Abstract
BACKGROUND. Although pathologic stage is currently the main prognostic indicator for patients with colorectal carcinoma (CRC), mounting evidence suggests that, in its current form, it is insufficient to predict clinical outcome. To assess biologic markers of primary CRC that may improve clinical staging and provide useful information for the application of novel therapeutic strategies, the authors investigated a panel of markers that included transforming growth factor-alpha (TGF-alpha), epithelial growth factor receptor (EGF-R; the protein product of the c-erb B2/HER-2 oncogene), matrix metalloproteinase 2 (MMP-2), insulin-like growth factor II (IGF-II), vascular endothelial growth factor (VEGF), and angiogenesis, as evaluated by microvessel density (MVD).
METHODS. Two groups of CRC were studied: 1) surgical samples from patients who achieved a disease free survival of at least 6 years (CRC-M0) and 2) surgical specimens of both primary tumors and synchronous or metachronous liver metastases (CRC-M1).
RESULTS. Chi-square analysis revealed that expression levels of TGF-a, c-erb 1321 HER-2 MMP-2, IGF-II, VEGF, and MVD (but not EGF-R) were significantly higher in CRC-M1 samples compared with CRC-M0 samples (P < 0.001, P < 0.05, P < 0.001, P < 0.001, P < 0.01, and P < 0.001, respectively). Logistic regression analysis showed that TGF-alpha, IGF-II, and MMP-2 had significantly greater expression in CRC-M1 samples independent of the other variables (including tumor classification, histologic grade, and patient age). If all three markers had greater than or equal to 25% expression, then the probability of developing liver metastasis was 99.5%.
CONCLUSIONS. Based on the evidence of this study, TGF-alpha MMP-2, and IGF-II seem suitable candidates for a selective panel of markers designed to provide significant additional information with respect to the current pathologic staging system for patients with colorectal carcinoma.