The Potential for Markers of Epithelial–Mesenchymal Transition to Improve Colorectal Cancer Outcomes: A Systematic Review

Abstract

Epithelial-mesenchymal transition (EMT) is thought to be an important mechanism of cancer cell metastasis. Clinical measurement of EMT markers in primary tumors could improve risk stratification and treatment decisions by identifying patients who potentially have metastatic disease. To evaluate the potential of EMT markers that could be used for risk stratification for patients with colorectal cancer, we conducted a systematic review of studies (N ¼ 30) that measured at least one of a selection of EMT markers in primary tumors and patient outcomes. Fifteen of 30 studies (50%) reported at least one statistically significant result supporting a role for one of the selected EMT markers in identifying patients at risk for worse outcomes. Importantly, however, we identified design inconsistencies that limited inferences and prevented meta-analysis of data. We offer a number of recommendations to make future studies more informative and standardized, including consistent sampling of different parts of the primary tumor, larger sample sizes, and measurement of both protein and RNA expression of a given EMT marker in the same tumors. Strengthening the literature per our recommendations could facilitate translating EMT markers to clinical use. Cancer Epidemiol Biomarkers Prev; 23(7); 1164-75. Ó2014 AACR.

Evaluating markers of epithelial-mesenchymal transition to identify cancer patients at risk for metastatic disease

“…Third, the selection of covariates for multivariate models has varied considerably and been without justification in previous studies [6]. Our approach was to identify a wide range of possibilities using prior literature and then determine whether to include or exclude each possibility based on directed acyclic graph theory [12].…”

“…We selected EMT markers for evaluation based on the results of previous studies and criteria discussed in our prior literature review [6]. Marker protein expression was measured using the following antibodies: E-cadherin [mouse monoclonal ready to use (RTU), clone 36B5 (cat #PA0387) from Leica Microsystems Inc. (Norwell, MA)] and Snail [goat polyclonal (ab53519) from Abcam (Cambridge, MA)].…”

“…Covariates for multivariate statistical models were selected based on prior studies [6], considerations of biological plausibility, and directed acyclic graph theory [12]. …”

“…Whether high expression is clinically desirable depends on the particular marker. High E-cadherin status would be expected to correlate with better outcomes (i.e., longer time-to-death) [4, 6, 13], whereas high Snail [4, 6] status would be expected to correlate with worse outcomes.…”

“…Past studies of associations between EMT markers in primary tumors and patient outcomes have measured and analyzed marker expression data using inconsistent methods [6]. For instance, different studies of the same marker measured using the same laboratory technique have often used different scoring scales and defined high versus low expression differently.…”