Map of Pancreatica Walks and Runs

Hedgehog Pathway Inhibition Slows Pancreatic Cancer Cell Growth

You may wonder what this has to do with pancreatic cancer, but please know that those of us who are old enough to remember once shivered and screamed in horror at the 1958 move, The Fly, whereby the protagonist ended up half human, half housefly (musca domestica).  This fear may not be too far from the truth, as the evolution of human DNA may include remnants of our flying antagonists.

In 1995, three biologists (Lewis, Nüsslein-Volhard and Wieschaus) shared the Noble Prize in Medicine for their work beginning in the late 1970s in studying genetic mutations related to body segmentation in the development of the fruit fly (Drosophila), including the identification of the three “hedgehog” genes related to this process. The name “hedgehog” was given as a result of the stubby and especially disordered and hairy look of the mutated drosophila denticles on the mutated larvae.

Not only are hedgehog genes active in flies, but their actions are integral to normal development in human embryos.  Also, the complex hedgehog signaling pathway appears to have key but not fully understood mechanisms in human adults, including the production of adult stem cells. Disruption of this signalling pathway can cause severe birth defects, miscarriage, and death. And the adult activation of the hedgehog pathway (overexpression of its components) appears to be related to the development of a number of especially difficult cancers, including pancreatic cancer. It is thought that undue activation of the hedgehog signaling pathway may transform the adult stem cells (generally: good) into specific cancer stem cells (generally: bad, as they may cause, protect and/or abet the rapid growth of the tumor).

Professor Tony Magee and researchers from the Imperial College London (along with a Danish colleague) and based on a grant from the UK’s Pancreatic Cancer Research Fund, on March 7, 2014 published the results of their pre-clinical work in the journal PLoS.  The researchers inhibited the effect of “hedgehog acyltransferase” in pancreatic cancer cells, an enzyme that appears to be critical in the signaling pathway.  As suspected, the result was that the growth and spread of the pancreatic cancer tumor cells were severely curtailed.

The authors’ conclusions were that hedgehog acyltransferase is in fact a key component of the hedgehog pathway, and that its amelioration may help impede pancreatic cancer growth and spread.

This careful and thoughtful work is early stage, but may prompt an important angle of attack by way of future pancreatic cancer research leading to clinical trials.

 

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Dale O’Brien, MD

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