Title: Power Surge: Supporting Cells “Fuel” Cancer Cell Mitochondria
Abstract: An emerging paradigm in tumor metabolism is that catabolism in host cells "fuels" the anabolic growth of cancer cells via energy transfer. A study in Nature Medicine (Nieman et al., 2011Nieman K.M. Kenny H.A. Penicka C.V. Ladanyi A. Buell-Gutbrod R. Zillhardt M.R. Romero I.L. Carey M.S. Mills G.B. Hotamisligil G.S. et al.Nat. Med. 2011; 17: 1498-1503Crossref PubMed Scopus (1152) Google Scholar) supports this; they show that triglyceride catabolism in adipocytes drives ovarian cancer metastasis by providing fatty acids as mitochondrial fuels. An emerging paradigm in tumor metabolism is that catabolism in host cells "fuels" the anabolic growth of cancer cells via energy transfer. A study in Nature Medicine (Nieman et al., 2011Nieman K.M. Kenny H.A. Penicka C.V. Ladanyi A. Buell-Gutbrod R. Zillhardt M.R. Romero I.L. Carey M.S. Mills G.B. Hotamisligil G.S. et al.Nat. Med. 2011; 17: 1498-1503Crossref PubMed Scopus (1152) Google Scholar) supports this; they show that triglyceride catabolism in adipocytes drives ovarian cancer metastasis by providing fatty acids as mitochondrial fuels. Our understanding of tumor metabolism is evolving. A new central concept in cancer metabolism is that tumor cells function as metabolic parasites to extract energy from supporting host cells, such as fibroblasts and adipocytes. It has recently been demonstrated that metabolic coupling exists in human tumors (Sotgia et al., 2011Sotgia F. Martinez-Outschoorn U.E. Pavlides S. Howell A. Pestell R.G. Lisanti M.P. Breast Cancer Res. 2011; 13: 213Crossref PubMed Scopus (127) Google Scholar). In two-compartment tumor metabolism, the tumor stroma and adjacent host tissues are catabolic and the cancer cells are anabolic (Figure 1). In this model, energy is transferred from the catabolic compartment to the anabolic compartment via the sharing of nutrients that promote tumor growth, behaving as onco-metabolites. Although most studies on two-compartment tumor metabolism were first performed on fibroblasts and breast cancer cells (Martinez-Outschoorn et al., 2011Martinez-Outschoorn U.E. Goldberg A. Lin Z. Ko Y.H. Flomenberg N. Wang C. Pavlides S. Pestell R.G. Howell A. Sotgia F. Lisanti M.P. Cancer Biol. Ther. 2011; 12: 924-938Crossref PubMed Scopus (129) Google Scholar, Sotgia et al., 2011Sotgia F. Martinez-Outschoorn U.E. Pavlides S. Howell A. Pestell R.G. Lisanti M.P. Breast Cancer Res. 2011; 13: 213Crossref PubMed Scopus (127) Google Scholar, Sotgia et al., 2012Sotgia F. Martinez-Outschoorn U.E. Howell A. Pestell R.G. Pavlides S. Lisanti M.P. Annu. Rev. Pathol. 2012; 7 (Published online November 7, 2011): 423-467https://doi.org/10.1146/annurev-pathol-011811-120856Crossref PubMed Scopus (212) Google Scholar, Whitaker-Menezes et al., 2011Whitaker-Menezes D. Martinez-Outschoorn U.E. Flomenberg N. Birbe R.C. Witkiewicz A.K. Howell A. Pavlides S. Tsirigos A. Ertel A. Pestell R.G. et al.Cell Cycle. 2011; 10: 4047-4064Crossref PubMed Scopus (188) Google Scholar), an elegant study in Nature Medicine now broadens this emerging paradigm to adipocytes and ovarian cancer cells (Nieman et al., 2011Nieman K.M. Kenny H.A. Penicka C.V. Ladanyi A. Buell-Gutbrod R. Zillhardt M.R. Romero I.L. Carey M.S. Mills G.B. Hotamisligil G.S. et al.Nat. Med. 2011; 17: 1498-1503Crossref PubMed Scopus (1152) Google Scholar). The tumor cellular microenvironment contains supporting host cells, including fibroblasts, adipocytes, smooth muscle cells, endothelia, and immune cells, which functionally promote tumor growth. In two-compartment tumor metabolism, anabolic cancer cells extract energy from the surrounding host cells by inducing catabolic processes, such as autophagy, mitophagy, and aerobic glycolysis. These processes provide high-energy mitochondrial fuels (L-lactate, ketones, and glutamine) for cancer cells to burn. In response, cancer cells amplify or hyperactivate their capacity for oxidative phosphorylation (OXPHOS) by increasing their mitochondrial mass (Sotgia et al., 2012Sotgia F. Martinez-Outschoorn U.E. Howell A. Pestell R.G. Pavlides S. Lisanti M.P. Annu. Rev. Pathol. 2012; 7 (Published online November 7, 2011): 423-467https://doi.org/10.1146/annurev-pathol-011811-120856Crossref PubMed Scopus (212) Google Scholar). For example, cancer-associated fibroblasts show a shift toward aerobic glycolysis and secrete L-lactate via MCT4 transporters. L-lactate is taken up by cancer cells via MCT1 transporters, leading to the generation of ATP via OXPHOS (Sotgia et al., 2012Sotgia F. Martinez-Outschoorn U.E. Howell A. Pestell R.G. Pavlides S. Lisanti M.P. Annu. Rev. Pathol. 2012; 7 (Published online November 7, 2011): 423-467https://doi.org/10.1146/annurev-pathol-011811-120856Crossref PubMed Scopus (212) Google Scholar). This process can be phenocopied by incubating cancer cells alone with high-energy fuels, such as L-lactate. Tumor cells can also exert metabolic effects at a distance, which leads to increased fatty acid generation in adipose tissue and catabolism in muscle (Das et al., 2011Das S.K. Eder S. Schauer S. Diwoky C. Temmel H. Guertl B. Gorkiewicz G. Tamilarasan K.P. Kumari P. Trauner M. et al.Science. 2011; 333: 233-238Crossref PubMed Scopus (319) Google Scholar). These key examples show that energy transfer occurs in human tumors and that cancer cells can exert metabolic effects locally, in different tumor compartments, and at distant sites. Over 80% of ovarian cancers are metastatic to the omental fat. It is not known why ovarian cancer cells preferentially seed the omentum as compared to other sites. To address this issue, the study by Nieman et al., 2011Nieman K.M. Kenny H.A. Penicka C.V. Ladanyi A. Buell-Gutbrod R. Zillhardt M.R. Romero I.L. Carey M.S. Mills G.B. Hotamisligil G.S. et al.Nat. Med. 2011; 17: 1498-1503Crossref PubMed Scopus (1152) Google Scholar uses SKOV3ip1 human ovarian cancer cells intraperitoneally (i.p.) injected into nude mice or cocultured with adipocytes. They describe how omental adipocytes are metabolically reprogrammed to become highly catabolic, generating free fatty acids that are transferred to cancer cells. Cancer cells then reutilize these fatty acids to generate ATP via mitochondrial β-oxidation. Utilization of adipocyte-derived fatty acids was related to the production of fatty acid binding protein 4 (FABP4) by adipocytes. Importantly, this study evaluates tumor metabolism in the more physiological context of its proper microenvironment. Energy production and apoptosis are important mitochondrial functions that are biologically linked in normal cells. For example, the mitochondrial proteins Bcl-2 and Bcl-xL are antiapoptotic and favor mitochondrial OXPHOS (Chen and Pervaiz, 2010Chen Z.X. Pervaiz S. Cell Death Differ. 2010; 17: 408-420Crossref PubMed Scopus (98) Google Scholar, Vander Heiden et al., 2001Vander Heiden M.G. Li X.X. Gottleib E. Hill R.B. Thompson C.B. Colombini M. J. Biol. Chem. 2001; 276: 19414-19419Crossref PubMed Scopus (315) Google Scholar). A "mitochondrial paradox" exists in cancer research, since it is not understood why cancer cells, which are resistant to apoptosis, would use energetically inefficient low mitochondrial metabolism (aerobic glycolysis, also known as the Warburg effect) (Le et al., 2010Le A. Cooper C.R. Gouw A.M. Dinavahi R. Maitra A. Deck L.M. Royer R.E. Vander Jagt D.L. Semenza G.L. Dang C.V. Proc. Natl. Acad. Sci. USA. 2010; 107: 2037-2042Crossref PubMed Scopus (870) Google Scholar, Fogal et al., 2010Fogal V. Richardson A.D. Karmali P.P. Scheffler I.E. Smith J.W. Ruoslahti E. Mol. Cell. Biol. 2010; 30: 1303-1318Crossref PubMed Scopus (209) Google Scholar). Interestingly, Nieman et al., 2011Nieman K.M. Kenny H.A. Penicka C.V. Ladanyi A. Buell-Gutbrod R. Zillhardt M.R. Romero I.L. Carey M.S. Mills G.B. Hotamisligil G.S. et al.Nat. Med. 2011; 17: 1498-1503Crossref PubMed Scopus (1152) Google Scholar demonstrate that ovarian cancer cells have high mitochondrial metabolic activity, specifically fatty acid β-oxidation, when cocultured with adipocytes. This type of mitochondrial metabolism was not observed when ovarian cancer cells were cultured alone, highlighting the importance of catabolite transfer to cancer cells. As such, high-energy nutrients provided by host cells may bolster mitochondrial metabolism in cancer cells, protecting them against apoptosis. The answer to the "mitochondrial paradox" may lie in the metabolic reprogramming of cancer cells toward anabolic metabolism in the presence of catabolic host cells, leading to mitochondrial biogenesis and OXPHOS in tumor cells, driving chemoresistance and distant metastasis. Thus, the authors demonstrate that it is crucial to include the supporting microenvironment when studying cancer cell metabolism and that simply examining primary cancer cells alone may not be adequate. Unfortunately, most traditional cancer metabolism studies have been carried out using tumor cells alone, or using whole tumors, without modeling the host microenvironment. As such, one might gain incomplete or inaccurate information by studying primary cancer cells or cancer cell lines in the absence of supporting host cells. Studies describing the compartmentalization of tumor metabolism and energy transfer may pave the way toward the development of related predictive biomarkers and targeted personalized therapies. It will be important to investigate whether metabolically uncoupling cancer cells from catabolic host cells can be used as a new effective anticancer strategy. Earlier studies have suggested that the detection of host-tumor metabolic coupling may be useful for identifying high-risk patients at diagnosis in human breast cancers. For example, loss of expression of the caveolin-1 protein in cancer-associated fibroblasts is a marker for tumor-stroma metabolic coupling (Sotgia et al., 2011Sotgia F. Martinez-Outschoorn U.E. Pavlides S. Howell A. Pestell R.G. Lisanti M.P. Breast Cancer Res. 2011; 13: 213Crossref PubMed Scopus (127) Google Scholar) and is tightly correlated with recurrence, metastasis, and tamoxifen resistance as well as poor clinical outcome. Metabolic coupling between host cells and breast cancer cells also results in the generation of reactive oxygen species and inflammatory cytokine production, such as IL-6 and IL-8 (Sotgia et al., 2012Sotgia F. Martinez-Outschoorn U.E. Howell A. Pestell R.G. Pavlides S. Lisanti M.P. Annu. Rev. Pathol. 2012; 7 (Published online November 7, 2011): 423-467https://doi.org/10.1146/annurev-pathol-011811-120856Crossref PubMed Scopus (212) Google Scholar). Most importantly, FDA-approved drugs that inhibit mitochondrial metabolism (metformin, arsenic trioxide) or strong antioxidants (catalase) can uncouple two-compartment tumor metabolism and induce apoptosis in cancer cells (Martinez-Outschoorn et al., 2011Martinez-Outschoorn U.E. Goldberg A. Lin Z. Ko Y.H. Flomenberg N. Wang C. Pavlides S. Pestell R.G. Howell A. Sotgia F. Lisanti M.P. Cancer Biol. Ther. 2011; 12: 924-938Crossref PubMed Scopus (129) Google Scholar, Sotgia et al., 2012Sotgia F. Martinez-Outschoorn U.E. Howell A. Pestell R.G. Pavlides S. Lisanti M.P. Annu. Rev. Pathol. 2012; 7 (Published online November 7, 2011): 423-467https://doi.org/10.1146/annurev-pathol-011811-120856Crossref PubMed Scopus (212) Google Scholar) (Figure 1). In conclusion, the importance of the host microenvironment and energy transfer in cancer metabolism is highlighted by Nieman et al., 2011Nieman K.M. Kenny H.A. Penicka C.V. Ladanyi A. Buell-Gutbrod R. Zillhardt M.R. Romero I.L. Carey M.S. Mills G.B. Hotamisligil G.S. et al.Nat. Med. 2011; 17: 1498-1503Crossref PubMed Scopus (1152) Google Scholar. More studies on two-compartment tumor metabolism will be necessary to understand and therapeutically exploit the metabolic coupling between "parasitic" tumor cells and their hosts. Uncoupling "parasitic" cancer cells should allow us to starve cancer cells and effectively treat advanced and metastatic cancers. New imaging techniques to visualize two-compartment tumor metabolism in real time will allow us to measure the effectiveness of anticancer therapies and facilitate more personalized cancer treatments.