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• W2912300441 abstract "The metabolic reprogramming associated with malignant transformation has led to a growing appreciation of the nutrients required to support anabolic cell growth. Less well studied is how cancer cells satisfy those demands in vivo, where they are dispersed within a complex microenvironment. Tumor-associated stromal components can support tumor growth by providing nutrients that supplement those provided by the local vasculature. These non-malignant stromal cells are phenotypically similar to those that accumulate during wound healing. Owing to their immediate proximity, stromal cells are inevitably affected by the metabolic activity of their cancerous neighbors. Until recently, a role for tumor cell metabolism in influencing the cell fate decisions of neighboring stromal cells has been underappreciated. Here, we propose that metabolites consumed and released by tumor cells act as paracrine factors that regulate the non-malignant cellular composition of a developing tumor by driving stromal cells toward a regenerative response that supports tumor growth. The metabolic reprogramming associated with malignant transformation has led to a growing appreciation of the nutrients required to support anabolic cell growth. Less well studied is how cancer cells satisfy those demands in vivo, where they are dispersed within a complex microenvironment. Tumor-associated stromal components can support tumor growth by providing nutrients that supplement those provided by the local vasculature. These non-malignant stromal cells are phenotypically similar to those that accumulate during wound healing. Owing to their immediate proximity, stromal cells are inevitably affected by the metabolic activity of their cancerous neighbors. Until recently, a role for tumor cell metabolism in influencing the cell fate decisions of neighboring stromal cells has been underappreciated. Here, we propose that metabolites consumed and released by tumor cells act as paracrine factors that regulate the non-malignant cellular composition of a developing tumor by driving stromal cells toward a regenerative response that supports tumor growth. Organs contain four major cell types: parenchymal cells performing the primary organ-specific function, mesenchymal cells providing extracellular matrix (ECM) for mechanical support, immune cells surveying organ integrity, and vascular cells controlling oxygen and nutrient supply. Delegating supportive functions to accessory cells enables parenchymal cells to optimize their primary function (Okabe and Medzhitov, 2016Okabe Y. Medzhitov R. Tissue biology perspective on macrophages.Nat. Immunol. 2016; 17: 9-17Crossref PubMed Scopus (138) Google Scholar). Nevertheless, a proper ratio of parenchymal and supportive cell types is essential to achieve optimal organ performance (Adler et al., 2018Adler M. Mayo A. Zhou X. Franklin R.A. Jacox J.B. Medzhitov R. Alon U. Endocytosis as a stabilizing mechanism for tissue homeostasis.Proc. Natl. Acad. Sci. USA. 2018; 115: E1926-E1935Crossref PubMed Scopus (1) Google Scholar, Raff, 1996Raff M.C. Size control: the regulation minireview of cell numbers in animal development.Cell. 1996; 86: 173-175Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Tumors are derived from organ-specific parenchymal cells that acquire oncogenic mutations (Hanahan and Weinberg, 2000Hanahan D. Weinberg R.A. The hallmarks of cancer.Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (18098) Google Scholar). The resulting cellular transformation and cell growth cause disruption of normal tissue architecture, which can compromise normal organ function (Egeblad et al., 2010Egeblad M. Nakasone E.S. Werb Z. Tumors as organs: complex tissues that interface with the entire organism.Dev. Cell. 2010; 18: 884-901Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar). While the progressive accumulation of cancer cells disrupts the normal organization of the adjacent stroma, tumor growth is nevertheless dependent on stromal support (Hanahan and Coussens, 2012Hanahan D. Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment.Cancer Cell. 2012; 21: 309-322Abstract Full Text Full Text PDF PubMed Scopus (1373) Google Scholar). This was first appreciated nearly 30 years ago, when several groups demonstrated that co-injection of cancer-associated fibroblasts (CAFs) with cancer cells enhanced the growth of xenograft tumors (Camps et al., 1990Camps J.L. Chang S.M. Hsu T.C. Freeman M.R. Hong S.J. Zhau H.E. von Eschenbach A.C. Chung L.W. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo.Proc. Natl. 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Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium.Cancer Res. 1999; : 5002-5011PubMed Google Scholar), suggesting that stromal cells could enhance malignant transformation. Of note, fibroblasts isolated from non-malignant tissues were not able to enhance tumor growth, suggesting that the capacity of stromal cells to facilitate tumorigenesis is acquired during tumor development. In some cancers such as gastric, mammary, or pancreatic tumors, stromal cells may account for up to 90% of cells within a tumor mass (Casazza et al., 2014Casazza A. Di Conza G. Wenes M. Finisguerra V. Deschoemaeker S. Mazzone M. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment.Oncogene. 2014; 33: 1743-1754Crossref PubMed Scopus (80) Google Scholar, Dvorak, 1986Dvorak H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.N. Engl. J. Med. 1986; 315: 1650-1659Crossref PubMed Google Scholar). How alterations in stromal composition and function support tumor growth is now the subject of intense study. For example, both mesenchymal cells themselves and the matrix proteins they produce provide an additional nutrient source in poorly vascularized regions where nutrient delivery is compromised (Commisso et al., 2013Commisso C. Davidson S.M. Soydaner-Azeloglu R.G. Parker S.J. Kamphorst J.J. Hackett S. Grabocka E. Nofal M. Drebin J.A. Thompson C.B. et al.Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.Nature. 2013; 497: 633-637Crossref PubMed Scopus (471) Google Scholar, Loo et al., 2015Loo J.M. Scherl A. Nguyen A. Man F.Y. Weinberg E. Zeng Z. Saltz L. Paty P.B. Tavazoie S.F. Extracellular metabolic energetics can promote cancer progression.Cell. 2015; 160: 393-406Abstract Full Text Full Text PDF PubMed Google Scholar, Olivares et al., 2017Olivares O. Mayers J.R. Gouirand V. Torrence M.E. Gicquel T. Borge L. Lac S. Roques J. Lavaut M.-N. 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Cancer. 1970; 24: 447-453Crossref PubMed Google Scholar), the immune cells found within tumors are primarily subtypes that suppress anti-tumor immunity, and accordingly, their presence is associated with poor prognosis in multiple malignancies (Leek et al., 1996Leek R.D. Lewis C.E. Whitehouse R. Greenall M. Clarke J. Harris A.L. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma.Cancer Res. 1996; 56: 4625-4629PubMed Google Scholar, Steidl et al., 2010Steidl C. Lee T. Shah S.P. Farinha P. Han G. Nayar T. Delaney A. Jones S.J. Iqbal J. Weisenburger D.D. et al.Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma.N. Engl. J. Med. 2010; 362: 875-885Crossref PubMed Scopus (728) Google Scholar, Wolf et al., 2005Wolf D. Wolf A.M. Rumpold H. Fiegl H. Zeimet A.G. Muller-Holzner E. Deibl M. Gastl G. Gunsilius E. Marth C. The expression of the regulatory t cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer.Clin. Cancer Res. 2005; 11: 8326-8331Crossref PubMed Scopus (0) Google Scholar) (Figure 1). While the recruitment of stromal cells to tumors, largely by chemotactic cues, has been studied (Balkwill, 2004Balkwill F. Cancer and the chemokine network.Nat. Rev. Cancer. 2004; 4: 540-550Crossref PubMed Google Scholar), how tumor cells directly instruct microenvironment-resident stromal cells to facilitate tumor growth is not fully understood. Of note, the environment of a tumor is reminiscent of a healing wound, where a variety of distinct cell types, including fibroblasts as well as immune cells, play a coordinated role in tissue regeneration (Dvorak, 2015Dvorak H.F. Tumors: wounds that do not heal-redux.Cancer Immunol. Res. 2015; 3: 1-11Crossref PubMed Google Scholar, Hagemann et al., 2008Hagemann T. Lawrence T. McNeish I. Charles K.A. Kulbe H. Thompson R.G. Robinson S.C. Balkwill F.R. “Re-educating” tumor-associated macrophages by targeting NF-kappaB.J. Exp. Med. 2008; 205: 1261-1268Crossref PubMed Scopus (488) Google Scholar) (Figures 1 and 2). Mimicking a regenerative environment may therefore be a mechanism by which tumor cells can redirect surrounding stromal cells to enhance tumor growth. We have previously proposed the metabolic interaction of cancer cells with the tumor microenvironment as a hallmark of cancer metabolism (Pavlova and Thompson, 2016Pavlova N.N. Thompson C.B. The emerging hallmarks of cancer metabolism.Cell Metab. 2016; 23: 27-47Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar). Here, we consider whether cancer cell metabolism can be sufficient to induce and maintain the stromal cell fate changes required to establish a continuous regenerative phenotype. While extracellular nutrients provide building blocks for cell growth, the resulting waste products serve as ideal paracrine factors to instruct cell fate decisions in surrounding cells. Accumulation or depletion of metabolites within the extracellular environment can exert direct paracrine effects by activating signal transduction cascades in neighboring stromal cells, as seen in both immune cells (Oh et al., 2010Oh D.Y. Talukdar S. Bae E.J. Imamura T. Morinaga H. Fan W. Li P. Lu W.J. Watkins S.M. Olefsky J.M. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.Cell. 2010; 142: 687-698Abstract Full Text Full Text PDF PubMed Scopus (1162) Google Scholar, Suganami et al., 2005Suganami T. Nishida J. Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2062-2068Crossref PubMed Scopus (652) Google Scholar) and endothelial cells (Ignarro et al., 1988Ignarro L.J. Byrns R.E. Buga G.M. Wood K.S. Chaudhuri G. Pharmacological evidence that endothelium-derived relaxing factor is nitric oxide: use of pyrogallol and superoxide dismutase to study endothelium-dependent and nitric oxide-elicited vascular smooth muscle relaxation.J. Pharmacol. Exp. Ther. 1988; 244: 181-189PubMed Google Scholar, Moncada et al., 1976Moncada S. Gryglewski R. Bunting S. Vane J.R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation.Nature. 1976; 263: 663-665Crossref PubMed Google Scholar). In addition, tumor-cell-driven changes in nutrient availability can activate nutrient-sensitive signaling pathways that alter the phenotypic state of stromal cells, at least in part through influencing chromatin organization and gene expression (Wellen et al., 2009Wellen K.E. Hatzivassiliou G. Sachdeva U.M. Bui T.V. Cross J.R. Thompson C.B. ATP-citrate lyase links cellular metabolism to histone acetylation.Science. 2009; 324: 1076-1080Crossref PubMed Scopus (871) Google Scholar). In this review, we will consider how metabolic alterations in the tumor microenvironment resulting from the metabolic activity of cancer cells can promote stromal cell evolution to support tumor development and progression. The concept that tumors co-opt the normal wound healing response is intriguing given Virchow’s hypotheses on cancer and irritation more than 150 years ago (reviewed in Balkwill and Mantovani, 2001Balkwill F. Mantovani A. Inflammation and cancer: back to Virchow?.Lancet. 2001; 357: 539-545Abstract Full Text Full Text PDF PubMed Scopus (4401) Google Scholar), which led Dvorak to coin his famous description of tumors as “wounds that do not heal” (Dvorak, 1986Dvorak H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.N. Engl. J. Med. 1986; 315: 1650-1659Crossref PubMed Google Scholar). Wound healing has four phases: hemostasis, inflammation, tissue formation, and tissue remodeling (Singer and Clark, 1999Singer A.J. Clark R.A. Cutaneous wound healing.N. Engl. J. Med. 1999; 341: 738-746Crossref PubMed Scopus (3650) Google Scholar). Tumor development shares many mechanistic similarities with this process and, with the exception of platelets, involves the same cell types (Dvorak, 2015Dvorak H.F. Tumors: wounds that do not heal-redux.Cancer Immunol. Res. 2015; 3: 1-11Crossref PubMed Google Scholar). The wound repair process is conserved across tissue types and injuries; thus, co-opting this process allows cancer cells to recruit and alter the stroma by similar means across a wide variety of tissue settings. The regenerative response to tissue damage is often initiated by cells of the innate immune system (Adler et al., 2018Adler M. Mayo A. Zhou X. Franklin R.A. Jacox J.B. Medzhitov R. Alon U. Endocytosis as a stabilizing mechanism for tissue homeostasis.Proc. Natl. Acad. Sci. USA. 2018; 115: E1926-E1935Crossref PubMed Scopus (1) Google Scholar, Coussens and Werb, 2002Coussens L.M. Werb Z. Inflammation and cancer.Nature. 2002; 420: 860-867Crossref PubMed Scopus (8112) Google Scholar) (Figure 2). Monocytes are recruited to the site of tissue injury in large part by the release of small molecules that act in a paracrine fashion. Many of these damage-associated molecular patterns (DAMPs) are metabolites, including ATP, uric acid, and nucleotides (Bianchi et al., 2007Bianchi R. Adami C. Giambanco I. Donato R. S100B binding to RAGE in microglia stimulates COX-2 expression.J. Leukoc. Biol. 2007; 81: 108-118Crossref PubMed Scopus (0) Google Scholar, Ishii et al., 2001Ishii K.J. Suzuki K. Coban C. Takeshita F. Itoh Y. Matoba H. Kohn L.D. Klinman D.M. Genomic DNA released by dying cells induces the maturation of APCs.J. 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Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds.PLoS Biol. 2004; 2: 206-214Crossref Scopus (656) Google Scholar, Chang et al., 2005Chang H.Y. Nuyten D.S.A. Sneddon J.B. Hastie T. Tibshirani R. Sørlie T. Dai H. He Y.D. van’t Veer L.J. Bartelink H. et al.Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival.Proc. Natl. Acad. Sci. USA. 2005; 102: 3738-3743Crossref PubMed Scopus (730) Google Scholar). Furthermore, manipulation of the extracellular environment by cancer cells is sufficient to induce this regenerative response, as culturing fibroblasts in cancer-cell-conditioned medium is sufficient to induce their activation (Rønnov-Jessen and Petersen, 1993Rønnov-Jessen L. Petersen O.W. Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia.Lab. Invest. 1993; 68: 696-707PubMed Google Scholar). This suggests that cancer cells can direct a regenerative response in stromal cells by manipulating the extracellular milieu. How might cancer cells reprogram the activity of their surrounding stroma? One approach that has been widely pursued by the research community is the study of tumor-produced cytokines and growth factors; these studies have been reviewed elsewhere (Coussens and Werb, 2002Coussens L.M. Werb Z. Inflammation and cancer.Nature. 2002; 420: 860-867Crossref PubMed Scopus (8112) Google Scholar, Turley et al., 2015Turley S.J. Cremasco V. Astarita J.L. Immunological hallmarks of stromal cells in the tumour microenvironment.Nat. Rev. Immunol. 2015; 15: 669-682Crossref PubMed Scopus (170) Google Scholar). 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The increased glucose consumption and lactate excretion within tumors have been well described for almost a century (Warburg et al., 1927Warburg O. Wind F. Negelein E. The metabolism of tumors in the body.J. Gen. Physiol. 1927; 8: 519-530Crossref PubMed Google Scholar). This metabolic behavior also radically alters the composition of the extracellular environment. As a result of constitutive glucose uptake and lactate excretion, glucose is rapidly depleted from the tumor microenvironment (Ho et al., 2015Ho P.C. Bihuniak J.D. MacIntyre A.N. Staron M. Liu X. Amezquita R. Tsui Y.C. Cui G. Micevic G. Perales J.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 (289) Google Scholar, Kamphorst et al., 2015Kamphorst J.J. Nofal M. Commisso C. Hackett S.R. Lu W. Grabocka E. Vander Heiden M.G. Miller G. Drebin J.A. Bar-Sagi D. 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), while lactate accumulates and is exported via the monocarboxylate transporter system (MCT) in cotransport with H+ ions, which causes acidification of the local environment (Schornack and Gillies, 2003Schornack P.A. Gillies R.J. Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors.Neoplasia. 2003; 5: 135-145Abstract Full Text PDF PubMed Google Scholar) (Figure 3). In addition to glucose, amino acids are the most highly consumed source of carbon for proliferating cells, and indeed comprise the majority of cellular biomass during proliferation (Hosios et al." @default.
• W2912300441 created "2019-02-21" @default.
• W2912300441 creator A5004784245 @default.
• W2912300441 creator A5034032647 @default.
• W2912300441 creator A5053752263 @default.
• W2912300441 date "2019-03-01" @default.
• W2912300441 modified "2023-10-14" @default.
• W2912300441 title "Cancer Metabolism Drives a Stromal Regenerative Response" @default.
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