Abstract
Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors.
Highlights
Hedgehog (Hh) signaling is a complex signaling pathway that was initially identified as a developmental signaling pathway
MDA-MB-231 breast cancer cells, we have shown that TGFβ stimulation increases expression of Gli2 and parathyroid hormone-related protein (PTHrP), which controls bone destruction [112]
We show that when Gli2 expression is repressed using a plasmid over-expressing Gli2 repressor, both PTHrP expression and bone destruction are significantly reduced [113]
Summary
Hedgehog (Hh) signaling is a complex signaling pathway that was initially identified as a developmental signaling pathway. Since its original discovery in 1980, its role in disease has been better defined. Aberrant Hh signaling has been demonstrated by numerous groups to contribute to multiple cancer types both through contributing to changes in tumor growth directly or altering the tumor microenvironment. Because of its role in multiple tumor types, Hh signaling is an attractive pathway for both basic research and drug development to identify new targets and new therapeutic approaches for inhibiting tumor growth and metastasis
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