AN EPITOPE LOCALIZED IN C-SRC NEGATIVE REGULATORY DOMAIN IS A POTENTIAL MARKER IN EARLY-STAGE OF COLONIC NEOPLASMS

In previous work, we established a new monoclonal antibody that specif ically recognizes the active form of c-Src tyrosine kinase (Kawakatsu et al, 1996). To determine whether c-Src is active in colorectal tumor igenesis, we examined the expression of an active form of c-Src in hum an normal mucosa, hyperplastic polyps, adenomas, and adenocarcinomas. The tissue distribution of the active form of c-Src was studied by imm unohistochemistry using this antibody, termed Clone 28. Among 66 cases of adenoma tested, 61 (92%) showed positive staining (adenoma with mi ld atypia, 3 of 3; adenoma with moderate atypia, 38 of 42; adenoma wit h severe atypia, 20 of 21). In contrast to the frequent and intense st aining in adenomas, adenocarcinoma showed weak staining with less freq uency in 4 of 16 (25%) cases. The number of specimens with positive st aining in well-and moderately differentiated adenocarcinomas was limit ed to an early stage. The active form of c-Src mainly localized to the nuclear membrane and the perinuclear region. These results provide th e first direct evidence that the activation of c-Src appears to be an early event in colonic carcinogenesis in situ. The findings of the pre sent study thus allow us to propose a molecular mechanism involving c- Src activation in the process of malignant transformation of the human colonic neoplastic cells.