Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment

Emanuela Heller, Michelle A. Hurchla, Jingyu Xiang, Xinming Su, Sara Chen, Jochen Schneider, Kyu Sang Joeng, Marcos Vidal, Leah Goldberg, Hongju Deng, Mary C. Hornick, Julie L. Prior, David Piwnica-Worms, Fanxin Long, Ross Cagan, Katherine N. Weilbaecher

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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.

Original languageEnglish
Pages (from-to)897-907
Number of pages11
JournalCancer research
Volume72
Issue number4
DOIs
StatePublished - Feb 15 2012

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