Metabolic Interactions in the Tumor Microenvironment

The tumor microenvironment is characterized by deregulated metabolic properties. Intrinsic features (e.g., genetic programs in cancer cells) and extrinsic characteristics (e.g., oxygen tension, nutrient availability, pH) contribute to the deregulated metabolic profile of a tumor. Malignant cells adapt through symbiotic metabolic interactions with other tumor cells. These processes in tumors are repurposed pathways of normal heterocellular metabolic crosstalk. Nutrient competition in the tumor microenvironment impairs effective antitumor immunity. Tumors are dynamic pseudoorgans that contain numerous cell types interacting to create a unique physiology. Within this network, the malignant cells encounter many challenges and rewire their metabolic properties accordingly. Such changes can be experienced and executed autonomously or through interaction with other cells in the tumor. The focus of this review is on the remodeling of the tumor microenvironment that leads to pathophysiologic interactions that are influenced and shaped by metabolism. They include symbiotic nutrient sharing, nutrient competition, and the role of metabolites as signaling molecules. Examples of such processes abound in normal organismal physiology, and such heterocellular metabolic interactions are repurposed to support tumor metabolism and growth. The importance and ubiquity of these processes are just beginning to be realized, and insights into their role in tumor development and progression are being used to design new drug targets and cancer therapies. Tumors are dynamic pseudoorgans that contain numerous cell types interacting to create a unique physiology. Within this network, the malignant cells encounter many challenges and rewire their metabolic properties accordingly. Such changes can be experienced and executed autonomously or through interaction with other cells in the tumor. The focus of this review is on the remodeling of the tumor microenvironment that leads to pathophysiologic interactions that are influenced and shaped by metabolism. They include symbiotic nutrient sharing, nutrient competition, and the role of metabolites as signaling molecules. Examples of such processes abound in normal organismal physiology, and such heterocellular metabolic interactions are repurposed to support tumor metabolism and growth. The importance and ubiquity of these processes are just beginning to be realized, and insights into their role in tumor development and progression are being used to design new drug targets and cancer therapies. In normal organ physiology, parenchymal cells form the organ and define its function. These cells are supported by the connective tissue, which maintains the structural framework and integrates organ systems. Cells of the immune system function to protect against infection and to support tissue repair following injury. Solid tumors are highly disorganized versions of normal organs populated with numerous cell types including endothelial cells (e.g., blood vessels), stromal fibroblasts, immune cells, and malignant cancer cells [1Egeblad M. et al.Tumors as organs: complex tissues that interface with the entire organism.Dev. Cell. 2010; 18: 884-901Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar]. Transformation and growth of organ-resident parenchymal cells lead to the development of malignant subtypes within a tumor. Clonal diversity is achieved as transformed cells accumulate mutations. This leads to changes in signal transduction, the epigenome, and gene expression, which endow a spectrum of differentiation, metabolic, and proliferative states across the cancer cell populations in the tumor [2Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (17795) Google Scholar, 3Makohon-Moore A. 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Interactions among the intrinsic metabolic networks and the extrinsic affecters lead to a spectrum of cancer cells within a tumor that exhibit varying metabolic requirements and properties (Figure 1). The cadre of stromal, immune, and malignant cells creates a TME that imposes many challenges for the cancer cells: physical pressure, oxidative stress, nutrient deprivation and competition, hypoxia, and immune surveillance. For example, stromal fibroblasts, commonly referred to as cancer-associated fibroblasts (CAFs), can become activated and proliferate, release growth factors and cytokines, and deposit extracellular matrix proteins [11Moscat J. et al.p62 in cancer: signaling adaptor beyond autophagy.Cell. 2016; 167: 606-609Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 12Valencia T. et al.Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.Cancer Cell. 2014; 26: 121-135Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 13Kalluri R. The biology and function of fibroblasts in cancer.Nat. Rev. Cancer. 2016; 16: 582-598Crossref PubMed Scopus (90) Google Scholar]. Cytokines recruit immune cells, which secrete extracellular matrix remodeling factors. Together, these processes change the architecture of the organ creating a stiff fibrotic matrix, marked by increased interstitial pressure, which hinders the activity of the vascular system [14DuFort C.C. et al.Interstitial pressure in pancreatic ductal adenocarcinoma is dominated by a gel-fluid phase.Biophys. J. 2016; 110: 2106-2119Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 15Jain R.K. et al.The role of mechanical forces in tumor growth and therapy.Annu. Rev. Biomed. Eng. 2014; 16: 321-346Crossref PubMed Scopus (118) Google Scholar, 16DuFort C.C. et al.Mounting pressure in the microenvironment: fluids, solids, and cells in pancreatic ductal adenocarcinoma.Gastroenterology. 2016; 150: 1545-1557.e2Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. Deregulated proliferation and growth factor release further influence blood vessel development, which is characterized by leaky vessels that inefficiently deliver nutrients and remove waste products of cellular metabolism, such as lactate [17Jain R.K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.Science. 2005; 307: 58-62Crossref PubMed Scopus (3123) Google Scholar, 18Carmeliet P. Jain R.K. Molecular mechanisms and clinical applications of angiogenesis.Nature. 2011; 473: 298-307Crossref PubMed Scopus (1844) Google Scholar]. In addition to nutrients and waste, insufficient tissue coverage and abnormal characteristics of tumor vasculature limit gas exchange and create regions of hypoxia. The hypoxic response leads to enhanced glycolytic activity of the tumor and additional lactate deposition. The buildup of lactate acidifies the TME, which influences how the immune system recognizes and responds to the tumor [19Choi S.Y. et al.Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?.J. Pathol. 2013; 230: 350-355Crossref PubMed Scopus (64) Google Scholar, 20Brand A. et al.LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells.Cell Metab. 2016; 24: 657-671Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 21Colegio O.R. et al.Functional polarization of tumour-associated macrophages by tumour-derived lactic acid.Nature. 2014; 513: 559-563Crossref PubMed Scopus (309) Google Scholar]. Furthermore, nutrient limitation in the TME provides a context in which immune, stromal, and cancer cells must compete for nutrients to carry out biosynthesis, bioenergetic, and effector activities. Immune cells tend to be less adapted for nutrient competition, and this is a principle mechanism regulating antitumor immunity. Numerous additional mechanisms in the TME influence tumor immunity [22Gajewski T.F. et al.Innate and adaptive immune cells in the tumor microenvironment.Nat. Immunol. 2013; 14: 1014-1022Crossref PubMed Scopus (620) Google Scholar, 23Vonderheide R.H. Bayne L.J. Inflammatory networks and immune surveillance of pancreatic carcinoma.Curr. Opin. Immunol. 2013; 25: 200-205Crossref PubMed Scopus (49) Google Scholar, 24Gabrilovich D.I. et al.Coordinated regulation of myeloid cells by tumours.Nat. Rev. Immunol. 2012; 12: 253-268Crossref PubMed Scopus (1154) Google Scholar], including the activity of intracellular metabolic pathways in immune cells. These topics have been the subject of several recent reviews [25Johnson M.O. et al.Nutrients and the microenvironment to feed a T cell army.Semin. Immunol. 2016; 28: 505-513Crossref PubMed Scopus (0) Google Scholar, 26Langston P.K. et al.Metabolism supports macrophage activation.Front. 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Examples of such processes abound in normal organismal physiology, including the glucose–lactate shuttle in the brain [28Allaman I. et al.Astrocyte-neuron metabolic relationships: for better and for worse.Trends Neurosci. 2011; 34: 76-87Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar], a role for lactate as a signaling molecule in vasoconstriction [29Yamanishi S. et al.Extracellular lactate as a dynamic vasoactive signal in the rat retinal microvasculature.Am. J. Physiol. Heart. Circ. Physiol. 2006; 290: H925-H934Crossref PubMed Scopus (0) Google Scholar], tryptophan–kynurenine metabolism in the brain and immune system [30Schwarcz R. et al.Kynurenines in the mammalian brain: when physiology meets pathology.Nat. Rev. Neurosci. 2012; 13: 465-477Crossref PubMed Scopus (387) Google Scholar], and the glucose–alanine cycle between muscle and liver [31Felig P. The glucose-alanine cycle.Metabolism. 1973; 22: 179-207Abstract Full Text PDF PubMed Scopus (362) Google Scholar]. Understanding the role of these metabolic interactions in tumor development and progression has the potential to inform the development of new drug targets and cancer therapies [32Anastasiou D. Tumour microenvironment factors shaping the cancer metabolism landscape.Br. J. Cancer. 2017; 116: 277-286Crossref PubMed Scopus (1) Google Scholar, 33Murray P.J. Amino acid auxotrophy as a system of immunological control nodes.Nat. Immunol. 2016; 17: 132-139Crossref PubMed Scopus (23) Google Scholar]. Significant metabolic heterogeneity exists among the cells in a tumor [34Birsoy K. et al.Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides.Nature. 2014; 508: 108-112Crossref PubMed Scopus (181) Google Scholar, 35LeBleu V.S. et al.PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.Nat. 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To counteract these metabolic challenges, heterocellular metabolite cross-feeding pathways are established that support bioenergetics, biosynthesis, and the clearance/reuse of metabolic waste products. In a similar but opposing manner, the lack of degradation of a metabolite can also have protumor growth properties. For example, metabolite catabolism by protumorigenic cells can lead to a state of nutrient deficiency, and thus impaired activity of immune cells involved in tumor destruction. These processes have been described for many metabolites, proteins, and cellular cargo and are discussed in the following sections. Data supporting cooperative metabolic pathways that coordinate lactate and glucose metabolism among cells in a tumor have been reported in several types of cancer [9Hensley C.T. et al.Metabolic heterogeneity in human lung tumors.Cell. 2016; 164: 681-694Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 39Kennedy K.M. et al.Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer.PLoS One. 2013; 8: e75154Crossref PubMed Scopus (0) Google Scholar, 40Sotgia F. et al.Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms.Annu. Rev. Pathol. 2012; 7: 423-467Crossref PubMed Scopus (136) Google Scholar, 41Draoui N. Feron O. Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments.Dis. Model. Mech. 2011; 4: 727-732Crossref PubMed Scopus (101) Google Scholar, 42Doherty J.R. Cleveland J.L. Targeting lactate metabolism for cancer therapeutics.J. Clin. Invest. 2013; 123: 3685-3692Crossref PubMed Scopus (212) Google Scholar]. For example, cancer cells in hypoxic tumor regions metabolize glucose through anaerobic glycolysis. This process is supported by well-oxygenated cancer cells, which consume lactate discarded by the hypoxic cancer cells to fuel mitochondrial metabolism [43Sonveaux P. et al.Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.J. Clin. Invest. 2008; 118: 3930-3942PubMed Google Scholar]. An important consideration for lactate sharing concerns the expression of appropriate intake/release transporters. Lactate is released from cells via monocarboxylate transporter 4 (MCT4), whose expression is increased in hypoxic tumor regions. By contrast, expression of the lactate importer MCT1 is increased in cancer cells in normoxic regions of tumors [43Sonveaux P. et al.Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.J. Clin. Invest. 2008; 118: 3930-3942PubMed Google Scholar, 44Guillaumond F. et al.Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 3919-3924Crossref PubMed Scopus (113) Google Scholar]. These results provide a rationale for the existence of this pathway (Figure 2A). To study the exchange of lactate among cancer cells more precisely, cell-based pancreatic cancer models were used to illustrate that hypoxic cancer cells released lactate through MCT4, and that those grown in normoxia utilized MCT1 to directly import and metabolize lactate [44Guillaumond F. et al.Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 3919-3924Crossref PubMed Scopus (113) Google Scholar] (Figure 2A). Similarly, acute hypoxia induced by pharmacological inhibition of angiogenesis drove pancreatic neuroendocrine cancer cells to reorganize into symbiotic networks that share glucose-derived carbon. In other words, glycolytic hypoxic cancer cells produced lactate, and this lactate was used by cancer cells in proximity to blood vessels, and thus oxygen [45Allen E. et al.Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling.Cell Rep. 2016; 15: 1144-1160Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. Similar results were also observed following antiangiogenic therapy in a breast cancer model [46Pisarsky L. et al.Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy.Cell Rep. 2016; 15: 1161-1174Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. In the studies described, this symbiotic intratumoral metabolism pathway is reported in pancreatic neuroendocrine cancer; pancreatic ductal adenocarcinoma; and lung, colon, and breast cancers, illustrating that it may represent a general phenomenon utilized across many cancer types (Figure 2A). Perhaps most importantly, co-targeting this pathway with antiangiogenesis agents and mechanistic target of rapamycin (mTOR) inhibitors revealed new, unique vulnerabilities in cancer metabolism, which occurred in part by activating glucose uptake in normoxic cancer cells [45Allen E. et al.Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling.Cell Rep. 2016; 15: 1144-1160Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. This model of symbiotic metabolism is reminiscent of the glucose–lactate shuttle observed in the brain, in which glucose-derived lactate derived from astrocytes is shuttled to neurons [28Allaman I. et al.Astrocyte-neuron metabolic relationships: for better and for worse.Trends Neurosci. 2011; 34: 76-87Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar]. The precise function of this pathway remains contentious and may serve several functions [47Dienel G.A. Brain lactate metabolism: the discoveries and the controversies.J. Cereb. Blood Flow Metab. 2012; 32: 1107-1138Crossref PubMed Scopus (163) Google Scholar]. Similarly, the wiring and function of this symbiotic metabolic pathway amongst cells in a tumor remain to be fully elucidated. It is not clear why well-oxygenated cancer cells with ready access to the blood stream utilize lactate in preference to glucose. This could potentially be explained by the profile and magnitude of glucose and lactate transporter expression, which are regulated by hypoxia. Further, the precise role(s) of lactate remain(s) to be determined (Figure 2B). It is suggested that lactate in this context is used for bioenergetics [43Sonveaux P. et al.Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.J. Clin. Invest. 2008; 118: 3930-3942PubMed Google Scholar], but lactate has myriad functions. In the neuron–astrocyte model, lactate–glucose shuttling is thought to balance other fluxes, like recycling of the neurotransmitter glutamate. Lactate uptake also directly affects the redox state as oxidative metabolism by lactate dehydrogenase results in NAD+ consumption and NADH production [48Kasparov S. Are astrocytes the pressure-reservoirs of lactate in the brain?.Cell Metab. 2016; 23: 1-2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Finally, lactate can act directly as a signaling metabolite to affect gene expression programs [20Brand A. et al.LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells.Cell Metab. 2016; 24: 657-671Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 49De Saedeleer C.J. et al.Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.PLoS One. 2012; 7: e46571Crossref PubMed Scopus (0) Google Scholar, 50Lee D.C. et al.A lactate-induced response to hypoxia.Cell. 2015; 161: 595-609Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 51Ruan G.X. Kazlauskas A. Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis.J. Biol. 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Concurrently, glycolytic activity is repressed in prostate cancer cells, and these cells begin to metabolize CAF-derived lactate. While oxygen availability does not regulate this pathway, it is similarly mediated by stabilized hypoxia-inducible factor 1α (HIF-1α) in the CAFs, via reactive oxygen species. Consistent with these studies, transforming growth factor-β and platelet-derived growth factor signaling in colon CAFs leads to the activation of aerobic glycolysis, which is also mediated by HIF-1α [54Zhang D. et al.Metabolic reprogramming of cancer-associated fibroblasts by IDH3alpha downregulation.Cell Rep. 2015; 10: 1335-1348Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. In this study, decreased intracellular alpha-ketoglutarate levels stabilized HIF-1α by preventing the prolyl hydroxylase 1-mediated degradation of HIF-1α. The phenomenon, whereby CAFs take in glucose and release lactate to cancer cells, has been coined the ‘reverse Warburg effect’ [40Sotgia F. et al.Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms.Annu. Rev. Pathol. 2012; 7: 423-467Crossref PubMed Scopus (136) Google Scholar, 55Pavlides S. et al.The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma.ABBV Cell Cycle. 2009; 8: 3984-4001Crossref PubMed Google Scholar]. However, this description does not reflect all CAF–cancer interactions, as numerous reports with opposing results exist. For example, breast and colon cancer cells consume glucose and release lactate to surrounding fibroblasts and mesenchymal stem cells [56Rattigan Y.I. et al.Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment.Exp. 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Similarly, pancreatic and ovarian CAFs have low glycolytic activity [58Sousa C.M. et al.Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.Nature. 2016; 536: 479-483Crossref PubMed Scopus (78) Google Scholar, 59Yang L. et al.Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth.Cell Metab. 2016; 24: 685-700Abstract Full Text Full Text PDF PubMed Google Scholar] and consume lactate [59Yang L. et al.Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth.Cell Metab. 2016; 24: 685-700Abstract Full Text Full Text PDF PubMed Google Scholar]. The observed discrepancies likely reflect dominant effects by the cell/tissue of origin on microenvironmental interactions. Glucose availability in the TME is inversely proportional to local utilization, and this access has a strong impact on the activity of antitumor effector T cells [60Chang C.H. et al.Metabolic competition in the tumor microenvironment is a driver of cancer progression.Cell. 2015; 162: 1229-1241Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 61Ho P.C. et al.Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses.Cell. 2015; 162: 1217-1228Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar]. For example, glucose consumption by cancer cells in melanoma mouse models limited glucose available to T cells, thereby dampening their effector activity [61Ho P.C. et al.Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses.Cell. 2015; 162: 1217-1228Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar] (Figure 3). This reduction occurred through a drop in the glycolytic intermediate phosphoenol pyruvate, which limited T cell receptor-mediated calcium signaling. Similarly, glucose deprivation inhibited T cell responses in a sarcoma model. T cell responses were restored by blocking glucose uptake in cancer cells, because more glucose was then available for the tumor infiltrating T cells [60Chang C.H. et al.Metabolic competition in the tumor microenvironment is a driver of cancer progression.Cell. 2015; 162: 1229-1241Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar]. Pancreatic CAFs [presumed to arise from activated pancreatic stellate cells (PSCs)] excrete the amino acid alanine in response to interaction with pancreatic cancer cells [58Sousa C.M. et al.Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.Nature. 2016; 536: 479-483Crossref PubMed Scopus (78) Google Scholar] (Figure 4). This alanine is captured by the pancreatic cancer cells and used to fuel macromolecular biosynthesis. Of note, alanine-derived carbon can outcompete glucose- and glutamine-derived carbon to fuel metabolism [58Sousa C.M. et al.Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.Nature. 2016; 536: 479-483Crossref PubMed Scopus (78) Google Scholar], two important biosynthetic substrates that are limited in the nutrient austere pancreatic TME [62Kamphorst J.J. et al.Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein.Cancer Res. 2015; 75: 544-553Crossref PubMed Google Scholar]. Furthermore, alanine secretion from PSCs requires the induction of autophagy, which is stimulated by cancer cells. In addition, genetic inhibition of autophagy in the PSCs blunts pancreatic tumor growth. Collectively, these results reveal a pathway of metabolic crosstalk between PSCs and cancer cells, where pancreatic cancer cells send signals to activate autophagy in PSCs, which stimulates access to alanine in the pancreatic TME to support tumor growth. Future studies will be required to determine how nutrients are obtained by PSCs, which also exist in the nutrient austere pancreatic TME. Utilization of metabolic waste products is likely an important contributor, as seen in the ovarian cancer–stroma crosstalk models described in the following section [59Yang L. et al.Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth.Cell Metab. 2016; 24: 685-700Abstract Full Text Full Text PDF PubMed Google Scholar, 63Salimian Rizi B. et al.Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells.Cancer Res. 2015; 75: 456-471Crossref PubMed Scopus (14) Google Scholar]. 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