Adenomatous polyps expand the pool of colon stem cells to become malignant, whereas hyperplastic polyps (HPPs) do not, and therefore remain benign, according to a study published in the September issue of Gastroenterology.
Many colorectal cancers arise from adenomatous polyps, which contain mutations that inactivate the tumor suppressor APC. These polyps accumulate additional mutations, such as those that activate KRAS—a GTPase that transmits signals from growth factors to activate proliferation. HPPs, in contrast, are common lesions of the colorectum that are not malignant, even though they also frequently have activating mutations in KRAS (but not inactivating mutations in APC); KRAS mutations are also found in lung and pancreatic tumors.
Eric Fearon and colleagues studied the effects of activation of Kras in colonic epithelium of mice to determine why some polyps with Kras mutations become malignant whereas others do not. They found that expression of the activated form of Kras in colon led to epithelial hyperplasia and changes in crypt architecture similar to that observed in human HPPs. Colons of these mice also had reduced numbers of Paneth cells and increased numbers of goblet cells.
Fearon determined that activated Kras induced these differentiation defects and colon cell proliferation via the mitogen-activated protein kinase (MAPK) signaling pathway and increased expression of the transcription factor Hes1, which regulates colon cell proliferation and differentiation.
However, they did not detect increased levels of stem cell markers (Lgr5, Msi1, or Olfm4) in colon epithelium or colony formation in their mice; this differs from colons of mice with inactivated APC, which have increased expression of stem cell markers and develop malignant tumors. Fearon et al. concluded that although activation of Kras does increase cell proliferation, it does not increase the numbers of crypt stem cells, and that these are required for progression of colorectal polyps to carcinomas.
In an accompanying editorial, Terrence Barrett and Linheng Li state that findings from the study might explain why polyps that contain only Kras mutations are less aggressive than those with Kras combined with Apc or p53 mutations (see figure).
Further studies are needed to determine why activation of Kras can induce formation of malignant tumors in other tissues, such as lung and pancreas, but not in colon. Fearon et al. propose that the difference in tumorigenic potential involves specific mechanisms of stem cell expansion in different organs.
More information on colon polyps:
Read the article online.
Feng Y, Bommer GT, Zhao J, et al. Mutant Kras promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology 2011;141:1003–1113.e10.
Read the accompanying editorial.
Barrett T, Li L. MAPing the role of Kras Mutations in hyperplastic polyps. Gastroenterology 2011;141:799–801.