LH/hCG-Receptor Expression May Have a Negative Prognostic Value in Low-Risk Endometrial Cancer

Introduction: A 51 years-old woman was diagnosed with endometrial cancer and underwent surgical staging. Pathologic evaluation showed a 2x1 cm G2 endometrioid endometrial cancer with a 30% myometrial deep invasion (FIGO stage 1A). The patient was classified as low-risk of recurrence and no adjuvant treatment was offered. Six months after surgery, the patient developed an early vescico-vaginal recurrence and chemotherapy treatment was started. Few months later a subsequent involvement of vaginal wall, ileum and omentum was detected and the patient underwent second surgery. Background: LH/hCG-receptor (LH/hCG-R) expression has been previously reported to be associated with an invasive phenotype in endometrial cancer cells. Moreover, in a preclinical mouse model of EC behaves as a pro metastatic molecular device. Discussion: We analysed the expression level of LH/hCG-R in cancer specimens collected during surgeries. Molecular and immunohistochemical analysis showed a strong expression of both mRNA and protein for LH/hCG-R in all specimens. Conclusion: LH/hCG-R expression may be assessed together with other clinicopathological parameters in order to better predict the risk of recurrence in low-risk endometrial cancer patients. Further clinical trials are warranted in order to validate LH/hCG-R as biomarker in endometrial cancer

SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis

5-Fluorouracil (5-FU) is a key component of chemotherapy for colorectal cancer (CRC). 5-FU efficacy is established by intracellular levels of folate cofactors and DNA damage repair strategies. However, drug resistance still represents a major challenge. Here, we report that alterations in serine metabolism affect 5-FU sensitivity in in vitro and in vivo CRC models. In particular, 5-FU-resistant CRC cells display a strong serine dependency achieved either by upregulating endogenous serine synthesis or increasing exogenous serine uptake. Importantly, regardless of the serine feeder strategy, serine hydroxymethyltransferase-2 (SHMT2)-driven compartmentalization of one-carbon metabolism inside the mitochondria represents a specific adaptation of resistant cells to support purine biosynthesis and potentiate DNA damage response. Interfering with serine availability or affecting its mitochondrial metabolism revert 5-FU resistance. These data disclose a relevant mechanism of mitochondrial serine use supporting 5-FU resistance in CRC and provide perspectives for therapeutic approaches

hERG1 Potassium Channels: Novel Biomarkers in Human Solid Cancers

Because of their high incidence and mortality solid cancers are a major health problem worldwide. Although several new biomarkers and potential targets for therapy have been identified through biomolecular research in the last years, the effects on patients’ outcome are still unsatisfactory. Increasing evidence indicates that hERG1 potassium channels are overexpressed in human primary cancers of different origin and several associations between hERG1 expression and clinicopathological features and/or outcome are emerging. Aberrant hERG1 expression may be exploited either for early diagnosis (especially in those cancers where it is expressed in the initial steps of tumor progression) or for therapy purposes. Indeed, hERG1 blockage impairs tumor cell growth both in vitro and in vivo in preclinical mouse model. hERG1-based tumor therapy in humans, however, encounters the major hindrance of the potential cardiotoxicity that many hERG1 blockers exert. In this review we focus on recent advances in translational research in some of the most frequent human solid cancers (breast, endometrium, ovary, pancreas, esophagus, stomach, and colorectum) that have been shown to express hERG1 and that are a major health problem

Transcriptomic data of bevacizumab-adapted colorectal adenocarcinoma cells HCT-116

A bioinformatic approach was applied to evaluate the effect of treatment with Bevacizumab on the gene expression profile of colorectal adenocarcinoma cells. The transcriptomic profile of Bevacizumab-adapted HCT-116 (Bev/A) colorectal adenocarcinoma cells was determined and compared with that of the corresponding control cell line by Agilent microarray analysis. Raw data were preprocessed, normalized, filtered, and subjected to a differential expression analysis using standard R/Bioconductor packages (i.e., limma, RankProd). As consequence of Bevacizumab adaptation, 166 differentially expressed genes (DEGs) emerged, most of them (123) resulted downregulated and 43 overexpressed. The list of statistically significant dysregulated genes was used as an input for functional overrepresentation analysis using ToppFun web tool. Such analysis pointed at cell adhesion, cell migration, extracellular matrix organization and angiogenesis as the main dysregulated biological process involved in Bevacizumab-adaptation of HCT116 cells. In addition, gene set enrichment analysis was performed using GSEA, searching for enriched terms within the Hallmarks (H), Canonical Pathways (CP), and Gene Ontology (GO) gene sets. GO terms that showed significant enrichment included: transportome, vascularization, cell adhesion and cytoskeleton, extra cellular matrix (ECM), differentiation and epithelial–mesenchymal transition (EMT), inflammation and immune response. Raw and normalized microarray data were deposited in the Gene Expression Omnibus (GEO) public repository with accession number GSE221948