Associate Biologist in Radiation Oncology
Edwin L. Steele Laboratory for Tumor Biology

617-726-8143

The Fundamental Nature of Angiogenesis and Microcirculation in Physiological and Pathophysiological Settings
The long-term goal of our research is to understand the fundamental nature of angiogenesis and microcirculation in physiological and pathophysiological settings such as solid tumors, and to use this knowledge for the detection and treatment of diseases.

Role of NO in tumor angiogenesis, microcirculation, and radiation therapy
Nitric oxide (NO) is a highly reactive mediator with a variety of physiological and pathological functions. We found that high levels of NO from Kupffer cells form the first line of defense against metastatic cancer cells. On the other hand, moderate levels of NO increase and/or maintain tumor blood flow, decrease leukocyte-endothelial interactions, and increase vascular permeability and, thus, may facilitate tumor growth. Furthermore, NO mediates angiogenesis. We found endothelial NO synthase predominantly mediates VEGF-induced angiogenesis and vascular permeability. Metastatic variant tumors produce more NO and exhibit aggressive angiogenesis. Chronic inhibition of NO synthesis resulted in reduced angiogenesis with more normal vessel-like morphology, revealing that NO mediates branching angiogenesis but inhibits luminal growth.

Role of tumor-host interactions in angiogenesis and microcirculation
Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic and vascular permeabilizing factors. Using transgenic mice harboring the green fluorescent protein (GFP) gene driven by the VEGF promoter, we found that the 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 50% 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 vessels in the tumor. Furthermore, various anti tumor treatments result in increased expression of host stromal cell VEGF and thus, may contribute to treatment resistance.

Engineering blood vessels
A major limitation of tissue engineering is the lack of functional blood and lymph vessels. First, we established an in vivo system to investigate blood vessel formation during adipogenesis. Using genetic inhibition of PPARy 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 10T 1/2 mesenchymal precursor cells accelerate the remodeling of 3-D endothelial cell structure to functional blood vessels, differentiate into peri-vascular cells, and stabilize the engineered vessel network for up to a year.

Selected Publications:
Fukumura D, Ushiyama A, Duda DG, Xu L, Tam J, Chatterjee VKK, Garkavtsev I, Jain RK. Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis. Circ Res 2003; 93:88e-e97.

Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK. Herceptin acts as an anti-angiogenic cocktail. Nature 2002; 416:279-280.

Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 2001; 61:6020-6024.

Fukumura D, Gohngi T, Kadambi A, Ang J, Yun CO, Buerk DG, Huang PL, Jain RK. Predominant role of endothelial nitric oxide synthase in VEGF-induced angiogenesis and vascular permeability. Proc Natl Acad Sci USA 2001; 98:2604-2609.

Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, Selig M, Nielsen G, Taksir T, Jain RK, Seed B. Tumor induction of VEGF promoter activity in stromal cells. Cell 1998; 94:715-25.