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Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61

Abstract

The Hedgehog (Hh) pathway is well known for its involvement in angiogenesis and vasculogenesis during ontogeny. The ligand, Sonic Hh (SHH), has an important role in vascular formation during development. However, SHH expression is upregulated on tumor cells and can impact the tumor microenvironment. We have investigated the effects of autocrine as well as paracrine Hh signaling on tumor cells as well as on endothelial cells, respectively. Upon constitutive expression of SHH, breast cancer cells showed aggressive behavior and rapid xenograft growth characterized by highly angiogenic tumors that were spontaneously metastatic. In these cells, SHH caused activation of the Hh transcription factor, GLI1, leading to upregulated expression of the potent pro-angiogenic secreted molecule, CYR61 (cysteine-rich angiogenic inducer 61). Silencing of CYR61 from these SHH-expressing Hh activated cells blunted the malignant behavior of the tumor cells and resulted in reduced tumor vasculature and limited hematogenous metastases. Thus, CYR61 is a critical downstream contributor to the Hh influenced pro-angiogenic tumor microenvironment. We also observed concomitant upregulation of SHH and CYR61 transcripts in tumors from patients with advanced breast cancer, further ratifying the clinical relevance of our findings. In summary, we have defined a novel, VEGF-independent, clinically relevant, pro-angiogenic factor, CYR61, that is a transcriptional target of Hh-GLI signaling.

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Abbreviations

CYR61:

cysteine-rich angiogenic inducer 61

Hh:

hedgehog pathway

MVD:

microvessel density

SHH:

Sonic hedgehog ligand

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Acknowledgements

We acknowledge support from the NIH (CA138850 to L.A.S. and CA140472 to R.S.S.), Department of Defense (IDEA Award BC061257 to L.A.S.), Mayer Mitchell Award (to L.A.S.) and the USA-Mitchell Cancer Institute. We also would like to thank Dr Laurie Owen, Scientific Director, USA-Mitchell Cancer Institute for her support of this work and the Department of Pathology and Prof Troy Stevens, Anna Buford and Linn Ayers, Center for Lung Biology, University of South Alabama for generously providing us with endothelial cells.

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Correspondence to L A Shevde.

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Harris, L., Pannell, L., Singh, S. et al. Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61. Oncogene 31, 3370–3380 (2012). https://doi.org/10.1038/onc.2011.496

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