Abstract
A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has been crucial for the development of clinical imaging modalities, it has become now evident that in contrast to prior beliefs, mitochondria play a key role in tumorigenesis. Recent findings demonstrated that a full genetic disruption of the Warburg effect of aggressive cancers does not suppress but instead reduces tumor growth. Tumor growth then relies exclusively on functional mitochondria. Besides having fundamental bioenergetic functions, mitochondrial metabolism indeed provides appropriate building blocks for tumor anabolism, controls redox balance, and coordinates cell death. Hence, mitochondria represent promising targets for the development of novel anti-cancer agents. Here, after revisiting the long-standing Warburg effect from a historic and dynamic perspective, we review the role of mitochondria in cancer with particular attention to the cancer cell-intrinsic/extrinsic mechanisms through which mitochondria influence all steps of tumorigenesis, and briefly discuss the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.
Highlights
These past decades have been marked by a growing number of studies dealing with cancer and have led to a better overall understanding of this disease, in particular the fact that (1) cancer is not a disease that could only originate from genetic and epigenetic modifications [1,2,3,4], and (2) tumor cells do not exclusively depend on aerobic glycolysis to satisfy their bioenergetic and anabolic demands [5,6,7,8]
After revisiting the Warburg effect from a historic/dynamic perspective, and seeing whether or not it is dispensable for cancer, we will discuss the role of mitochondria in cancer by detailing the mechanisms through which they can impact on tumorigenicity, and we will briefly highlight the therapeutic opportunities of targeting mitochondrial metabolism as an anticancer strategy
In contrast to what Otto Warburg stated almost a century ago, the respiration of all cancer cells is not damaged and even more, it has become evident that mitochondrial metabolism does influence the functionality and aggressiveness of tumor cells
Summary
These past decades have been marked by a growing number of studies dealing with cancer and have led to a better overall understanding of this disease, in particular the fact that (1) cancer is not a disease that could only originate from genetic and epigenetic modifications [1,2,3,4], and (2) tumor cells do not exclusively depend on aerobic glycolysis to satisfy their bioenergetic and anabolic demands [5,6,7,8]. Mitochondria have been recognized as important mediators of cancer behavior in all steps of tumorigenesis [9,10] These long-standing misconceptions stem from the “self/non-self” discrimination—which suggests that the immune system can only recognize foreign entities [11,12]—and the so-called “Warburg effect”, referring to Otto Warburg, who described in 1927 an increased ability of tumors to uptake glucose [6,13,14,15]. One of the biggest challenging issues with targeting mitochondria as a relevant approach to efficiently eradicate tumor cells (or at least make them vulnerable after treatment exposure) is that all differentiated tissues are dependent on oxidative phosphorylation (OXPHOS) to survive [33,34,35] This would lead to the establishment of refined therapeutic strategies, whereby tumor cells would be selectively targeted, while non-tumor/normal differentiated cells would be spared from—or unresponsive to—the treatment-derived effects. After revisiting the Warburg effect from a historic/dynamic perspective, and seeing whether or not it is dispensable for cancer, we will discuss the role of mitochondria in cancer by detailing the mechanisms through which they can impact on tumorigenicity, and we will briefly highlight the therapeutic opportunities of targeting mitochondrial metabolism as an anticancer strategy
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