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Materials and MethodsThe genomic effects of tumor-endothelial interactions in cancer are not yet well characterized. To study this interaction in breast cancer, we set up an ex vivo coculture model with human benign and malignant breast epithelial cells with endothelial cells to determine the associated gene expression changes using DNA microarrays. Results The most prominent response to coculture was the induction of the M-phase cell cycle genes in a subset of breast cancer cocultures that were absent in cocultures with normal breast epithelial cells. In monoculture, tumor cells that contained the stem cell-like CD44+/CD24- signature had a lower expression of the M-phase cell cycle genes than the CD44-/CD24+ cells, and in the CD44+/CD24- cocultures, these genes were induced. Pretreatment gene expression profiles of early-stage breast cancers allowed evaluating in vitro effects in vivo. The expression of the gene set derived from the coculture provided a basis for the segregation of the tumors into two groups. In a univariate analysis, early-stage tumors with high expression levels (n = 137) of the M-phase cell cycle genes had a significantly lower metastasis-free survival rate (P = 1.8e - 5, 50% at 10 years) and overall survival rate (P = 5e - 9, 52% at 10 years) than tumors with low expression (n = 158; metastasis-free survival, 73%; overall survival, 84%). Conclusions Our results suggest that the interaction of endothelial cells with tumor cells that express the CD44+/CD24- signature, which indicates a low proliferative potential, might explain the unexpected and paradoxical association of the CD44+/CD24- signature with highly proliferative tumors that have an unfavorable prognosis.

BACKGROUND: Molecular predictors for the effectiveness of adjuvant chemotherapy in colorectal cancer are of considerable clinical interest. To this aim, we analyzed the serine threonine receptor-associated protein (STRAP), an inhibitor of TGF-βsignaling, with regard to prognosis and prediction of adjuvant 5-FU chemotherapy benefit. i The gene copy status of STRAP was determined using quantitative realtime polymerase chain reaction in 166 colorectal tumor biopsies, which had been collected from a randomized multicenter trial of 5-fluorouracil (5-FU)/mitomycin C (MMC) adjuvant chemotherapy of the Swiss Group for Clinical Cancer Research (SAKK). RESULTS: Amplification of STRAP was found in 22.8% of the tumors. When left without adjuvant chemotherapy, patients bearing tumors with a STRAP amplification had a significantly better prognosis (hazard ratio for death: 0.26; P = .004). Interestingly, these patients, when receiving adjuvant treatment, had a worse survival (hazard ratio for death: 3.48; P = .019) than without chemotherapy, whereas patients carrying tumors with diploidy or deletion of STRAP benefited from the treatment (hazard ratio for death: 0.44; P = .052). This suggests the amplification of STRAP as a strong predictor of an unfavorable effect of 5-FU-based adjuvant chemotherapy. CONCLUSION: If confirmed, the STRAP gene copy status might provide a parameter to decide about the use of 5-FU-based adjuvant chemotherapy.

BACKGROUND: Improved risk stratification of early colorectal cancer might help to better select patients for adjuvant treatment. Alterations in the transforming growth factor-β (TGIF-β) pathway have frequently been found in colorectal cancer, but their impact on prognosis remains controversial. We therefore analyzed two transcriptional corepressors of the TGF-β signaling pathway with respect to prognosis and prediction of chemotherapy benefit in early colorectal cancer. METHODS: The gene copy status of SKI and SNON was analyzed by use of quantitative real-time polymerase chain reaction in 179 colorectal tumor biopsies, which had been collected from a randomized multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK). RESULTS: Partial or complete allelic loss was found in 41.5% and 55.2% for SKI and SNON, whereas amplification was found in 10.1% and 15.1%, respectively. Multivariate Cox analysis showed that gene amplification of SKI independently predicted reduced relapse-free [hazard ratio (HR) for relapse 2.08, P = .049] and overall survival (HR for death 2.62, P =.012). In contrast, deletion of SKI and the gene copy status of SNON were not significantly correlated with prognosis. CONCLUSION: Amplification of SKI is a negative prognostic marker in early-stage colorectal cancer. This marker should help to improve risk stratification to better select patients for adjuvant therapy. Confirmatory investigations are warranted.