TY - JOUR
T1 - The tumor metabolic microenvironment
T2 - Lessons from lactate
AU - García-Canaveras, Juan C.
AU - Chen, Li
AU - Rabinowitz, Joshua D.
N1 - Funding Information:
We thank members of the Rabinowitz laboratory for comments and suggestions. This work was supported by funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 751423 (to J.C. García-Cañaveras), the Rutgers Cancer Institute of New Jersey (P30CA072720 to J.D. Rabinowitz), and the US National Institutes of Health (R01CA163591 to J.D. Rabinowitz). Research supported by a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (Grant Number: SU2C-AACR-DT20-16 to J.D. Rabinowitz). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C.
Funding Information:
We thank members of the Rabinowitz laboratory for comments and suggestions. This work was supported by funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 751423 (to J.C. García-Ca~naveras), the Rutgers Cancer Institute of NewJersey (P30CA072720 to J.D. Rabinowitz), and the US National Institutes ofHealth (R01CA163591 to J.D. Rabinowitz). Research supported by a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (Grant Number: SU2C-AACR-DT20-16 to J.D.Rabinowitz). StandUp ToCancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - The extracellular milieu of tumors is generally assumed to be immunosuppressive due in part to metabolic factors. Here, we review methods for probing the tumor metabolic microenvironment. In parallel, we consider the resulting available evidence, with a focus on lactate, which is the most strongly increased metabolite in bulk tumors. Limited microenvironment concentration measurements suggest depletion of glucose and modest accumulation of lactate (less than 2-fold). Isotope tracer measurements show rapid lactate exchange between the tumor and circulation. Such exchange is catalyzed by MCT transporters, which cotransport lactate and protons (H+). Rapid lactate exchange seems at odds with tumor lactate accumulation. We propose a potential resolution to this paradox. Because of the high pH of tumor cells relative to the microenvironment, H+-coupled transport by MCTs tends to drive lactate from the interstitium into tumor cells. Accordingly, lactate may accumulate preferentially in tumor cells, not the microenvironment. Thus, although they are likely subject to other immunosuppressive metabolic factors, tumor immune cells may not experience a high lactate environment. The lack of clarity regarding microenvironmental lactate highlights the general need for careful metabolite measurements in the tumor extracellular milieu.
AB - The extracellular milieu of tumors is generally assumed to be immunosuppressive due in part to metabolic factors. Here, we review methods for probing the tumor metabolic microenvironment. In parallel, we consider the resulting available evidence, with a focus on lactate, which is the most strongly increased metabolite in bulk tumors. Limited microenvironment concentration measurements suggest depletion of glucose and modest accumulation of lactate (less than 2-fold). Isotope tracer measurements show rapid lactate exchange between the tumor and circulation. Such exchange is catalyzed by MCT transporters, which cotransport lactate and protons (H+). Rapid lactate exchange seems at odds with tumor lactate accumulation. We propose a potential resolution to this paradox. Because of the high pH of tumor cells relative to the microenvironment, H+-coupled transport by MCTs tends to drive lactate from the interstitium into tumor cells. Accordingly, lactate may accumulate preferentially in tumor cells, not the microenvironment. Thus, although they are likely subject to other immunosuppressive metabolic factors, tumor immune cells may not experience a high lactate environment. The lack of clarity regarding microenvironmental lactate highlights the general need for careful metabolite measurements in the tumor extracellular milieu.
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U2 - 10.1158/0008-5472.CAN-18-3726
DO - 10.1158/0008-5472.CAN-18-3726
M3 - Review article
C2 - 31171526
AN - SCOPUS:85068851716
SN - 0008-5472
VL - 79
SP - 3155
EP - 3162
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -