13C-pyruvate imaging reveals alterations in glycolysis that precede c-Myc-induced tumor formation and regression.

Tumor cells have an altered metabolic phenotype characterized by increased glycolysis and diminished oxidative phosphorylation. Despite the suspected importance of glycolysis in tumorigenesis, the temporal relationship between oncogene signaling, in vivo tumor formation, and glycolytic pathway activity is poorly understood. Moreover, how glycolytic pathways are altered as tumors regress remains unknown. Here, we use a switchable model of Myc-driven liver cancer, along with hyperpolarized (13)C-pyruvate magnetic resonance spectroscopic imaging (MRSI) to visualize glycolysis in de novo tumor formation and regression. LDHA abundance and activity in tumors is tightly correlated to in vivo pyruvate conversion to lactate and is rapidly inhibited as tumors begin to regress, as are numerous glycolysis pathway genes. Conversion of pyruvate to alanine predominates in precancerous tissues prior to observable morphologic or histological changes. These results demonstrate that metabolic changes precede tumor formation and regression and are directly linked to the activity of a single oncogene.

[1]  Michaela Diamant,et al.  Alanine aminotransferase as a marker of non‐alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease , 2006, Diabetes/metabolism research and reviews.

[2]  Ru Wei,et al.  The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth , 2008, Nature.

[3]  D. Burk,et al.  On respiratory impairment in cancer cells. , 1956, Science.

[4]  Kathryn A. O’Donnell,et al.  Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis , 2005, Molecular and Cellular Biology.

[5]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[6]  Jonghwan Kim,et al.  Global Identification of Myc Target Genes Reveals Its Direct Role in Mitochondrial Biogenesis and Its E-Box Usage In Vivo , 2008, PloS one.

[7]  A. Tward,et al.  Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC , 2007, Nature Medicine.

[8]  C. Dang.  PKM2 Tyrosine Phosphorylation and Glutamine Metabolism Signal a Different View of the Warburg Effect , 2009, Science Signaling.

[9]  Jan Henrik Ardenkjaer-Larsen,et al.  Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. , 2006, Cancer research.

[10]  Albert P. Chen,et al.  Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive biomarkers for prostate cancer detection and grading. , 2008, Cancer research.

[11]  Chi V Dang,et al.  Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. , 2010, Cancer research.

[12]  J. Ardenkjær-Larsen,et al.  Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Lucio Frydman,et al.  Kinetics of hyperpolarized 13C1-pyruvate transport and metabolism in living human breast cancer cells , 2009, Proceedings of the National Academy of Sciences.

[14]  P. Leder,et al.  Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. , 2006, Cancer cell.

[15]  Nicola Zamboni,et al.  Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells , 2007, The Journal of cell biology.

[16]  R A Jungmann,et al.  c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  G. Semenza,et al.  Oncogenic alterations of metabolism. , 1999, Trends in biochemical sciences.

[18]  Yu Wei,et al.  Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. , 2008, Cancer cell.

[19]  Michael Lustig,et al.  3D compressed sensing for highly accelerated hyperpolarized 13C MRSI with in vivo applications to transgenic mouse models of cancer , 2010, Magnetic resonance in medicine.

[20]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[21]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Chlebowski,et al.  Metabolic abnormalities in the cancer patient , 1985, Cancer.

[23]  Christopher H. Contag,et al.  MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer , 2004, Nature.

[24]  Jan Wolber,et al.  Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy , 2007, Nature Medicine.

[25]  Anthony Mancuso,et al.  Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction , 2008, Proceedings of the National Academy of Sciences.

[26]  G. Semenza,et al.  Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression , 2010, Proceedings of the National Academy of Sciences.