Scientists are constantly striving to understand the molecular events that predate the onset of cancer.

Now, a study in Science has shown that an increase in the number of immature cells in the lining of the bowel predisposes to the development of colon cancer. This novel phenotype was seen in mice that had been genetically manipulated to express twice the normal amount of the imprinted gene insulin-like growth factor (Igf)2.

In humans, loss of imprinting of IGF2 is associated with several tumour types, including colorectal cancer. Surprisingly, in the mutant mice, doubling the amount of this growth factor did not affect the turnover of intestinal cells but instead seemed to block their maturation, which increased the numbers of immature cells in the gut lining. Importantly, mice that had both defective Igf2 imprinting and an additional tumour-promoting mutation developed twice as many bowel tumours as mice with the tumour-promoting mutation alone. This indicates that the immature bowel cells are a 'hot-spot' for neoplastic transformation.

This study shows how a combination of epigenetic and genetic misfortune can have catastrophic results. As co-author Christine Iacobuzio-Donahue explains: “In the mice with a double dose of IGF2, everything is pretty normal except for the extra precursor cells ... But when the genetic mutation is present, too, we found a clear cost for what otherwise appears to be a benign effect of extra IGF2.” (myDNA.com, 25 February 2005).

Andrew Feinberg, main author, is excited by the prospect that “...this discovery should expand attention in colon cancer to earlier events, situations present well before tumors appear.” (bio.com, 24 February 2005). The hope is that this will lead to effective cancer prevention strategies.