Dai Fukumura, MD, PhD
Associate Professor of Radiation Oncology
Harvard Medical School
Edwin L. Steele Laboratory for Tumor Biology
Role of NO in Tumor Angiogenesis, Lymphangiogensis, Microcirculation and Radiation Therapy
As part of the Edwin L. Steele Laboratory for Tumor Biology, the long term goal of the Fukumura Laboratory's research is to uncover the fundamental nature of vascular biology including angiogenesis, lymphangiogensis, microcirculation and microenvironment in both physiological and pathophysiological settings, and to utilize this knowledge for detection and treatment of diseases.
Nitric oxide (NO) is a highly reactive mediator with a variety of physiological and pathological functions. NO increases and/or maintains tumor blood flow, decreases leukocyte-endothelial interactions, and increases vascular permeability and thus, may facilitate tumor growth. Furthermore, NO mediates angiogenesis and vessel maturation predominantly through endothelial NO synthase. We recently found that selective NO localization around blood vessels improves structure and function of tumor vessels, tissue oxygenation and response to radiation therapy. We also found that NO mediates lymph-angiogenesis and metastasis as well as function of lymphatic vessels.
Role of Tumor-Host Interactions in Angiogenesis, Tumor Growth and Metastasis
Using transgenic mice harboring the green fluorescent protein (GFP) gene driven by vascular endothelial growth factor (VEGF) promoter we found that VEGF promoter of nontransformed stromal cells is strongly activated by the tumor microenvironment. Using tumor cells carrying the same gene construct we found, for the first time, that hypoxia and low pH independently upregulate VEGF in vivo. Using VEGF-/- and wild type ES cell derived tumors we found that the host cells contribute approximately half of total VEGF production in this model. Novel multiphoton laser-scanning microscopy (MPLSM) allowed us to observe deep inside the tumor with high spatial resolution and revealed that VEGF expressing stromal cells are closely associated with angiogenic vessel in the tumor. The association of VEGF-expressing stromal cells spatially correlates with the extravasation of nanoparticles. Furthermore, various anti-tumor treatments result in increased expression of host stromal cell VEGF and thus, may contribute to treatment resistance.
Our recent data indicate that stromal cells in the primary tumor travel with tumor cells and facilitate survival and growth of metastatic tumors. Finally, the blockade of VEGF signaling can transiently normalize tumor vasculature and potentiate radiation therapy.
Engineering Blood Vessels
A major limitation of tissue engineering is the lack of functional blood and lymph vessels. First, we established in vivo system to investigate blood vessel formation during adipogenesis. Using genetic inhibition of PPARg and pharmacological inhibition of VEGFR2 signaling we found provocative reciprocal regulation of adipogenesis and angiogenesis, suggesting a novel strategy to treat obesity. Next, we established a model to monitor tissue engineered blood vessels in vivo using MPLSM. We found that mesenchymal precursor 10T1/2 cells accelerate remodeling of 3-D endothelial cell structure to functional blood vessels, differentiate into peri-vascular cells, and stabilize engineered vessel network for up to a year. We then showed that human ES cell-derived endothelial cells form functional blood vessels in vivo using the tissue engineered blood vessel model.
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