Role of Bone Marrow-Derived Cells in Tumor Angiogenesis and Progression

The goal of my research is to gain fundamental insight into solid tumor cellular biology. My area of expertise is the biology of bone marrow-derived cells (BMDCs) in tumor progression and the development of biomarkers of antiangiogenic therapies for cancer. I aim to translate this knowledge into improved therapies by conducting preclinical and clinical studies.

BMDCs in Tumors

BMDCs may directly or indirectly participate in new vessel formation in tumors, but their involvement in tumor growth has been controversial. I characterized their role in tumors by using genetic tagging with green fluorescent protein combined with state-of-the-art intravital microscopy, and demonstrated that the contribution of BMDCs to functional tumor vessels is marginal, and dependent on tumor type, stage, site, and mouse strain. Moreover, I showed that adult bona fide endothelial precursor cells have limited capacity of forming functional vessels compared to their cord blood counterparts. In addition, I established new methodologies and showed that myeloid cells repair injured vasculature. Finally, in a model of tumor relapse after non-curative radiotherapy, I showed that the major contribution of BMDCs was carried out by myelo-monocytes and was mediated by SDF1a/CXCR4 pathway. This work has been supported from 2002 by grants from the Cancer Research Institute, AACR, and NIH (P01 Project, R01 and R21 grants).

BMDCs as Biomarkers

In correlative studies performed in multiple clinical trials, I characterized subpopulations of circulating BMDCs. I found that these cells and plasma angiogenic and inflammatory molecules (soluble VEGFR1, soluble collagen IV, SDF1a, PlGF and circulating monocytes) are biomarker candidates for response and resistance to therapy in rectal cancer, recurrent glioblastoma and advanced sarcoma, ovarian and liver cancer. I am currently evaluating these biomarkers in cancer patients in over twenty-five NCI-sponsored clinical trials, funded through R21 and Proton Beam Federal Share grants.

BMDCs in Metastasis

Against the current wisdom, I have determined that metastasis formation is independent of VEGFR1 activity. Moreover, I used transgenic models to demonstrate that SDF1a/CXCR4 pathway might represent the escape pathway after VEGFR1 inhibition in macrophages by mediating the recruitment of immunosuppressive and pro-angiogenic Gr1+ BMDCs. I am currently dissecting the role of SDF1a/CXCR4 pathway in prostate carcinoma (R01 and ACS grants) and liver cancers (P01 grant).

BMDCs and Adipogenesis

I established an in vivo system to investigate the angiogenesis in fat tissue and uncovered the reciprocal regulation between adipogenesis and angiogenesis. Next, I demonstrated the transplantability of fat tissues and the role of VEGF, and measured BMDC-vasculogenesis in adipose tissue using in vivo microscopy and transgenic mice.

I am teaching experimental techniques through daily supervision of nine postdoctoral research fellows, three graduate and nineteen undergraduate students. In the past six years, I have been teaching in the MIT-HMS/HST Program, MGH-Chinese Oncologist Visiting Program, and ASTRO, ESTRO and RTOG translational meetings for residents and clinicians, and in the yearly Methods in Bioengineering course that I am organizing at MGH since 2002.