title: Tumor stroma interaction is mediated by monocarboxylate metabolism.
abstract: Human breast tumors contain significant amounts of stromal cells. There exists strong evidence that these stromal cells support cancer development and progression by altering various pathways (e.g. downregulation of tumor suppressor genes or autocrine signaling loops). Here, we suggest that stromal carcinoma-associated fibroblasts (CAFs), shown to be generated from bone marrow-derived mesenchymal stem cells, may (i) recycle tumor-derived lactate for their own energetic requirements, thereby sparing glucose for neighboring glycolytic tumor cells, and (ii) subsequently secrete surplus energetically and biosynthetically valuable metabolites of lactate oxidation, such as pyruvate, to support tumor growth. Lactate, taken up by stromal CAFs, is converted to pyruvate, which is then utilized by CAFs for energy needs as well as excreted and shared with tumor cells. We have interrogated lactate oxidation in CAFs to determine what metabolites may be secreted, and how they may affect the metabolism and growth of MDA-MB-231 breast cancer cells. We found that CAFs secrete pyruvate as a metabolite of lactate oxidation. Further, we show that pyruvate is converted to lactate to promote glycolysis in MDA-MB-231 cells and helps to control elevated ROS levels in these tumor cells. Finally, we found that inhibiting or interfering with ROS management, using the naturally occurring flavonoid phloretin (found in apple tree leaves), adds to the cytotoxicity of the conventional chemotherapeutic agent doxorubicin. Our work demonstrates that a lactate-pyruvate, reciprocally-supportive metabolic relationship may be operative within the tumor microenvironment (TME) to support tumor growth, and may be a useful drug target.
authors.affiliation: Department of Pharmacology and Graduate School of Biomedical Sciences, Rutgers Biomedical Health Sciences, Rutgers, The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ 08854, United States.
authors.forename: Brijesh B
authors.initials: BB
authors.lastname: Patel
authors.affiliation: Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ackerstaff
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Inna S
authors.initials: IS
authors.lastname: Serganova
authors.affiliation: Department of Bioinformatics, Rutgers Biomedical Health Sciences, Rutgers, The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ 08854, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Kerrigan
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Blasberg
authors.affiliation: Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Weill Cornell Medicine, Graduate School of Medical Sciences, 1300 York Ave., New York, NY 10065, United States.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Koutcher
authors.affiliation: Department of Pharmacology and Graduate School of Biomedical Sciences, Rutgers Biomedical Health Sciences, Rutgers, The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ 08854, United States. Electronic address: banerjed@rwjms.rutgers.edu.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Banerjee
mesh_terms: D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002250:Carbon Radioisotopes / Q000378:metabolism; D002450:Cell Communication; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006019:Glycolysis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D019289:Pyruvic Acid / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D002250:Carbon Radioisotopes; D019344:Lactic Acid; D019289:Pyruvic Acid
keywords: MR spectroscopy; Metabolism; Monocarboxylate; Stroma