Therefore, glycolytic metabolic reprogramming is critical for the maintenance of CSCs and is associated with the progression of cancer

Therefore, glycolytic metabolic reprogramming is critical for the maintenance of CSCs and is associated with the progression of cancer. While the above reported studies show that CSCs mainly rely on glycolysis, several other studies showed that CSCs possess a preference for mitochondrial oxidative metabolism. in current cancer research. The targeting of CSC metabolism may provide new effective therapies to reduce the risk of recurrence and metastasis. In this review, we summarize the most significant discoveries regarding the metabolism of CSCs and highlight recent approaches in targeting CSC metabolism. glycolysis and OXPHOS intermediates (8, 9). To compensate for this inefficient metabolic PS 48 process for energy production per unit of glucose consumed, cancer cells uptake glucose and glutamate at a rate of more than about PS 48 200 times that of normal cells. In addition to glucose and glutamate as the core metabolic sources, increasing body of evidence suggests that various nutrients and metabolic pathways support the altered energy metabolism of cancer cells. Various metabolic fuel sources have been identified in cancer cells. These include acetate, lactate, fatty acids, serine, glycine, and branched chain amino acids. The metabolic alteration of cancer cells also has a beneficial effect on cancer survival and resisting cell death. The environmental conditions of cancer cells compared to those of normal cells is spatially and temporally heterogeneous and frequently sparse in levels of glucose, glutamine, and oxygen (10). The altered metabolic pathway of cancer cells enables cancer cells to survive in these metabolically stressful conditions found in the tumor microenvironment (such as low oxygen or nutrient levels) (11). It is known that the mitochondrial membrane permeabilization process, which is a mitochondrial apoptosis control mechanism, is inactivated in most cancer cells. These cytopathic mechanisms are known to be regulated by mitochondrial metabolism, especially hexokinase related with the glycolysis pathway; changes in cancer metabolism are therefore closely related to the anti-apoptotic property of cancer cells (12). In addition, changes in the metabolic pathway have been shown to be involved in gene expression by regulating the activity of epigenetic modification enzymes or by controlling the amount of substrate for epigenetic modification. Somatic mutations in IDH1 and IDH2 occur in up to 70% of glioma as well as in 20% of leukemia, and these IDH mutants acquire a neomorphic activity to convert -ketoglutarate to PS 48 (D)-2-hydroxyglutarate. The subsequent accumulation of 2-hydroxyglutarate results in epigenetic dysregulation via inhibition of -ketoglutarate-dependent histones and DNA demethylases, and suppress expression of many tumor suppressor gene (13C15). Lactate, a final product of glycolysis, acidifies the surrounding environment of cancer cells, inhibits the activation of NK and CTL cells, and plays an important role in the growth of cancer (16). Therefore, the reprogramed metabolic pathway of cancer plays an important role not only in tumor growth, but also in metastasis and chemo resistance through energy supply, survival under unfavorable environmental conditions, immune avoidance, and epigenetic modification (Fig. 2). Open in a separate window Fig. 2 Functions of metabolic alteration in cancer. Genetic mutations and growth signals in cancer cells and microenvironments within large tumors can dynamically alter metabolic pathways and modulate the regulation of metabolic pathways. This results in increased biosynthesis and abnormal bioenergy production, both of which promote cell proliferation, avoidance of immune-based destruction, metastasis, and survival. Furthermore, metabolic remodeling regulates tumor epigenetic alterations by regulating the activity of epigenetic modification enzymes because of the effect on gene expression in cancer. CANCER STEM CELL The heterogeneous nature of cell populations within a tumor has been recognized for several decades (3, 17). CSCs are defined as undifferentiated, slow-cycling cells that are able to form tumor tissue even from a single cell. In accordance with CSC model, heterogeneous and hierarchical cellular organization have been found in most tumors, with a group of undifferentiated cells at the apex of the hierarchy. CSCs typically exist as minority subpopulation within the entire tumor mass (0.001C0.1%) and are responsible for the generation of highly proliferative cancer cells forming the bulk of the tumor, even in the recurrence of cancer after therapy (17C19). After prospective identification of CSCs in leukemia for the first time in 1994 (20), CSCs have been continuously identified in various solid tumors including those of breast cancer (21, 22), brain tumors (23, 24), colorectal cancer (25), prostate cancer (26), lung cancer (27), PS 48 and melanoma (28). This new concept for intraclonal and functional heterogeneity of cancer cells can fundamentally change the way we diagnose and treat cancer. Accumulating evidence suggests that CSCs are responsible for metastasis, chemoresistance, and tumor relapse, and the elimination of CSCs may thus represent one of the most Abcc9 important challenges in treatment of cancer (3, 29, 30). CSCs possess various biological features of normal stem cells: the self-renewal ability; the expression of surface markers such as CD44, CD133, and aldehyde dehydrogenase;.