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Adaptive Exploitation of Stromal Cell Metabolism by Tumor Cells
Author(s) -
Patel Brij,
Rattigan Yanique,
Ackerstaff Ellen,
Koutcher Jason,
Sukenick George,
Glod John,
Banerjee Debabrata
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.966.5
Subject(s) - stromal cell , glycolysis , tumor microenvironment , monocarboxylate transporter , secretion , cancer cell , metabolism , chemistry , biology , microbiology and biotechnology , biochemistry , transporter , cancer research , cancer , tumor cells , genetics , gene
BACKGROUND/OBJECTIVE Glycolytic tumors secrete lactate into the tumor microenvironment (TME). Glycolytic muscle cells also secrete lactate, while neighboring oxidative muscle cells use this lactate as an energy source. We propose that lactate mediates tumor‐TME metabolic coupling similar to that of muscle cells. Using in vitro ‐derived activated TME cells (CAFs), we investigated the role that lactate may play in CAF‐mediated support of tumor growth. METHODS/RESULTS [1] We find that MDA‐MB‐231 (MDA) breast cancer cells secrete 3‐fold more lactate under hypoxia, and that lactate recruits CAF precursors towards MDAs . [2] Lactate is transported by monocarboxylate transporters (MCTs); it is taken up via MCT1 and effluxed via MCT4. MDAs have low MCT1 but high MCT4 expression, while CAFs show high MCT1 but low MCT4 expression, implying that tumor‐extruded lactate is taken up by CAFs . [3] 13 C NMR spectroscopic analyses indicate that 13 C‐lactate is indeed metabolized via the Krebs cycle in CAFs. This implies that CAFs oxidatively metabolize lactate . [4] MDAs co‐cultured with CAFs display greater uptake of exogenous pyruvate, and subsequent 13 C‐pyruvate tracking assays indicate the presence of 13 C‐labeled lactate. Collectively this suggests that tumor cells may derive sources of energy from lactate‐oxidizing components of their TME . [5] Ongoing studies investigating MCT1 blockers CHC and Leutolin indicate that inhibiting lactate transport in CAFs may inhibit tumor growth . CONCLUSIONS To our knowledge this is the first in vitro model system demonstrating tumor/TME metabolic coupling by which tumor cells exploit stromal cells. A better understanding of the molecular mechanisms governing metabolic cooperation within the tumor milieu will potentially identify new targets for therapeutic intervention. Grant Funding Source: NIH P50 CA86438 & NJCCR‐10‐1964‐CCR‐EO Grant Funding Source : NJCCR‐10‐1964‐CCR‐EO