Abstract 3370: Metabolic profiling of the tumor interstitial fluid using 1H MRS: contribution of breast cancer subtypes and VEGF overexpression
Authors: Dore-Savard Louis , Bharti Santosh K. , Popel Aleksander S. , Bhujwalla Zaver M. 
Published: July 2016

One of the least examined, and yet critically important factors of the tumor microenvironment (TME) is the tumor interstitial fluid (TIF) that contains the tumor secretome. This fluid surrounds cancer and stromal cells and contains various cytokines, and nutritional and molecular factors that shape the outcome of nearly all aspects of tumor angiogenesis, growth, metastasis, and response to treatment. As mining of targets to treat cancer expands into the TME, the TIF represents an important source of identifying new targets in cancer treatment. Angiogenesis, one of the major hallmarks of cancer, is essential for cancers to establish vasculature for growth and hematogenous metastasis. To further understand the TIF and plasma metabolite content in breast cancer, and the role of VEGF in modifying metabolite concentrations in the TME, here we used 1H MRS to characterize metabolites in TIF collected from the triple negative MDA-MB-231 and the ER-positive MCF-7 human breast cancer xenografts with and without VEGF overexpression implanted in SCID mice. We created a collection chamber to collect IF from the tumors. The chamber was implanted with small tumor pieces in the subcutaneous space until the tumor encompassed the chamber (4 to 12 weeks depending on cell types). The tumor was then excised and the TIF and blood plasma were collected from euthanized mice. We also collected normal subcutaneous IF (SCIF) using the same chamber in healthy mice. 1H spectra showed several differences in metabolites in TIF compared to SCIF, between MDA-MB-231 and MCF-7 TIF, and with VEGF overexpression. We observed a consumption of amino acids in the TME with decreases ranging from 17% (glycine) to 77% (methionine) compared to normal SCIF. Lipids, especially polyunsaturated fatty acids, were markedly increased by VEGF overexpression in both MCF-7 and MDA-MB-231 TIF compared to the wild type TIF. Choline metabolism was also modified by VEGF overexpression and we measured increases of 69% and 20% in free choline in MDA-MB-231_VEGF and MCF-7_VEGF respectively, compared to their wild type counterpart. A stable glucose concentration was associated with a decrease in lactate (30%) and pyruvate (44%) in MDA-MB-231 tumors while an opposite pattern was observed in MDA-MB-231_VEGF TIF with decreased glucose (55%) and increased lactate (109%). Ketonic metabolism was also modified in those tumors. Beta-hydroxybutyrate and acetoacetate were higher (81% and 46% increase vs SCIF, respectively) in MDA-MB-231 TIF while acetone was increased in both VEGF-overexpressing TIF compared to the wild type (+48% for MDA-MB-231_VEGF and +44% for MCF-7_VEGF). The TIF represents an importance source of information to understand mechanisms that drive aggressiveness, and identify new targets for diagnosis and therapy of cancer.

Citation Format: Louis Dore-Savard, Santosh K. Bharti, Aleksander S. Popel, Zaver M. Bhujwalla. Metabolic profiling of the tumor interstitial fluid using 1H MRS: contribution of breast cancer subtypes and VEGF overexpression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3370.