Abstract
Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced beta CATENIN (beta CAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH-GLI pathway. Unexpectedly, they acquire a high HEDGEHOG-GLI (HH-GLI) signature coincident with the development of metastases. We show that the growth of CC xenografts, their recurrence and metastases require HH-GLI function, which induces a robust epithelial-to-mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self-renewal of CC stem cells in vivo relies on HH-GLI activity. Our results indicate a key and essential role of the HH-GLI1 pathway in promoting CC growth, stem cell self-renewal and metastatic behavior in advanced cancers. Targeting HH-GLI1, directly or indirectly, is thus predicted to decrease tumour bulk and eradicate CC stem cells and metastases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Carcinoma / drug therapy
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Carcinoma / genetics
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Carcinoma / metabolism*
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Carcinoma / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cells, Cultured
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / pathology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Gene Expression Regulation, Neoplastic
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Hedgehog Proteins / antagonists & inhibitors
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Humans
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Mice
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Neoplasm Metastasis / drug therapy
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Neoplasm Metastasis / pathology
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Neoplasm Recurrence, Local / metabolism
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Neoplasm Recurrence, Local / pathology
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Neoplastic Stem Cells / cytology*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Signal Transduction / drug effects
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Veratrum Alkaloids / therapeutic use
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Zinc Finger Protein GLI1
Substances
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GLI1 protein, human
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Hedgehog Proteins
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Transcription Factors
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Veratrum Alkaloids
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Zinc Finger Protein GLI1
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cyclopamine