ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance.

The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC) transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs), endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype. To summarize, we suggest that the increased expression of ABC transporters in CSCs may have precise functional roles and provide the opportunity to target, particularly these cells, by using specific ABC transporter inhibitors.

Bioactive lipids in cancer stem cells.

Tumours are known to be a heterogeneous group of cells, which is why they are difficult to eradicate. One possible cause for this is the existence of slow-cycling cancer stem cells (CSCs) endowed with stem cell-like properties of self-renewal, which are responsible for resistance to chemotherapy and radiotherapy. In recent years, the role of lipid metabolism has garnered increasing attention in cancer. Specifically, the key roles of enzymes such as stearoyl-CoA desaturase-1 and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase in CSCs, have gained particular interest. However, despite accumulating evidence on the role of proteins in controlling lipid metabolism, very little is known about the specific role played by lipid products in CSCs. This review highlights recent findings on the role of lipid metabolism in CSCs, focusing on the specific mechanism by which bioactive lipids regulate the fate of CSCs and their involvement in signal transduction pathways.

Pancreatic cancer tumorspheres are cancer stem-like cells with increased chemoresistance and reduced metabolic potential.

Cancer stem cells are a population of slow-cycling cells within the tumour bulk, with self-renewal capacity that attracts interest as a therapeutic target. In highly heterogeneous tumours, like pancreatic ductal adenocarcinoma (PDAC) however, the characterisation of cancer stem cells has led to controversial results due to the lack of consensus on specific markers. Here we investigated the characteristics of a population of pancreatic cancer tumorspheres derived from different human pancreatic cancer cell lines and a primary line from a genetically engineered KPC mouse model, using flow cytometry and western blotting to analyse surface and stemness markers. We analysed tumorspheres tumorigenic potential using anchorage-independent soft agar assay as well as their metabolic plasticity and chemoresistance. Pancreatic cancer tumorspheres display a heterogeneous pattern of surface and stemness markers, nevertheless they are characterised by an increased tumorigenic potential and higher chemoresistance. In addition, we have shown that pancreatic cancer tumorspheres have a unique metabolic profile with reduced metabolic potential. Together our results indicate that, despite the heterogeneity characterising pancreatic cancer tumorspheres, we can identify a functional vulnerability that represents a window for pharmacological intervention and development of novel therapeutic strategies.