References of "Hurchla, M. A."
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See detailHedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment.
Heller, E. UL; Hurchla, M. A.; Xiang, J. et al

in Trends in Cancer Research (2012), 72(4), 897-907

Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we demonstrate that inhibition of Hh pathway activity inhibits tumor growth through effects on the ... [more ▼]

Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we demonstrate that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacological inhibition of the Hh effector Smoothened (Smo) increased trabecular bone in vivo and inhibited osteoclastogenesis in vitro. In addition, enhanced Hh signaling due to heterozygosity of the Hh inhibitory receptor Patched (Ptch1+/-) increased bone resorption, suggesting direct regulation of osteoclast activity by the Hh pathway. Ptch1+/- mice had increased bone metastatic and subcutaneous tumor growth, suggesting that increased Hh activation in host cells promoted tumor growth. Subcutaneous growth of Hh-resistant tumor cells was inhibited by LDE225, a novel orally bioavailable Smo antagonist, consistent with effects on tumor microenvironment. Knockdown of the Hh ligand Sonic Hh (SHH) in these cells decreased subcutaneous tumor growth and decreased stromal cell production of IL-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings demonstrate that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, osteoclasts and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases. [less ▲]

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See detailThe ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling
Su, X.; Floyd, D. H.; Hughes, A. et al

in Journal of Clinical Investigation (2012), 122(10), 3579-3592

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac ... [more ▼]

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss. [less ▲]

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