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'Hedgehog' Pathway Key to Colon Cancer Therapy
Reported August 31, 2009
(Ivanhoe Newswire) -- Scientists in Switzerland have discovered a way
to block the growth of human colon cancer cells, preventing the disease from
reaching advanced stages and developing liver metastases. The research shows
that blocking the so-called Hedgehog-GLI pathway can prevent the growth of
tumors, metastatic lesions and cancer stem cells, the cells thought to lie
at the root of cancer growth.
Colon cancer often begins in a treatable form when it is confined to the
bowel wall, but later it can develop to an incurable metastatic stage. A
Geneva-based research team has discovered the essential role played by
HH-GLI in the progression of colon cancer to these late and incurable
stages. HH-GLI is a signaling pathway used by cells to communicate with each
other to determine position, growth and survival.
"Previous works hinted at the possible role of HH-GLI in colon cancer, but
this was denied by other studies, so its involvement was never entirely
clear," lead researcher Professor Ariel Ruiz i Altaba of Geneva University
is quoted as saying. "In this study we have proven that HH-GLI is essential
for the development and growth of colon cancers. The research demonstrates
the active presence of HH-GLI signaling in epithelial cells of colon
cancers. Moreover, we find that metastatic tumors rely on this pathway for
sustained growth. This identifies HH-GLI as a target for novel anti-cancer
therapies against so-far incurable forms of colon cancer in distant organs,
such as the liver."
This research opens the possibility of new anti-cancer therapies,
specifically the use of RNA interference and of Cyclopamine, a plant product
known to block Hedgehog pathway activity. This and other similar molecules
can now be considered for future research as a treatment for terminal
patients with metastatic disease and to fight resurgent forms of the
disease.
"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 Ruiz i Altaba. "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."
Using these genetic or pharmacologic methods to block HH-GLI activity also
prevents cancer stem cell self-renewal. Using a new in vivo assay to test
the participation of cancer stem cells in a growing tumor, the research team
demonstrated the essential role of this pathway for the maintenance and
survival of cancer stem cells.
"This work firmly establishes the critical action of HH-GLI in human colon
cancer cells, providing the platform for preclinical and future clinical
work." concluded Ruiz i Altaba. "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."
SOURCE: EMBO Molecular Medicine, August, 2009 |
