平成22年度私立大学戦略的研究基盤形成支援事業
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開催日時：
平成22年12月10日（金）
開催場所：
医学部第一臨床講堂
開催時間：
午後６時〜７時
講師：
Dr. Kristian Pietras
Associate Professor, Department of Medical Biochemistry, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
演題名:
Contrasting effects of TGFb signaling in the pro-angiogenic tumor stroma

Cancer results from the concerted performance of tumor cells interacting with their microenvironment. The formation of a reactive stroma contributes to tumor initiation, growth and progression by providing growth-regulatory factors, supporting tumor angiogenesis, and facilitating invasion. As a rich source of cancer-promoting factors, the tumor stroma is an underestimated target for the development of novel therapeutics. Members of the transforming growth factor (TGF) β family have been linked to vascular formation through mouse genetic studies. However, contradictory reports on the role of TGFβ signaling in physiological and pathological angiogenesis make the need for mechanistic studies apparent. Herein, we describe functional studies on the role of the TGFβ receptor activin receptor-like kinase (ALK) 1 and its co-receptor endoglin in tumor angiogenesis. We demonstrate by genetic and pharmacological means that diminution of ALK1 gene dosage, or systemic treatment with an ALK1-Fc fusion protein retarded tumor growth and progression by inhibition of angiogenesis. Moreover, we uncovered an unexpected synergy through which the combined action of different ALK1 ligands augmented endothelial cell responses to angiogenic stimuli. In parallel studies, genetic targeting of endoglin was revealed to give rise to an initial block in tumor angiogenesis, which was overcome through acquired resistance characterized by an increased metastatic spread. Taken together, our studies delineate a decisive role for signaling by TGFβ family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking TGFβ signaling in oncology.

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