Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Paracrine Hedgehog signaling: Roles in tumor microenvironment and metastasis (#193)

Lalita A Shevde 1 , Shamik Das 1 , Shikha Khullar 2 , J Allan Tucker 3 , Rajeev S Samant 1
  1. Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
  2. Department of Radiology, University of South Alabama, Mobile, Alabama, USA
  3. Department of Pathology, University of South Alabama, Mobile, Alabama, USA

The Hedgehog (Hh) signaling pathway is aberrantly activated in multiple malignancies. This pathway controls cell proliferation and differentiation during embryonic development and when mis-regulated, contributes to tumorigenesis. Our investigations show that the Hedgehog (Hh) developmental pathway is aberrantly activated in breast cancer and melanoma. Our studies have revealed that Hh signaling promotes tumor vascularity and metastasis by promoting expression of CYR61 (cysteine-rich angiogenic inducer 61) and the oncogenic protein, OPN (osteopontin). Moreover, active Hh signaling facilitated the development of osteolytic metastasis characterized by increased tumor biomass in femur and tibia in experimental animals. In contrast, inhibiting Hh signaling in tumor cells by stable silencing of the transcription factor GLI1 reduced the intensity and incidence of osteolysis in an intracardiac model of bone colonization concomitant with decreased tumor biomass in the bone.
As such, our results demonstrate that the Hh pathway plays an important role in the metastatic behavior of breast cancer cells and regulates their ability to cause osteolytic metastasis. Our findings suggest that administration of pharmacological Hh inhibitors can inhibit Hh signaling in both, breast cancer cells and osteoclasts and may reduce breast cancer-mediated bone loss in metastatic disease. This strategy targets the tumor cells as well as the bone microenvironment and thus can reduce tumor burden and tumor-derived bone lesions.