Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2018 Oct 1.
Published in final edited form as: Curr Opin Cell Biol. 2017 Jun 9;48:47–53. doi: 10.1016/j.ceb.2017.05.006

Metabolism Shapes the Tumor Microenvironment

Miguel Reina-Campos 1, Jorge Moscat 2, Maria Diaz-Meco 2,3
PMCID: PMC5650101  NIHMSID: NIHMS880804  PMID: 28605656

Abstract

Tumors are strongly influenced by the surrounding normal tissue, which forms a specialized niche termed the tumor microenvironment (TME). The TME is modeled by cancer cells for their own benefit through a complex array of interactions. The identification of new forms of communication within the TME, which are dependent on the tumor’s metabolic activity, has expanded our understanding of this heterocellular regulation and has revealed potential therapeutic targets. This review will summarize recent findings on the metabolic regulation of tumor cells by the TME. The concepts to be discussed include the existence of metabolic intratumoral heterogeneity, the contribution of cancer associated fibroblasts (CAFs) to tumor progression, and the regulation of tumor immunology by tumor-secreted metabolites.

Graphical abstract

graphic file with name nihms880804u1.jpg

Introduction

Tumor cells have an extraordinarily elevated requirement for nutrients to sustain their demanding anabolic needs and energy production rates. Thus, extracellular nutrients dictate the rate at which tumor cells proliferate. However, unlike normal cells, cancer cells have greater metabolic plasticity, which allows them to better adapt to lower or changing nutrient conditions [1] in ways that can, in turn, reshape the TME.

The TME (the non-cancerous components in close proximity to tumor tissue) has recently become the focus of intense research because of its clear role in the establishment and progression of cancer [2]. Thus, understanding the regulatory mechanisms that influence the TME could reveal novel avenues for cancer treatment. In solid tumors, the cancer microenvironment has two main components, cellular and non-cellular, whose proportion and composition vary depending on the tumor location and stage. The cellular components include fibroblasts, mesenchymal stem cells, adipocytes, pericytes, endothelial cells from the mesenchymal lineage, and tumor-infiltrating lymphocytes (TIL) and tumor-resident macrophages (TRM) from the lymphoid and myeloid lineages respectively [3]. Non-cellular components include mainly the extracellular matrix (ECM), which is composed of proteins, glycoproteins, and proteoglycans that act as a scaffold and maintain the tissue architecture [2].

In this review, we will summarize recent key discoveries that add to our understanding of tumor metabolism and how it affects the composition of the two main cellular constituents of the TME: fibroblasts and immune cells.

Tumor Metabolic Heterogeneity

One of the most striking characteristics of cancer cells is their ability to adapt to changing environmental conditions by utilizing a wide range of nutrients [4]. This is usually dictated by the supply of oxygen and nutrients delivered to the TME by the tumor vasculature [5], which is often not uniformly distributed across the tumor bulk. In this regard, a new study from Hensley et al. (2016) found that non-small cell lung cancers (NSCLC) exhibit heterogeneous intratumoral substrate utilization due to variations in tissue perfusion [6]••. By using intraoperative 13C-glucose infusion in NSCLC patients [7], the authors found that tumor regions closer to well-vascularized areas, like normal lung tissue, were able to utilize fuels other than glucose to sustain growth, while less perfused regions used glucose as the main carbon source [6]•• (Figure 1A). Importantly, the authors corroborated their model in two different NSCLC oncogenotypes, mutant EGFR and KRAS. Because oncogenes can modulate tumor metabolism [8,9], it still remains to be fully determined if other oncogenic drivers, other tissues of origin, or a more complex oncogenic composition in the tumor bulk [10,11] can also regionally influence substrate utilization. Supporting this concept, Kerr et al. (2016) recently showed that the acquisition of additional mutant KRasG12D alleles was linked to more advanced NSCLC in mice [12]••. Specifically, the authors showed that homozygous mutant KRasG12D cells had increased flux of glucose-derived carbon into the TCA cycle and glutathione biosynthesis, as compared to heterozygous counterparts. Ultimately, the gain in mutant allelic content allowed them to strengthen their glutathione-mediated detoxification [12]•• (Figure 1B). This study provided the first in vivo evidence of how mutagenic load directly affects tumor metabolism and promotes tumor progression. Given that additional mutant KRasG12D are acquired during tumor progression, there is a point in time where homozygous and heterozygous KRasG12D-containing cells with different metabolic activities coexist in the tumor bulk. This suggests that intratumoral mutational differences might, in addition to differential tissue perfusion, also contribute to a tumor’s metabolic heterogeneity [6]••.

Figure 1. Tumor Metabolic Heterogeneity.

Figure 1

Open in a new tab

(A) Differential tumor vasculature perfusion promotes different carbon source usage in NSCLC. Low perfused areas use mainly glucose while highly perfused areas use other sources. (B) Oncogenic KRasG12D mutation load dictates a metabolic switch to an increased TCA-supported metabolism and augmented glutathione biosynthesis that increases the ROS-detoxifying ability.

Reprogrammed CAFs and Stellate Cells Sustain Tumor Growth

CAFs make up a key stromal component that plays a fundamental role in tumor initiation, growth, invasion, and dissemination [13]. While normal fibroblasts (NF) undergo a reversible process of activation upon acute injury, known as the wound healing response [14], CAFs are chronically activated by environmental cues, mostly derived from the tumor’s activity. Activated CAFs (also termed myofibroblasts) differ phenotypically from activated NFs in several ways including lower contractility, increased survival potential, increased proliferation, and augmented ECM remodeling ability [14].

Metabolic reprogramming is an emerging hallmark of CAF activation. Although more commonly attributed to tumor cells [15], a growing body of evidence shows that CAFs also undergo radical changes in their metabolism during activation. For instance, CAFs use aerobic glycolysis to sustain their augmented proliferation activity instead of relying on oxidative phosphorylation (OXPHOS) [16]. Their metabolism is also characterized by an increase in autophagy [17–20]• as a mechanism to mobilize internal sources of nutrients to provide the TCA with metabolic intermediates. A new study from Sousa et al. 2016 has provided a novel link between a myofibroblast-like cell, pancreatic stellate cells (PSCs), and tumor behavior. They showed that activated PSCs, in the context of pancreatic ductal adenocarcinoma (PDAC), secrete autophagy-derived alanine to sustain tumor metabolism [21]••. They also found that PSC-supplied free alanine could supplant glucose-derived carbon in TCA-cycle metabolites while diverting glucose utilization towards the serine and glycine one-carbon (SGOC) pathway, which functions in the de-novo synthesis of nucleotides [22] (Figure 2). This newly described mechanism could contribute to the resistance to nutrient stress observed in PDAC tumors by relieving the dependence on glucose and other nutrients. Similarly, Yang et al. 2016 recently reported that, under glutamine scarcity such as that observed in core regions of ovarian tumors, tumor-engaged CAFs harnessed carbon from diverse sources to produce glutamine for tumor cells [23]. Importantly, branched-chain amino acids (BCAA) and aspartate were the major substrates contributing to the nitrogen supply for glutamine synthesis in ovarian CAFs. Ultimately, the authors showed that combining simultaneous tumor and stromal targeting of glutamine usage pathways could efficiently prevent tumor growth in a mouse model of ovarian cancer [23]•• (Figure 2). Both studies, Sousa et al. 2016 and Yang et al. 2016, reported new tumor-feeding strategies of activated PSC and CAFs, respectively, which add to our understanding of TME crosstalk and offer potentially actionable targets. However, it is worth noting that PSC and ovarian CAFS rely on different mechanisms to mobilize amino acids (Figure 2). The specific signaling cascades that dictate which mechanism is used by CAFs and PSC to meet the nutritional demands of the tumor are not known. Additionally, since other tumor-feeding strategies have been discovered, such as exosome-mediated delivery of amino acids and TCA intermediates [24], it is yet to be determined whether there are tumor-derived cues that engage CAFs to deliver a specific nutrient or input back to the tumor. In this regard, recent work by Tape et al 2016 reported that a particular oncogene in tumor epithelial cells was able to induce CAF-dependent signaling. Specifically, they showed that KRasG12D was able to affect additional signaling pathways in tumor cells by non-cell autonomously engaging local heterotypic fibroblasts through SMO/Gli activity to signal back to tumor cells through an IGF1R/AXL-Akt-dependent axis. In this way, distinct metabolic, proliferative, anti-apoptotic, and anchorage-independent growth phenotypes in tumor cells would only be activated when tumor cells are in the presence of CAFs [25] (Figure 2). Taken together, these results suggest that there are, indeed, specific signaling mechanisms in the tumor that can hijack stromal components to promote tumor growth. However, it is yet to be determined whether other oncogenes and tumor suppressors can exert similar reciprocity with fibroblasts or other components of the TME.

Figure 2.

Figure 2

Open in a new tab

Activated CAFs and PSCs maintain tumor growth by supplying free amino acids. Activated CAFs and PSCs mobilize free aminoacids by increasing glutamine biosynthesis and autophagy, respectively. Free aminoacids are fed to the tumor to sustain its metabolic demands of Non-Essential Amino Acids (NEAA), lipids and nucleotides. Also, oncogenic KRasG12D is able to extent cell-autonomous signaling by hijacking CAFs metabolism to obtain reciprocal signaling and support tumor growth, survival and metabolism.

Since tumors clearly benefit from engaging CAFs, the TME offers a potential target that could be exploited therapeutically [26]. Moreover, fibroblasts are genetically stable and more easily accessible by the vasculature than tumor core regions. However, finding actionable targets that allow simultaneous targeting of tumor epithelia and TME components remains a considerable challenge. One of the reasons for this is that some potential target proteins have opposite cell-dependent functions. That is, they behave as tumor promoters in one cellular compartment and tumor suppressors in another. For instance, metabolic reprogramming of prostate CAFs is mediated by the downregulation of the signaling adaptor Sqstm1 (p62), which impairs metabolic detoxification and increases IL-6 secretion through inhibition of the mTORC1/c-Myc axis, which, in turn, promotes inflammation and tumorigenesis [20]•. Conversely, in the prostate tumor epithelium, p62-dependent mTORC1 activation in response to amino acids promotes tumor proliferation [27] (Figure 3A). A similar cell-dependent role for p62 is also found in liver tumors. While p62 accumulation in hepatocytes, due to partial autophagy inhibition, inflammation, and oxidative stress, leads to non-mutational activation of mTORC1 that can initiate hepatocellular carcinoma (HCC) development [28]••, hepatic stellate cell (HSC)-specific KO of p62 potentiates liver fibrosis, inflammation, and HCC progression [29]••. Importantly, full-body KO of p62, in the context of a commonly used HCC inducer cocktail, diethylnitrosamine (DEN), and high-fat diet administration, enhanced HCC development [29]••, which suggests that the tumor-suppressor role of p62 in the stromal fibroblast compartment [20,23,29] outweighs its tumor-promoting effects in the tumor epithelium [27–31]. Mechanistic studies revealed that p62 loss in the HSC compartment reduced the anti-fibrotic and anti-inflammatory effects of vitamin D receptor (VDR) agonists, thus promoting HSC activation [29]•• (Figure 3B). These results are of immediate clinical relevance as there are several ongoing clinical trials testing vitamin D analogs as a way to block stellate cell activation [32]• (clinicaltrials.gov, NCT02603757). Given that p62 degradation is concomitant to HSC activation, highly inflamed and fibrotic tumors with reduced levels of p62 will probably not respond to the tumor-suppressor effects of vitamin D analogs [29]••. Thus, p62 levels in the stroma could be used clinically to determine potential responders. Taken together, these results illustrate how inhibition of an oncogenic target in tumor cells could potentially backfire by increasing stromal reactivity and inflammation.

Figure 3. Opposed and cell-dependent role of p62 in tumor epithelia vs stromal CAFs and HSCs.

Figure 3

Open in a new tab

(A) Amino acids (AAs) can activate mTORC1 in a p62-dependent manner in Prostate Cancer (PCa) epithelial cells, which promotes anabolism and cell growth and blocks autophagy. Autophagy inhibition leads to accumulation of p62 and further mTORC1 activation. In the CAF compartment, p62 is downregulated, which negatively affects mTORC1 and c-Myc’s ability to sustain adequate metabolic detoxification, which leads to elevation of ROS and paracrine and autocrine signaling by IL6 and TGFβ. (B) In the liver, accumulation of p62 leads to increased NRF2 and NFκB transcriptional activation that in turns mediates redox resistance and supports HCC development. Also, p62 promotes mTORC1 and c-Myc activity which sustains proliferation and metabolism conducive to HCC. In the stromal compartment, HSC activation leads to lower p62 levels, which prevent adequate VDR-RXR heterodimer formation and anti-fibrotic effects of Vitamin D.

Tumor-Derived Metabolic Intermediates Influence Immune Cell Function

While it has long been known that cancer cells can present cancer-specific peptide-MHC complexes to T cells [33], it was not known why naturally occurring immune responses failed to stop tumor growth [34]. Currently, evasion from immune surveillance is considered a hallmark of cancer that allows tumor cells to grow despite acquiring potential neo-antigens [35]. The mechanisms by which tumors dodge the immune system include display of immunomodulatory proteins on the tumor cell surface, secretion of soluble cytokines, and, as recently reported, changes in localized concentrations of tumor-derived metabolites [36].

Tumor-derived metabolites accumulate in the TME as a result of an accelerated and imbalanced metabolism. For example, hypoxic environments lead to high concentrations of extracellular tumor-produced adenosine, which exerts immunosuppressive actions by binding to adenosine receptors present in various immune cell types [37]. In addition, lactate, a by-product of glycolysis, is also frequently found at high concentrations in solid tumors as a result of hypoxic environments and extreme glycolytic rates [38,39]. Importantly, build-up of extracellular lactate has both cell-intrinsic effects on metabolism and non-tumor cell autonomous effects that drive tumorigenesis [40], including metabolic reprogramming [41], tumor inflammation [42], and angiogenesis [43,44]. The tumor-promoting actions of lactate include blocking the differentiation and activation of monocytes and T cells [45,46]. Recently, Colegio et al. 2014 demonstrated how lactate promotes vascular endothelial growth factor secretion and M2 macrophage polarization by an HIF1α-dependent mechanism [47]••. In turn, secretion of Arginase1 by M2-polarized macrophages signaled back to tumor cells and promoted growth [47] (Figure 4). In another study, Brand et al. 2016 described a link between secreted lactate and the immunosuppressive effect observed on tumor-infiltrated T and NK cells [48]••. In a proof-of-principle experiment, the authors reported that LDHA-low tumor cells had impaired growth compared to control cells when implanted into WT mice, while removing T and B cell populations (Rag2−/−) or T, B, and NK cell populations (Rag2 −/− γC −/−) from recipient mice had a permissive effect on tumor growth of LDHA-low cells. Because control cells grew equally well in mice regardless of their immunocompetent status, they concluded that neither NK nor T cells could block tumor growth unless the tumor cells were deficient in lactate production. Mechanistically, the authors found that lactate directly impaired nuclear factor of activated T- cells 1 (NFAT) activity, which resulted in reduced IFN-γ production (Figure 3). On the other hand, LDHA activity in the immune compartment has been recently linked to the maintenance of high levels of Acetyl-CoA to support histone acetylation and transcription of inflammatory cytokines such as IFN-γ [49]. Taken together, these results offer a new perspective on the functions of lactate in shaping the composition of the TME and offer new rationale for therapeutic strategies that target its extracellular secretion [39].

Figure 4. Tumor metabolic activity exerts immunosuppressive functions.

Figure 4

Open in a new tab

Low oxygen, nutritional competition and altered tumor metabolism induce an immunosuppressed TME. Accumulation of LDHA-derived lactate inhibits NK and T cell function, while polarizing macrophages into an M2 state that secretes Arginase 1 to the tumor. Also, low levels of arginine prevent memory-like T cell formation while low levels of glutamine induce an epigenetic rearrangement in tumor cells that lead to immune evasion.

Environmental cues [50], nutrient availability [51], and oxygen concentration [52] all act in concert to produce proper T cell effector responses. Because nutrients are typically scarce in the TME, any available nutrients can have a substantial impact on activation and differentiation of T cells, which rely mainly on augmented glucose, fatty acid, and amino acid consumption to sustain increased activity and proliferation [53,54]. In this regard, Geiger et al. 2016 reported that T cell activation and memory formation is dependent on intracellular arginine [55]••. They described how increased intracellular arginine concentrations could promote a shift from glycolysis to oxidative phosphorylation during T cell memory formation, thus endowing cells with a central memory-like phenotype that included increased survival and anti-tumor capacity [55] (Figure 4). This study offers a novel mechanism by which extracellular nutrients can directly influence T cell activation and differentiation to control tumor evolution. Although arginine provided through the diet was able to affect T cell function [55], it is not known whether tumor metabolism could likewise dictate extracellular arginine levels to affect T cell function. Additionally, new studies are focusing on how nutrient availability influences epigenetic regulation and tumor behavior that can ultimately lead to remodeling of TME composition [56–60]••. For example, the intratumoral shortage of glutamine has been shown to contribute to tumor metabolic heterogeneity and therapeutic responses by limiting epigenetic enzyme cofactors such as α-ketoglutarate, whose intracellular decrease leads to global H3K27 hypermethylation [61]•• (Figure 4). This regulatory mechanism could explain other reported examples of epigenetic regulation, including the Polycomb repressor complex 2 (PRC2)- and DNA methyltransferase 1 (DNMT1)-dependent silencing of inflammatory cytokines CXCL9 and CXCL10 by the tumor, with a direct impact on T cell helper 1 trafficking to the TME [56]•.

Tumor metabolic heterogeneity [6] could also play a role in differential intratumoral immune recruitment. Of note, the nature, density, functional orientation, and location of adaptive immune cells within the tumor (the “Immunoscore”) has proven to be highly predictive of patient outcome [62–64]• and has allowed for the discovery of mechanisms controlling anti-tumor T cell responses [65]•. The composition and degree of immune infiltration in different areas of a given tumor is now known to be a key aspect of tumor biology. Therefore, future studies should explore how different metabolic activities within one tumor influence immune cell distribution in the tumor and how pharmacologic intervention could switch the TME to a more permissive ecosystem that allows anti-tumor immune responses.

Future Perspectives

The naturally occurring reprogramming of the TME is likely to benefit a tumor’s growth. Therefore, it is a priority to evaluate newly identified actionable targets that can be used to disengage the cellular components of the TME and allow a permissive anti-tumor state. To this end, new studies on stroma reciprocity in oncogene-driven tumors have revealed the importance of using heterocellular systems for drug screening to account for additional non-tumor-dependent effects. Additionally, a growing interest in the metabolite-dependent epigenetic reprogramming of cellular components of the TME is likely to yield interesting insights into the “field cancerization” effect [66,67] that is currently poorly understood. Finally, the newly reported tumor metabolic heterogeneity in NSCLC will likely spur further research on how it might affect irregular distribution of TME cellular components, such as local CAF activation or immune infiltration.

Highlights.

  • Differential vasculature perfusion and oncogenic load promote tumor metabolic heterogeneity

  • Activated cancer associated fibroblasts and pancreatic stellate cells supply nutrients to foster tumor growth

  • Opposing cell-dependent functions in the tumor microenvironment promoted by different signaling routes

  • Tumor metabolic activity halts efficient immune responses

Acknowledgments

Our research is funded by grants from NIH (R01CA192642 to M.T.D.-M.; R01DK108743, R01CA172025 to J.M. and and 5P30CA030199 to M.T.D-M. and J.M.). M.R.C is supported by “La Caixa” fellowship for studies in North America. We thank Diantha LaVine for the artwork, and Maryellen Daston for editing the manuscript.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest

•• of outstanding interest

•• Of Outstanding Interest Papers:

  • 1.Pavlova NN, Thompson CB. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016;23:27–47. doi: 10.1016/j.cmet.2015.12.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196:395–406. doi: 10.1083/jcb.201102147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells - what challenges do they pose? Nat Rev Drug Discov. 2014;13:497–512. doi: 10.1038/nrd4253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. [DOI] [PubMed] [Google Scholar]
  • 5.Guillaumond F, Leca J, Olivares O, Lavaut MN, Vidal N, Berthezene P, Dusetti NJ, Loncle C, Calvo E, Turrini O, et al. Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc Natl Acad Sci U S A. 2013;110:3919–3924. doi: 10.1073/pnas.1219555110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6••.Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, Jiang L, Ko B, Skelton R, Loudat L, et al. Metabolic Heterogeneity in Human Lung Tumors. Cell. 2016;164:681–694. doi: 10.1016/j.cell.2015.12.034. The authors perform in-vivo tracing of glucose by intraoperative 13C-glucose infusion in NSCLC patients, which allows them to observe how differently perfused tumor areas use different carbon sources. The authors highlight the fact that poorly perfused areas use mainly glucose, while well perfused regions use other fuels such as fatty acids, aminoacids, ketones and lactate to produce Acetyl-CoA for the TCA. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Sellers K, Fox MP, Bousamra M, 2nd, Slone SP, Higashi RM, Miller DM, Wang Y, Yan J, Yuneva MO, Deshpande R, et al. Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J Clin Invest. 2015;125:687–698. doi: 10.1172/JCI72873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496:101–105. doi: 10.1038/nature12040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–765. doi: 10.1038/nature07823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JM, Papaemmanuil E, Brewer DS, Kallio HM, Hognas G, Annala M, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520:353–357. doi: 10.1038/nature14347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–892. doi: 10.1056/NEJMoa1113205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12••.Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature. 2016;531:110–113. doi: 10.1038/nature16967. Based on the observation that aggressive NSCLC tumors tend to have KRasG12D allelic enrichment in a p53 null background, the authors describe how gaining additional mutated copies of this oncogene promotes a metabolic switch that drives tumor progression. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–252. doi: 10.1038/nrc2618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–598. doi: 10.1038/nrc.2016.73. [DOI] [PubMed] [Google Scholar]
  • 15.Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308. doi: 10.1016/j.ccr.2012.02.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–1033. doi: 10.1126/science.1160809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP, Capozza F, et al. Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle. 2010;9:3515–3533. doi: 10.4161/cc.9.17.12928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Liu FL, Mo EP, Yang L, Du J, Wang HS, Zhang H, Kurihara H, Xu J, Cai SH. Autophagy is involved in TGF-beta1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment. Oncotarget. 2016;7:4122–4141. doi: 10.18632/oncotarget.6702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Wang Q, Xue L, Zhang X, Bu S, Zhu X, Lai D. Autophagy protects ovarian cancer-associated fibroblasts against oxidative stress. Cell Cycle. 2016;15:1376–1385. doi: 10.1080/15384101.2016.1170269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20•.Valencia T, Kim JY, Abu-Baker S, Moscat-Pardos J, Ahn CS, Reina-Campos M, Duran A, Castilla EA, Metallo CM, Diaz-Meco MT, et al. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell. 2014;26:121–135. doi: 10.1016/j.ccr.2014.05.004. Activated CAFs play an important role in tumor progression. In this study, the authors find that p62 downregulation is a hallmark of activated CAFs of the prostate. Loss of p62 induces a metabolic reprogramming by inhibition of mTORC1 and c-Myc that ultimately leads to IL6 and TGFβ secretion, further contributing to inflammation of the TME and promoting tumor progression. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21••.Sousa CM, Biancur DE, Wang X, Halbrook CJ, Sherman MH, Zhang L, Kremer D, Hwang RF, Witkiewicz AK, Ying H, et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature. 2016;536:479–483. doi: 10.1038/nature19084. PDAC is characterized by an extreme fibrotic response that is mostly driven by activated PSCs. Adding a new role for PSCs in PDAC, the authors describe how these stromal cells are able to mobilize free aminoacids from autophagic routes to supply nutrients to the tumor and maintain its metabolism. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Mehrmohamadi M, Liu X, Shestov AA, Locasale JW. Characterization of the usage of the serine metabolic network in human cancer. Cell Rep. 2014;9:1507–1519. doi: 10.1016/j.celrep.2014.10.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Yang L, Achreja A, Yeung TL, Mangala LS, Jiang D, Han C, Baddour J, Marini JC, Ni J, Nakahara R, et al. Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth. Cell Metab. 2016;24:685–700. doi: 10.1016/j.cmet.2016.10.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Zhao H, Yang L, Baddour J, Achreja A, Bernard V, Moss T, Marini JC, Tudawe T, Seviour EG, San Lucas FA, et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife. 2016;5:e10250. doi: 10.7554/eLife.10250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Tape CJ, Ling S, Dimitriadi M, McMahon KM, Worboys JD, Leong HS, Norrie IC, Miller CJ, Poulogiannis G, Lauffenburger DA, et al. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation. Cell. 2016;165:1818. doi: 10.1016/j.cell.2016.05.079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Hansen JM, Coleman RL, Sood AK. Targeting the tumour microenvironment in ovarian cancer. Eur J Cancer. 2016;56:131–143. doi: 10.1016/j.ejca.2015.12.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Linares JF, Duran A, Reina-Campos M, Aza-Blanc P, Campos A, Moscat J, Diaz-Meco MT. Amino Acid Activation of mTORC1 by a B1-Domain-Driven Kinase Complex Cascade. Cell Rep. 2015;12:1339–1352. doi: 10.1016/j.celrep.2015.07.045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28••.Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, Zhong Z, Subramaniam S, Raghunandan S, Duran A, et al. p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. Cancer Cell. 2016;29:935–948. doi: 10.1016/j.ccell.2016.04.006. Oxidative stress and inflammation in the liver are conducive of HCC. The authors of this study found that p62 accumulation in the hepatocytes, caused by inhibited autophagy in the context or mTORC1 activation or induced genetic overexpression, is able to induce NRF2 activation that counteracts the oxidative stress and promotes the emergence of HCC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29••.Duran A, Hernandez ED, Reina-Campos M, Castilla EA, Subramaniam S, Raghunandan S, Roberts LR, Kisseleva T, Karin M, Diaz-Meco MT, et al. p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer. Cancer Cell. 2016;30:595–609. doi: 10.1016/j.ccell.2016.09.004. HSC activation is a hallmark of the fibrotic response in the liver that causes inflammation and profound ECM remodeling. Vitamin D has been showed to attenuate the fibrotic response by repress stellate cell activation. The authors of this study found that p62 acts as a scaffold for the VDR-RXR heterodimer formation, that is essential for the anti-fibrotic functions of Vitamin D. During HSC activation p62 is lost, which impairs RXR-VDR heterodimer formation and makes HSC, and liver tumors, insensitive to the beneficial effects of Vitamin D. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137:1062–1075. doi: 10.1016/j.cell.2009.03.048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, Moscat J. The signaling adaptor P62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell. 2008;13:343–354. doi: 10.1016/j.ccr.2008.02.001. [DOI] [PubMed] [Google Scholar]
  • 32•.Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, Connor F, Van Dyke T, Kozlov S, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159:80–93. doi: 10.1016/j.cell.2014.08.007. Activated PSCs take part in the strong stromal response characteristic of PDAC. In this study, the authors reported how Vitamin D plays an anti-fibrotic role by blocking PSCs activation program. Combination of a Vitamin D analog, calcipotriol, is able to reduce markers of inflammation and fibrosis in the stromal compartment, and combined with gemcitabine, decrease tumor burden and increase overall survival in mice. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Boon T, Cerottini JC, Van den Eynde B, van der Bruggen P, Van Pel A. Tumor antigens recognized by T lymphocytes. Annu Rev Immunol. 1994;12:337–365. doi: 10.1146/annurev.iy.12.040194.002005. [DOI] [PubMed] [Google Scholar]
  • 34.Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. doi: 10.1016/j.immuni.2013.07.012. [DOI] [PubMed] [Google Scholar]
  • 35.Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74. doi: 10.1126/science.aaa4971. [DOI] [PubMed] [Google Scholar]
  • 36.Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HM, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):S185–198. doi: 10.1016/j.semcancer.2015.03.004. [DOI] [PubMed] [Google Scholar]
  • 37.Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, Huang X, Caldwell S, Liu K, Smith P, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A. 2006;103:13132–13137. doi: 10.1073/pnas.0605251103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Romero-Garcia S, Moreno-Altamirano MM, Prado-Garcia H, Sanchez-Garcia FJ. Lactate Contribution to the Tumor Microenvironment: Mechanisms, Effects on Immune Cells and Therapeutic Relevance. Front Immunol. 2016;7:52. doi: 10.3389/fimmu.2016.00052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest. 2013;123:3685–3692. doi: 10.1172/JCI69741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, Mueller-Klieser W. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000;60:916–921. [PubMed] [Google Scholar]
  • 41.Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, Lanciotti M, Serni S, Cirri P, Chiarugi P. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 2012;72:5130–5140. doi: 10.1158/0008-5472.CAN-12-1949. [DOI] [PubMed] [Google Scholar]
  • 42.Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D'Acquisto F, Bland EJ, Bombardieri M, Pitzalis C, Perretti M, et al. Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions. PLoS Biol. 2015;13:e1002202. doi: 10.1371/journal.pbio.1002202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011;71:2550–2560. doi: 10.1158/0008-5472.CAN-10-2828. [DOI] [PubMed] [Google Scholar]
  • 44.Sonveaux P, Copetti T, De Saedeleer CJ, Vegran F, Verrax J, Kennedy KM, Moon EJ, Dhup S, Danhier P, Frerart F, et al. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One. 2012;7:e33418. doi: 10.1371/journal.pone.0033418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Dietl K, Renner K, Dettmer K, Timischl B, Eberhart K, Dorn C, Hellerbrand C, Kastenberger M, Kunz-Schughart LA, Oefner PJ, et al. Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol. 2010;184:1200–1209. doi: 10.4049/jimmunol.0902584. [DOI] [PubMed] [Google Scholar]
  • 46.Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109:3812–3819. doi: 10.1182/blood-2006-07-035972. [DOI] [PubMed] [Google Scholar]
  • 47••.Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559–563. doi: 10.1038/nature13490. Macrophages surveil the TME and interact with its cellular components. The authors of this study describe how tumor-derived lactate is able to induce macrophage M2 polarization, that in turn, produces angiogenic factors (VEGF) and Arginase1 to promote tumor growth. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48••.Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, et al. LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. 2016;24:657–671. doi: 10.1016/j.cmet.2016.08.011. Tumors consume high amounts of glucose and generate high amounts of lactate by converting pyruvate to lactate by the LDHA. The authors of this study found that LDHA-derived lactic acid is responsible to blunt NK and T cell functions by impairing NFAT activation and IFN-γ response. [DOI] [PubMed] [Google Scholar]
  • 49.Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science. 2016;354:481–484. doi: 10.1126/science.aaf6284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Doedens AL, Rubinstein MP, Gross ET, Best JA, Craig DH, Baker MK, Cole DJ, Bui JD, Goldrath AW. Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance. Cancer Immunol Res. 2016;4:799–811. doi: 10.1158/2326-6066.CIR-15-0178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT, Velica P, You J, Chia GS, Sim J, Doedens A, et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature. 2016;540:236–241. doi: 10.1038/nature20165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, Eil RL, Hickman HD, Yu Z, Pan JH, et al. Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche. Cell. 2016;166:1117–1131. e1114. doi: 10.1016/j.cell.2016.07.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Buck MD, O’Sullivan D, Pearce EL. T cell metabolism drives immunity. J Exp Med. 2015;212:1345–1360. doi: 10.1084/jem.20151159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162:1229–1241. doi: 10.1016/j.cell.2015.08.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55••.Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, Kogadeeva M, Picotti P, Meissner F, Mann M, et al. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. Cell. 2016;167:829–842. e813. doi: 10.1016/j.cell.2016.09.031. By using high-resolution mass spectrometry, the authors found that intracellular concentration of arginine is a key determinant of T cell fate. While low arginine concentration promotes T cell activation, intracellular arginine elevation fosters acquisition of a T cell memory-like phenotype that promotes anti-tumor activity in a mouse model. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56•.Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015;527:249–253. doi: 10.1038/nature15520. The authors found an unexpected link between epigenetic reprogramming of the tumor epithelia and immune T cell infiltration. By studying human ovarian cancers, the authors described how PRC2/DNMT1-mediated silencing of two T cell recruiting chemokines, CXCL9 and CXCL10, is responsible for the lack of T cell recruitment to the tumor bulk. Additionally, the authors demonstrate that inhibition of the epigenetic machinery that leads to chemokine silencing removes the repression and enhances effector T cell responses. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Janke R, Dodson AE, Rine J. Metabolism and epigenetics. Annu Rev Cell Dev Biol. 2015;31:473–496. doi: 10.1146/annurev-cellbio-100814-125544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Lu C, Thompson CB. Metabolic regulation of epigenetics. Cell Metab. 2012;16:9–17. doi: 10.1016/j.cmet.2012.06.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Mentch SJ, Mehrmohamadi M, Huang L, Liu X, Gupta D, Mattocks D, Gomez Padilla P, Ables G, Bamman MM, Thalacker-Mercer AE, et al. Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism. Cell Metab. 2015;22:861–873. doi: 10.1016/j.cmet.2015.08.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.van der Knaap JA, Verrijzer CP. Undercover: gene control by metabolites and metabolic enzymes. Genes Dev. 2016;30:2345–2369. doi: 10.1101/gad.289140.116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61••.Pan M, Reid MA, Lowman XH, Kulkarni RP, Tran TQ, Liu X, Yang Y, Hernandez-Davies JE, Rosales KK, Li H, et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol. 2016;18:1090–1101. doi: 10.1038/ncb3410. Nutrients are scarce in the TME. The authors of this study found that regional glutamine deficiency in melanoma tumors bearing BRAF mutations promotes epigenetic changes as a result of a drastic reduction in intracellular a-ketoglutarate levels, which are needed as cofactor for histone demethylases, in turn, this promotes cancer cell dedifferentiation and resistance to BRAF inhibitor treatment. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62•.Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39:782–795. doi: 10.1016/j.immuni.2013.10.003. In a large-scale approach, the authors explore the spatio-temporal dynamics of different immune cell types infiltrating tumors and provide a snapshot of the immune landscape in cancer. The authors observed a strong correlation between the composition and extent of specific immune cell types and tumor progression and verify their findings in a model of orthotopic colorectal cancer. [DOI] [PubMed] [Google Scholar]
  • 63.Galon J, Fox BA, Bifulco CB, Masucci G, Rau T, Botti G, Marincola FM, Ciliberto G, Pages F, Ascierto PA, et al. Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J Transl Med. 2016;14:273. doi: 10.1186/s12967-016-1029-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Galon J, Pages F, Marincola FM, Angell HK, Thurin M, Lugli A, Zlobec I, Berger A, Bifulco C, Botti G, et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med. 2012;10:205. doi: 10.1186/1479-5876-10-205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65•.Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523:231–235. doi: 10.1038/nature14404. Some melanoma tumors respond better than other to immune therapy. By comparing T cell infiltrated vs non-T cell-infiltrated tumors, the authors discovered that tumor beta-catenin signaling promotes an immunosuppressive state that prevent T cell infiltration and resistance to anti-CTLA4/anti-PD-L1 monoclonal antibody therapy. [DOI] [PubMed] [Google Scholar]
  • 66.Vanharanta S, Massague J. Field cancerization: something new under the sun. Cell. 2012;149:1179–1181. doi: 10.1016/j.cell.2012.05.013. [DOI] [PubMed] [Google Scholar]
  • 67.Baba Y, Ishimoto T, Kurashige J, Iwatsuki M, Sakamoto Y, Yoshida N, Watanabe M, Baba H. Epigenetic field cancerization in gastrointestinal cancers. Cancer Lett. 2016;375:360–366. doi: 10.1016/j.canlet.2016.03.009. [DOI] [PubMed] [Google Scholar]

RESOURCES