Abstract
Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention.
Highlights
In the early twentieth century Otto Warburg pioneered the work that investigated a metabolic phenomenon found in the majority of cancers, which is known as the “Warburg effect” [1,2,3,4].Warburg originally hypothesized that mitochondrial impairments that lead to irreversibly defective respiration of cells could cause the development of cancer [3,4]
More recent studies revealed that tumor protein p53 (TP53), a key tumor suppressor frequently mutated in cancers, inhibits glycolysis and increases mitochondrial respiration in cancer cells [10]
As the tumor microenvironment is in constant acidotic flux it is becoming evident that the effects of acidosis on tumor cell biology should be viewed in terms of acute versus chronic [14]
Summary
In the early twentieth century Otto Warburg pioneered the work that investigated a metabolic phenomenon found in the majority of cancers, which is known as the “Warburg effect” [1,2,3,4]. Warburg originally hypothesized that mitochondrial impairments that lead to irreversibly defective respiration of cells could cause the development of cancer [3,4]. This hypothesis was driven by the observation that cancer cells exhibited an increased glycolytic phenotype in comparison to untransformed cells even in the presence of oxygen [2,4]. Acidosis has recently been shown to suppress glycolysis and augment mitochondrial respiration in cancer cells [17,18] These observations illustrate the close and complex interaction between cancer cell metabolism and the tumor microenvironment (Figure 1). We will discuss how molecular signaling pathways associated with metabolic alterations in cancer cells as well as hypoxia and acidosis in the tumor microenvironment can be exploited to develop new approaches for cancer therapy and prevention
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