Abstract 1004: Hedgehog signaling promotes tumor vascularization, growth and metastasis of breast cancer via upregulation of CYR61

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 8_Supplement; p. 1004
• Main Authors: Harris, Lillianne G., Pannell, Lewis K., Samant, Rajeev S., Shevde, Lalita A.
• Format: Journal Article
• Language: English
• Published: 15.04.2011
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-1004

Abstract Several clinical trials have used chemotherapeutic drugs that specifically target vascular endothelial cell growth factor (VEGF). Although these trials have demonstrated significant improvements in response rates, findings to date have not indicated substantial benefits in terms of survival. This is likely to be due to the ability of tumor cells to utilize several alternative pathways to establish vasculature. Hence, there is an urgent need to define and target other active pathways that contribute to angiogenesis, such that the vascularity of the tumor can be effectively reduced. Hedgehog (Hh) signaling, which promotes cell growth and vascularization during fetal development, is activated in several cancers and has been implicated to play a role in promoting cancer progression. We have investigated the role of Hh signaling in impacting tumor malignancy by promoting tumor vascularity. We engineered sonic hedgehog (SHH)-deficient, tumorigenic breast cancer lines, MDA-MB-231 and MCF10AT, to ectopically express the Hh activating ligand, SHH such that the pathway is constitutively activated. Upregulation of SHH-mediated signaling results in the acquisition of enhanced malignant behavior in vitro (increased growth, invasion, migration, and anchorage independent growth) and in vivo (increased tumor take rate and rapidly growing tumors). Furthermore, the SHH expressing cells are able to enhance migration, invasion and network formation of endothelial cells in vitro and elicit increased vasculature in tumor xenografts, in vivo. Using mass spectrometry-mediated analysis of the secretome of the breast cancer cells with constitutive Hh signaling, we identified CYR61 (cysteine-rich angiogenic inducer 61) as a potential mediator of the angiogenic effects of breast cancer cells. Further, our studies show that CYR61 plays a critical role in mediating the vasculature-enhancing effects of breast cancer cells. Taken together, our lab has identified a robust contributor of tumor vascularization which may be an effective VEGF-independent anti-vascularization therapeutic target. We acknowledge grant support from the Department of Defense-Breast Cancer Research Program (07-1-0400). 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 1004. doi:10.1158/1538-7445.AM2011-1004