Purpose Examination of the entire colon by colonoscopy remains the golden standard for screening of colorectal cancer (CRC). However, patients are reluctant to perform invasive colonoscopies because of interference with their intimacy. Therefore, the potential use of non-invasive analysis of microRNAs expression in liquid biopsy as a novel biomarker for early CRC has investigated in several studies. In this study, we analyzed the expression of two novel microRNAs: miR-506 and miR-4316, which have never been examined in CRC. Methods Plasma samples were collected from 56 patients (median age of 68 years) with operable colorectal cancer and from 70 healthy individuals (median age of 59 years). Expression of plasma microRNAs was evaluated by quantitative reverse transcription polymerase chain reaction using Eco real-time PCR device (Illumina, USA). Results We found a significant elevated expression of both examined microRNAs in early CRC patients when compared to those in healthy individuals (p = 0.0054 for miR-506 and p = 0.0025 for miR-4316). The expression of miR-506 and miR-4316 did not depend on gender, age, disease stage, and tumor localization of CRC patients. ROC curve analysis showed that both examined microRNAs could differentiate early stage colorectal cancer from healthy individuals with 76.8% specificity and 60.7% sensitivity for miR-506 analysis and 76.8% specificity and 75% specificity for miR-4316 analysis. Conclusion Our study revealed that elevated expression of miR-506 and miR-4316 in peripheral blood were potential molecular markers for early colorectal cancer.

Proteasome machinery is a major proteostasis control system in human cells, actively compensated upon its inhibition. To understand this compensation, we compared global protein landscapes upon the proteasome inhibition with carfilzomib, in normal fibroblasts, cells of multiple myeloma, and cancers of lung, colon, and pancreas. Molecular chaperones, autophagy, and endocytosis-related proteins are the most prominent vulnerabilities in combination with carfilzomib, while targeting of the HSP70 family chaperones HSPA1A/B most specifically sensitizes cancer cells to the proteasome inhibition. This suggests a central role of HSP70 in the suppression of the proteasome downregulation, allowing to identify pathways impinging on HSP70 upon the proteasome inhibition. HSPA1A/B indeed controls proteasome-inhibition-induced autophagy, unfolded protein response, and endocytic flux, and directly chaperones the proteasome machinery. However, it does not control the NRF1/2-driven proteasome subunit transcriptional bounce-back. Consequently, targeting of NRF1 proves effective in decreasing the viability of cancer cells with the inhibited proteasome and HSP70.

Background: In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial. Methods: Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (Tcell_infGEP) and 10 non-Tcell_infGEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-β, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for Tcell_infGEP (prespecified α=0.05) and the 10 non-Tcell_infGEP signatures (multiplicity-adjusted; prespecified α=0.10). Results: RNA sequencing data were available for 137 patients in each treatment group. Tcell_infGEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The Tcell_infGEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the Tcell_infGEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel. Conclusions: This exploratory analysis of tumor Tcell_infGEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. Tcell_infGEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis. Trial registration number: NCT02370498.

Colorectal cancer (CRC) is the second most common cancer in Europe and a leading cause of death worldwide. Patient-derived xenograft (PDX) models maintain complex intratumoral biology and heterogeneity and therefore remain the platform of choice for translational drug discovery. In this study, we implanted 37 primary CRC tumors and five CRC cell lines into NU/J mice to develop xenograft models. Primary tumors and established xenografts were histologically assessed and surveyed for genetic variants and gene expression using a panel of 409 cancer-related genes and RNA-seq, respectively. More than half of CRC tumors (20 out of 37, 54%) developed into a PDX. Histological assessment confirmed that PDX grading, stromal components, inflammation, and budding were consistent with those of the primary tumors. DNA sequencing identified an average of 0.14 variants per gene per sample. The percentage of mutated variants in PDXs increased with successive passages, indicating a decrease in clonal heterogeneity. Gene Ontology analyses of 4180 differentially expressed transcripts (adj. p value < 0.05) revealed overrepresentation of genes involved in cell division and catabolic processes among the transcripts upregulated in PDXs; downregulated transcripts were associated with GO terms related to extracellular matrix organization, immune responses, and angiogenesis. Neither a transcriptome-based consensus molecular subtype (CMS) classifier nor three other predictors reliably matched PDX molecular subtypes with those of the primary tumors. In sum, both genetic and transcriptomic profiles differed between donor tumors and PDXs, likely as a consequence of subclonal evolution at the early phase of xenograft development, making molecular stratification of PDXs challenging.

Article: The risk of anastomotic leakage after anterior resection: retrospective analysis of 501 rectal cancer patients operated without protective stoma - Minerva Chirurgica 2017 December;72(6):491-8 - Minerva Medica - Journals