Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation.
Chondrosarcoma is a malignant cartilage tumor that may arise from benign precursor lesions, such as enchondromas. Some cases of multiple enchondromas are caused by a mutation that results in constitutive activation of Hedgehog-mediated signaling. We found that chondrosarcomas expressed high levels of the Hedgehog target genes PTCH1 and GLI1. Treatment with parathyroid hormone-related protein down-regulated Indian Hedgehog (IHH) expression in normal growth plates but not in chondrosarcoma or enchondroma organ cultures. Treatment of the chondrosarcoma organ cultures with Hedgehog protein increased cell proliferation rate, whereas addition of chemical inhibitors of Hedgehog signaling decreased the proliferation rate. Chondrosarcoma xenografts from 12 different human tumors were established in NOD-SCID mice. Treatment with triparanol, an inhibitor of Hedgehog signaling, resulted in a 60% decrease in tumor volume, a 30% decrease in cellularity, and a 20% reduction in proliferation rate. These results show that Hedgehog signaling is active in chondrosarcoma and benign cartilage tumors and regulates tumor cell proliferation. Our data raise the intriguing possibility that Hedgehog blockade could serve as an effective treatment for chondrosarcoma, a tumor for which there are currently no universally effective nonsurgical management options.
Tiet
Tri Dung
TD
The Hospital for Sick Children, 555 University Ave., Suite S107, Toronto, Ontario, Canada, M5G 1X8.
Hopyan
Sevan
S
Nadesan
Puviindran
P
Gokgoz
Nalan
N
Poon
Raymond
R
Lin
Alvin C
AC
Yan
Taiqiang
T
Andrulis
Irene L
IL
Alman
Benjamin A
BA
Wunder
Jay S
JS
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002813:Chondrosarcoma / Q000378:metabolism*; D004252:DNA Mutational Analysis; D053823:Hedgehog Proteins; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015513:Oncogene Proteins / Q000096:biosynthesis; D009924:Organ Culture Techniques; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D018807:Polymorphism, Single-Stranded Conformational; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis; D014308:Triparanol / Q000494:pharmacology; D015854:Up-Regulation; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D000960:Hypolipidemic Agents; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D044162:Parathyroid Hormone-Related Protein; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D014308:Triparanol