3rd Annual BMRP Investigator Meeting - Abstract
WNT Signaling in Inflammatory Bowel Disease-Related Colon Cancer
Randall F. Holcombe1,a, Peter Bryant2, Joann Yu1 and Tatjana Milovanovic1
1Division of Hematology/Oncology and 2Department of Developmental and Cell Biology, University of California, Irvine (Irvine, California, U.S.A.)
There is preliminary evidence that specific components of the WNT signaling pathway are involved in the pathogenesis of colon cancer in patients with inflammatory bowel disease (IBD). While mutations in APC, a critical protein of the WNT pathway, are common in sporadic colon cancer, such mutations are rare in IBD. In these studies, we test the hypothesis that the expression of non-APC components of the WNT pathway, including frizzled (Fz) receptors, disheveled (DVL) family proteins, axin and CK1e is dysregulated in colon cancers derived from patients with IBD.
Paraffin sections of colon cancers arising in patients with IBD were obtained through the University of California, Irvine and the National Cancer Institute-sponsored Cooperative Tissue Network and examined by immunohistochemistry. Results indicate that Fz 1/2 receptors are expressed in normal colonic epithelium in patients with IBD and even more strongly expressed in the dysplasia-rich transition zones between normal mucosa and cancer. However, the IBD-associated cancer tissues had minimal expression. This is in marked contrast to patients who develop sporadic colon cancer. In these individuals, Fz 1/2 is expressed in cancers along the invasion margin but generally minimal or no expression is seen in normal mucosa. DVL2 and DVL3 are abundantly expressed in normal colonic mucosa from patients with IBD and are also expressed in the dysplasia-rich transition zones between normal mucosa and colon cancer. Surprisingly, virtually no DVL2 and DVL3 expression was seen in IBD-associated colon cancers, even when normal mucosa from the same individual did exhibit expression. These results are consistent with the Fz data, suggesting a prominent role for WNT signaling in non-malignant IBD colonic mucosa. Mutational analysis of CK1e revealed only intronic alterations. Mutational analysis of axin, a scaffolding protein which complexes with APC, reveals two specific mutations in the coding sequences at base pairs 821 and 930 in samples of IBD-associated colon cancer. Studies to define the frequency of occurrence of these mutations in IBD colon cancer are ongoing via analysis of multiple different tumor specimens.
The data suggest that WNT signaling may be activated in the “normal” colonic mucosa of IBD patients. This could result in increased cell turnover, increased proliferation and a propensity for malignant transformation. Alternatively, the WNT activation may be the result of ongoing inflammatory stimuli present in individuals with IBD that may be absent in non-affected individuals. If the former is true, identifying ways to block WNT signaling will be important in order to prevent the eventual development of colon cancer. If the latter is true, components of the WNT pathway may serve as sensitive markers of disease activity.
aPrincipal Investigator