Microsatellite instability, KRAS mutations and cellular distribution of TRAIL-receptors in early stage colorectal cancer.

Thus, we evaluated the immunofluorescence pattern of
TRAIL-receptors and E-cadherin to assess the fraction of
membrane-bound TRAIL-receptors in 231 selected patients with
early-stage CRC undergoing surgical treatment only. Moreover, we
investigated whether membrane staining for TRAIL-receptors as well
as the presence of KRAS mutations or of microsatellite instability
(MSI) had an effect on survival and thus a prognostic effect. The
fact that the receptors for the TNF-related apoptosis inducing
ligand (TRAIL) are almost invariably expressed in colorectal cancer
(CRC) represents the rationale for the employment of
TRAIL-receptors targeting compounds for the therapy of patients
affected by this tumor. Yet, first reports on the use of these
bioactive agents provided disappointing results. We therefore
hypothesized that loss of membrane-bound TRAIL-R might be a feature
of some CRC and that the evaluation of membrane staining rather
than that of the overall expression of TRAIL-R might predict the
response to TRAIL-R targeting compounds in this tumor. As expected,
almost all CRC samples stained positive for TRAIL-R1 and 2.
Instead, membrane staining for these receptors was positive in only
71% and 16% of samples respectively. No correlation between KRAS
mutation status or MSI-phenotype and prognosis could be detected.
TRAIL-R1 staining intensity correlated with survival in univariate
analysis, but only membranous staining of TRAIL-R1 and TRAIL-R2 on
cell membranes was an independent predictor of survival (cox
multivariate analysis: TRAIL-R1: p = 0.019, RR 2.06[1.12-3.77];
TRAIL-R2: p = 0.033, RR 3.63[1.11-11.84]). In contrast to the
current assumptions, loss of membrane staining for TRAIL-receptors
is a common feature of early stage CRC which supersedes the
prognostic significance of their staining intensity. Failure to
achieve therapeutic effects in recent clinical trials using
TRAIL-receptors targeting compounds might be due to insufficient
selection of patients bearing tumors with membrane-bound
TRAIL-receptors.