Olfactomedin-4, a Novel Marker of Intestinal Stem Cell Identity, Is Upregulated in Long-Standing Ulcerative Colitis and Accompanying Low Grade Dysplasia
OH Yilmaz, AK Bhan, GY Lauwers, V Deshpande. Massachusetts General Hospital, Boston, MA
Background: Long-standing ulcerative colitis (UC) is associated with a significant increase in the incidence of cancer. Chromosomal instability and p53 mutations are known markers of dysplasia in UC. It has been proposed that the cell-origin for sporadic colorectal carcinoma (CRC) are intestinal cells (ISCs), but to date very little is known about ISCs in chronic colitis or neoplastic transformation that arises in the background of UC. Towards this end, we tested the expression of Olfactomedin-4 (OLMF4), a recently identified novel marker for ISCs, in non-dysplastic and neoplastic epithelium from UC patients.
Design: Tissue microarrays were constructed using colectomy specimens from patients with long-standing UC (>10 yrs) and included cores from non-dysplastic mucosa (n=26), low-grade dysplasia (LGD)(n=14), high-grade dysplasia (HGD) (n=5), and carcinoma (CA)(n=4). Furthermore, inflamed colonic mucosa from patients with early UC (biopsy in first year of disease) (n=18) were studied. Immunohistochemical stains for OLMF4 and p53 were performed and scored for intensity, percent positive cells, and percentage of colonic crypt involvement.
Results: Expression in normal mucosa: OLMF4 expression was confined to 5-6 cells at the base of the crypts (stem cell zone). Expression in non-neoplastic epithelium: Long-standing UC cases (19/23, 83%) showed OLMF4 expression in the upper half of the colonic crypts, whereas only 1 of 18 (6%) early UC cases showed a similar pattern (p<0.0001). The intensity of OLMF4 expression within the non-dysplastic mucosa of the late UC cohort was significantly stronger than in the early UC cases (2+ staining in 22/26 vs. 1/18, p<0.001). Expression in neoplastic epithelium: While OLMF4 was widely expressed in LGD, it marked fewer but strongly positive (2+) neoplastic cells in high-grade neoplasia.
|OLMF4 in >30% of cells||9/13 (69%)||2/5 (40%)||0/4 (0%)|
|p53 in upper 1/2 of crypt||12/14 (86%)||6/6 (100%)||5/5 (100%)|