Colon Cancer Progression Relies on the Hedgehog Signaling Pathway

Blocking the Hedgehog-GLI (HH-GLI) signaling pathway that is essential for tumor growth, recurrence, metastasis, and stem cell survival and expansion can prevent human colon cancer from progressing to untreatable metastases.

Human colon cancers often start as benign adenomas that can be managed efficiently, but often progress to invasive carcinomas and incurable metastases through additional metabolic changes. Investigators from the University of Geneva (Switzerland) have now shown that some critical metabolic changes are brought about through the activity of the HH-GLI signaling pathway.

The researchers reported in the August 27, 2009, online edition of the journal EMBO Molecular Medicine that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbored an active HH-GLI pathway. These cells acquired a high-HH-GLI signature coincident with the development of metastases. The growth of CC xenografts, their recurrence, and metastases required HH-GLI function, which induced a vigorous epithelial-to-mesenchymal transition (EMT). Moreover, a novel tumor-cell competition assay showed that the self-renewal of CC stem cells in vivo relied on HH-GLI activity.

"Recurrence is a major problem in cancer treatment. Even after a patient has displayed an apparent complete recovery from a primary tumor, recurrence at nearby or distal locations has a poor prognosis,” said senior author Dr. Ariel Ruiz i Altaba, professor of medicine at the University of Geneva. "While monitoring recovering mice we noted that tumors began to recur in all cases except for those treated with cyclopamine for a short period of time after tumor disappearance. The treated mice were kept for up to one year after the treatment and remained healthy and tumor free.”

Cyclopamine inhibits the hedgehog-signaling pathway by influencing the balance between the active and inactive forms of the Smoothened protein. "The finding that a blockade of HH-GLI for a relatively short period was sufficient to eliminate the tumor and prevent recurrence, without negatively affecting the health of the mice, opens the possibility for the use of a therapeutic window to eradicate the tumor without major side effects,” said Dr. Ruiz i Altaba.

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