches, we propose to characterize the kinetics, phenotype and function of myeloid BMDCs in tumors. The proposed studies will unambiguously elucidate the role of myeloid BMDCs in tumor angiogenesis and growth, often overlooked in preclinical and clinical protocols using antiangiogenic therapies for cancer. Furthermore, our results will offer strategies for the inhibition of tumor relapse after radiotherapy by targeting molecular pathways that are critical for both angiogenesis and myeloid BMDC recruitment. ? ? ?
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