title: Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment.
abstract: Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we show that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacologic 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 (OC) 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 interleukin-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings show that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, OCs, and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases.
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Heller
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Hurchla
authors.forename: Jingyu
authors.initials: J
authors.lastname: Xiang
authors.forename: Xinming
authors.initials: X
authors.lastname: Su
authors.forename: Sara
authors.initials: S
authors.lastname: Chen
authors.forename: Jochen
authors.initials: J
authors.lastname: Schneider
authors.forename: Kyu-Sang
authors.initials: KS
authors.lastname: Joeng
authors.forename: Marcos
authors.initials: M
authors.lastname: Vidal
authors.forename: Leah
authors.initials: L
authors.lastname: Goldberg
authors.forename: Hongju
authors.initials: H
authors.lastname: Deng
authors.forename: Mary C
authors.initials: MC
authors.lastname: Hornick
authors.forename: Julie L
authors.initials: JL
authors.lastname: Prior
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.forename: Ross
authors.initials: R
authors.lastname: Cagan
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D001842:Bone and Bones / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D000072086:Smoothened Receptor; D059016:Tumor Microenvironment; D014704:Veratrum Alkaloids / Q000494:pharmacology*
chemical_list: D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; C000541:cyclopamine