Metabolic reprogramming: the emerging concept and associated therapeutic strategies

Abstract

Tumor tissue is composed of cancer cells and surrounding stromal cells with diverse genetic/epigenetic backgrounds, a situation known as intra-tumoral heterogeneity. Cancer cells are surrounded by a totally different microenvironment than that of normal cells; consequently, tumor cells must exhibit rapidly adaptive responses to hypoxia and hypo-nutrient conditions. This phenomenon of changes of tumor cellular bioenergetics, called “metabolic reprogramming”, has been recognized as one of 10 hallmarks of cancer. Metabolic reprogramming is required for both malignant transformation and tumor development, including invasion and metastasis. Although the Warburg effect has been widely accepted as a common feature of metabolic reprogramming, accumulating evidence has revealed that tumor cells depend on mitochondrial metabolism as well as aerobic glycolysis. Remarkably, cancer-associated fibroblasts in tumor stroma tend to activate both glycolysis and autophagy in contrast to neighboring cancer cells, which leads to a reverse Warburg effect. Heterogeneity of monocarboxylate transporter expression reflects cellular metabolic heterogeneity with respect to the production and uptake of lactate. In tumor tissue, metabolic heterogeneity induces metabolic symbiosis, which is responsible for adaptation to drastic changes in the nutrient microenvironment resulting from chemotherapy. In addition, metabolic heterogeneity is responsible for the failure to induce the same therapeutic effect against cancer cells as a whole. In particular, cancer stem cells exhibit several biological features responsible for resistance to conventional anti-tumor therapies. Consequently, cancer stem cells tend to form minimal residual disease after chemotherapy and exhibit metastatic potential with additional metabolic reprogramming. This type of altered metabolic reprogramming leads to adaptive/acquired resistance to anti-tumor therapy. Collectively, complex and dynamic metabolic reprogramming should be regarded as a reflection of the “robustness” of tumor cells against unfavorable conditions. This review focuses on the concept of metabolic reprogramming in heterogeneous tumor tissue, and further emphasizes the importance of developing novel therapeutic strategies based on drug repositioning.

Bioenergetic adaptations in chemo-resistant ovarian cancer cells

“…There is an emerging school of thought that most ovarian cancer cells may utilize either an increased glycolysis or OXPHOS and that such flexibility confers a higher level of 'cellular fitness' 19,26,41 . This concept has also been observed and defined in other studies 50 . Our work also demonstrated that the 2 chemoresistant ovarian cancer cell lines (C200 and PEO4) 51,52 exhibited a high metabolically active phenotype as compared to their respective sensitive counterparts (A2780 and PEO1).…”

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…The brain possesses unique metabolic characteristics with respect to glucose availability, such as metabolic coupling between astrocytes and neurons, commonly referred to as the "lactate shuttle." In this scenario, lactate secreted by astrocytes is taken up by neurons to fuel OXPHOS-dependent metabolism (2). Thus, as a consequence of the lactate shuttle, available glucose concentrations are variable and may be growth limiting for brain metastases.…”

“…This metabolic symbiosis may be controlled by the differential expression of distinct lactate transporters such as the monocarboxylate transporters, MCT1 and MCT4 (56). Hypoxic/ glycolytic cancer cells express high level of MCT4 that functions as a major lactate exporter, whereas oxygenated/aerobic cells express MCT1, which promotes lactate uptake (2).…”

“…In addition, metabolic reprogramming is a key determinant allowing cancer stem cells (CSC) to survive drastic changes in the tumor microenvironment and maintain their unique self-renewal abilities (2,58,59).…”

“…Cellular energetics or "oncometabolism" is now considered one of the defining hallmarks of cancer (1). Metabolic heterogeneity arises and is maintained through coupled metabolic interactions that occur between distinct tumor cell populations within the tumor, as well as between the tumor and the stroma (2).…”