Dr. Arbiser’s research focuses on the regulation of angiogenesis and tumorigenesis by signal transduction pathways. Our laboratory has chosen three model systems to study these relationships. The first area is the common vascular birthmarks of children and their malignant counterparts, angiosarcomas. The second application of these studies are benign neoplasms which develop in the autosomal dominant syndrome tuberous sclerosis (TS). The third application of these studies is in the pathogenesis of malignant melanoma. Our initial studies in this field have focused on the relationship of hemangiomas, the most common and benign lesion of childhood, versus angiosarcoma, a highly malignant endothelial tumor of adulthood. Treatment of life-threatening hemangiomas is imperfect, and some do not respond to therapy. Dr Arbiser has developed the hypothesis that oncogenes disrupt the balance between angiogenesis stimulators and inhibitors. His fellowship in the Folkman lab allowed the acquisition of numerous techniques and approaches to assessing such factors in vitro and in vivo. As a consequence, Dr Arbiser developed a murine model of proliferative vascular lesions through sequential introduction of SV40 large T antigen and oncogenic H-ras into murine endothelial cells. This

model recapitulates clinical and histologic features of both hemangiomas and angiosarcomas (PNAS 1997;94:861-6). Using this model, and human microvascular endothelial cells, Dr Arbiser’s laboratory is studying the signal transduction pathways involved in the upregulation of angiogenesis stimulators and downregulation of angiogenesis inhibitors. They have observed that introduction of VEGF 121 into murine endothelial cells is a transforming event, involving interaction between VEGF 121 and VEGFR2 (Am J Pathol, 2000;156:1469-76)). This model has also been extremely useful in screening for angiogenesis inhibitors from natural products (Molecular Med 1998; 4:376-83) (J Am Acad Dermatol 1999;40: 925-9), which have lead to human clinical trials of these agents. The results of these experiments have led to the development of a novel theory of synergy between tumor suppressor genes and signal transduction pathways. We hypothesize that activation of the phosphoinositol-3-kinase pathway synergizes with p53 loss, and that activation of the MAP kinase pathway synergizes with loss of p16.

Dr. Arbiser’s lab is also using expertise in signal transduction to study angiogenesis in the human disorder tuberous sclerosis. Tuberous sclerosis is a common autosomal dominant disorder characterized by the development of benign and malignant tumors of the skin, kidney, and brain. Our laboratory has developed relevant cell lines from these tumors which can be tested for sensitivity to drugs that may ameliorate tuberous sclerosis (Amer J Pathol 2002;161:781-6, Amer J Pathol 2001;159:483-91). In addition, cell lines have been developed from murine tumors of mice heterozygous for tuberin, a major tuberous sclerosis gene, which will allow both in vitro and in vivo testing for drugs which may prevent and treat the neoplastic complications of tuberous sclerosis. Finally, transgenic mice have been developed in our lab, which overexpress a mutant tuberin in all tissues, yet results in a tissue specific phenotype in skin and brain. Our mice may help explain the tissue specific nature of hamratomas and neoplasms in tuberous sclerosis, and may separate the hamartoma phenotype from the neoplastic phenotype.

Finally, our laboratory in interested in determining the factors which cause transformation in melanoma, especially the transition from radial growth (noninvasive) melanoma to vertical growth (invasive) melanoma. We have already demonstrated that MAP kinase activation is required for the development of early radial growth melanoma (Clin Cancer Research, 2002;12:3728-33, J Biol Chem 2003, in press), and currently demonstrating the role of phosphoinositol-3 kinase, reactive oxygen, and NFkB activation in the formation of melanoma. Fellows in Dr Arbiser’s lab will be involved in a variety of cell biologic, molecular biological, immunohistochemical and biochemical approaches to investigating angiogenesis and neoplastic disease.