title: Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment.
abstract: Human mesenchymal stem cells (hMSCs) are bone marrow-derived stromal cells, which play a role in tumor progression. We have shown earlier that breast cancer cells secrete higher levels of interleukin-6 (IL-6) under hypoxia, leading to the recruitment of hMSCs towards hypoxic tumor cells. We found that (i) MDA-MB-231 cells secrete significantly higher levels of lactate (3-fold more) under hypoxia (1% O(2)) than under 20% O(2) and (ii) lactate recruits hMSCs towards tumor cells by activating signaling pathways to enhance migration. The mRNA and protein expression of functional MCT1 in hMSCs is increased in response to lactate exposure. Thus, we hypothesized that hMSCs and stromal carcinoma associated fibroblasts (CAFs) in the tumor microenvironment have the capacity to take up lactate expelled from tumor cells and use it as a source of energy. Our (13)C NMR spectroscopic measurements indicate that (13)C-lactate is converted to (13)C-alpha ketoglutarate in hMSCs and CAFs supporting this hypothesis. To our knowledge this is the first in vitro model system demonstrating that hMSCs and CAFs can utilize lactate produced by tumor cells.
authors.affiliation: Graduate School of Biomedical Sciences, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: Yanique I
authors.initials: YI
authors.lastname: Rattigan
authors.forename: Brijesh B
authors.initials: BB
authors.lastname: Patel
authors.forename: Ellen
authors.initials: E
authors.lastname: Ackerstaff
authors.forename: George
authors.initials: G
authors.lastname: Sukenick
authors.forename: Jason A
authors.initials: JA
authors.lastname: Koutcher
authors.forename: John W
authors.initials: JW
authors.lastname: Glod
authors.forename: Debabrata
authors.initials: D
authors.lastname: Banerjee
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D006019:Glycolysis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D019344:Lactic Acid / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000502:physiology
chemical_list: D019344:Lactic Acid