Role of Glutamine in Cancer: Therapeutic and Imaging Implications

  • Rajagopalan K
  • DeBerardinis R
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Abstract

Metabolic imaging has great clinical potential in cancer be-cause perturbations of metabolism are common hallmarks of malignant cellular transformation. Novel imaging strategies fo-cused on glutamine could provide a valuable complement to 18 F-FDG PET, because glutamine complements glucose in the metabolic platforms that support tumor growth at the cellular level. Furthermore, recent work has demonstrated that distinct aspects of glutamine metabolism are under the control of onco-genes and tumor suppressors. It is plausible that imaging glu-tamine metabolism could predict both the presence of specific transforming mutations in the tumor and the sensitivity to ther-apeutic agents designed to target glutamine use. Here, we review the essential aspects of glutamine metabolism in cancer cells and discuss opportunities for imaging in cancer patients. Molecular imaging in cancer has the potential to nonin-vasively illuminate biologic properties of a tumor in order to individualize treatment and improve the accuracy of prog-nosis counseling. Although conventional anatomic imaging offers crucial information about tumor size and location, it pro-vides little insight into the molecular characteristics of the tumor. Imaging key aspects of tumor metabolism adds an informative dimension to existing modalities because metabolism reports many clinically relevant aspects of tumor biology, including histologic grade, aggressiveness, and effects of the microenvir-onment. Warburg's seminal work on cancer metabolism in the 1920s, in particular his observation that some tumors have high rates of glucose uptake relative to normal tissue, paved the way for 18 F-FDG PET, now the most commonly used form of meta-bolic imaging. This technique capitalizes on the fact that enhanced glucose uptake is a common effect of many of the mutations that lead to malignant transformation (1). It is used in the clinic to pinpoint the location and distribution of tumor tissue, to determine therapeutic response, and to monitor for recurrence. Despite the success of 18 F-FDG PET in clinical oncology, the information it provides about tumor metabolism is actually quite limited. Because PET provides no information about the fate of the tracer after it enters the tumor, the user is unaware of subtleties of intracellular tumor glucose handling. Further-more, tumors do not consume glucose as their sole nutrient, and their use of other substrates is also exploited with PET (2,3). For example, analogs of methionine or tyrosine labeled with 18 F or 11 C have been used successfully, and their accu-mulation within tumors probably reflects increased surface expression of amino acid transporters in cancer cells (4). Among the other nutrients consumed by tumors, glutamine is the most versatile and probably the most rapidly consumed (5). Glutamine is the most abundant amino acid in plasma and occupies a unique niche in intermediary metabolism by pro-viding a major interorgan shuttle for both nitrogen and carbon (6). Here, we discuss the reasons why glutamine is a crucial nutrient for the maintenance and growth of tumors and why glutamine metabolism is an appealing target for new molecular imaging strategies in cancer.

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Authors

  • K. N. Rajagopalan

  • R. J. DeBerardinis

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