Abstract
Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.
Highlights
Cancer and Cancer Stem CellsCancer is one of the leading causes of death in modern society
Tumour cells develop from normal cells that make mistakes in their DNA repair mechanisms and accumulate mutations, which results in the acquisition of new properties, such as an uncontrolled cell division that usually leads to non-malignant tissue hyperplasia
Both pancreatic ductal adenocarcinoma (PDAC) and GBM cancer stem cells (CSCs) rely mainly on oxidative phosphorylation to produce ATP, but certain subpopulations can switch to glycolysis if needed
Summary
Cancer and Cancer Stem CellsCancer is one of the leading causes of death in modern society. Fourteen million new cancer cases are diagnosed and eight million people die of cancer yearly worldwide (Torre et al, 2016). Cancer is characterised by specific genetic alterations, genome-widespread epigenetic alterations and chromosomal aberrations. This leads to key genes either gaining or losing their molecular function and signaling pathways, and reflecting changes in the physiological function of the affected cell type and tissue. Tumour cells develop from normal cells that make mistakes in their DNA repair mechanisms and accumulate mutations, which results in the acquisition of new properties, such as an uncontrolled cell division that usually leads to non-malignant tissue hyperplasia. Malignant cells are capable of de-differentiation, tissue invasion, nutrient recruitment through blood by angiogenesis induction, self-sufficient growth, insensitivity to negative growth control and apoptosis initiation, and limitless replicative potential (Hanahan and Weinberg, 2011)
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