A ‘metastasis-prone’ signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics

Abstract

Metastasis is the major cause of cancer mortality. We aimed to find a metastasis-prone signature for early stage mismatch-repair proficient sporadic colorectal cancer (CRC) patients for better prognosis and informed use of adjuvant chemotherapy. The genome-wide expression profiles of 82 age-, ethnicity- and tissue-matched patients and healthy controls were analyzed using the Affymetrix U133 Plus 2 array. Metastasis-negative patients have 5 years or more of follow-up. A 10 x 10 two-level nested cross-validation design was used with several families of classification models to identify the optimal predictor for metastasis. The best classification model yielded a 54 gene-set (74 probe sets) with an estimated prediction accuracy of 71%. The specificity, sensitivity, negative and positive predictive values of the signature are 0.88, 0.58, 0.84 and 0.65, respectively, indicating that the gene-set can improve prognosis for early stage sporadic CRC patients. These 54 genes, including node molecules YWHAB, MAP3K5, LMNA, APP, GNAQ, F3, NFATC2, and TGM2, integrate multiple bio-functions in various compartments into an intricate molecular network, suggesting that cell-wide perturbations are involved in metastasis transformation. Further, querying the ;Connectivity Map' with a subset (70%) of these genes shows that Gly-His-Lys and securinine could reverse the differential expressions of these genes significantly, suggesting that they have combinatorial therapeutic effect on the metastasis-prone patients. These two perturbagens promote wound-healing, extracellular matrix remodeling and macrophage activation thus highlighting the importance of these pathways in metastasis suppression for early-stage CRC.

Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass

“…50,51 Few of the tested markers showed decreasing transcript levels including ALIX, which was one of the most widely examined exosome markers in cancer development. 29,30,52,53 Our gene expression data correlated well with those gained from independent databases, [36][37][38][39] showing similarly reduced ALIX mRNA levels during adenoma-carcinoma sequence, which was also validated at the in situ protein level. Similar alterations between whole biopsy mRNA and protein level in epithelial compartment suggest that the majority of ALIX originated from these components.…”

“…[36][37][38][39] In adenoma vs normal comparison, results of GSE8671 data set completely supported the exosome marker mRNA level alterations revealed in analysis of our microarray data sets (Supplementary Table 2). …”

“…Detailed patients data were described previously. [33][34][35] For confirmation of exosome marker mRNA expression results revealed from our microarray data originate from all stages of colorectal adenoma-carcinoma sequence, four additional GEO data sets were also involved in the analysis, three of them includes HGU133 Plus2.0 microarray data of colorectal carcinoma (n = 99) and normal/normal adjacent tissue (NAT) (n = 39) tissue samples (GSE18105, 36 GSE4107 37 and GSE9348 38 ) and one of them with HGU133 Plus2.0 microarray data of adenoma (n = 32) and normal/NAT (n = 32) biopsy samples (GSE8671) 39 (Supplementary Table 1). …”

Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion

“…hCDC14A mRNA levels are significantly down-regulated in a range of cancers (34)(35)(36)(37) (Fig. S6 C-E).…”

“…Excitingly, the in vitro "tumor formation activity" of HCT116 cells in soft agar assays was enhanced by the hCDC14A inactivating mutation hCDC14A PD . We therefore propose that the down-regulation of hCDC14A mRNA seen in many tumors makes a significant contribution to the propagation of cancers by decreasing cell adhesion and enhancing cell migration (34)(35)(36)(37).…”