Abstract SY16-04: Contrasting effects of TGF-β signaling in the proangiogenic tumor stroma

Abstract Cancer results from the concerted performance of tumor cells interacting with their microenvironment. The formation of a reactive stroma evidently 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 TGF-β signaling in physiological and pathological angiogenesis make the need for mechanistic studies apparent. Here, we describe functional studies on the role of the TGF-β 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 primed endothelial cells to respond to prototypical angiogenic stimuli both in vitro and in vivo. In parallel studies, genetic targeting of endoglin was revealed to give rise to an initial block in the angiogenic switch of tumors, which was overcome through acquired resistance characterized by an increased metastatic spread. The rise in metastatic dissemination was consequential to a loss of junctional patency in the endoglin-deficient vasculature due to ongoing endothelial-to-mesenchymal transition. Taken together, our studies delineate a decisive role for signaling by TGF-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking TGF-β signaling in oncology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY16-04. doi:10.1158/1538-7445.AM2011-SY16-04