Junya Yoneda

Cancer Usurps Skeletal Muscle as an Energy Repository

Cancer cells produce energy through aerobic glycolysis, but contributions of host tissues to cancer energy metabolism are unclear. In this study, we aimed to elucidate the cancer-host energy production relationship, in particular, between cancer energy production and host muscle. During the development and progression of colorectal cancer, expression of the secreted autophagy-inducing stress protein HMGB1 increased in the muscle of tumor-bearing animals. This effect was associated with decreased expression of pyruvate kinase PKM1 and pyruvate kinase activity in muscle via the HMGB1 receptor for advanced glycation endproducts (RAGE). However, muscle mitochondrial energy production was maintained. In contrast, HMGB1 addition to colorectal cancer cells increased lactate fermentation. In the muscle, HMGB1 addition induced autophagy by decreasing levels of active mTOR and increasing autophagy-associated proteins, plasma glutamate, and (13)C-glutamine incorporation into acetyl-CoA. In a mouse model of colon carcinogenesis, a temporal increase in HMGB1 occurred in serum and colonic mucosa with an increase in autophagy associated with altered plasma free amino acid levels, increased glutamine, and decreased PKM1 levels. These differences were abolished by administration of an HMGB1 neutralizing antibody. Similar results were obtained in a mouse xenograft model of human colorectal cancer. Taken together, our findings suggest that HMGB1 released during tumorigenesis recruits muscle to supply glutamine to cancer cells as an energy source.

GM-CSF-transduced B16 melanoma cells are highly susceptible to lysis by normal murine macrophages and poorly tumorigenic in immune-compromised mice.

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)‐transduced B16‐F10 murine melanoma cells had lower tumorigenicity in both syngeneic and nude mice than parental or LacZ‐transduced (control) cells. The subcutaneous (s.c.) tumors producing GM‐CSF were densely infiltrated with macrophages, whereas the control tumors were not. In vitro studies showed that GM‐CSF‐transduced B16 cells were susceptible to lysis mediated by nonactivated murine macrophages, whereas control B16 cells were not. Macrophage‐mediated cytotoxicity against GM‐CSF‐transduced B16 cells was independent of the presence of NO, H2O2, O2‐, tumor necrosis factor α, and matrix metalloproteinase. Coculture experiments using GM‐CSF‐producing and ‐nonproducing B16 cells demonstrated that GM‐CSF produced by the transduced B16 cells activated macrophages to kill the bystander non‐GM‐CSF‐producing tumor cells. The results suggest that GM‐CSF released by tumor cells can induce macrophage‐mediated cytotoxicity, which in turn can inhibit the in vivo growth of GM‐CSF‐transduced tumor cells. J. Leukoc. Biol. 65: 102–108; 1999.

Clinical Implementation of Metabolomics

Metabolomics, which is also referred to as metabonomics, metabolic profiling or metabolic fingerprinting, is the comprehensive quantitative measurement of endogenous metabolites within a biological system (Fiehn, 2002; Kaddurah-Daouk et al, 2008; Spratlin et al, 2009). Detection of metabolites is in general carried out in cell extracts, tissue specimens, or various biological fluids including serum, plasma, urine and cerebrospinal fluid (CSF) by liquid chromatography mass spectrometry (LC-MS), gas chromatography–mass spectrometry (GCMS), capillary electrophoresis–mass spectrometry (CE-MS) or nuclear magnetic resonance spectroscopy (NMR). Metabolomics captures the status of diverse biochemical pathways in a particular situation and can define the metabolic status of an organism (Aranibar et al, 2011; DeFeo et al, 2011; Lu et al, 2008; Roux et al, 2011; Soga, 2007; Yuan et al, 2007). In clinical settings, biomarkers generated from metabolomics have become one of the most essential diagnostic criteria that can be objectively measured and evaluated as indicators of normal or pathological states, as well as a tool to assess responses to therapeutic interventions (Hunter, 2009; Spratlin et al, 2009; van der Greef et al, 2006; Zeisel, 2007). As we describe in this chapter, novel metabolomic markers, for instance, for cancer therapy, glucose intolerance, hepatic steatosis, nephrotic and psychiatric disorders, and their incorporation into clinical decision-making may considerably change future health care.

Alteration of the Plasma Free Amino Acids Profiles in Cancer Patients is Associated with Dysregulated Metabolism in Skeletal Muscle

Plasma free amino acids (PFAAs) are sensitive metabolites indicative of cancer related critical illness. Changes in protein metabolism, as reflected by the PFAA profile, may represent a new diagnostic tool for cancer. High-mobility group B1 (HMGB1) is a multifunctional protein, which associated with cancer development, progression and metastasis with suppression of anti-cancer immunity by induction of monocyte-linage cells. HMGB1 played an important role in cause of PFAA alteration. HMGB1 induced degradation in the skeletal muscle through inhibiting glycogen utilization by pyruvate kinase suppression and activation of autophagy by dephosphorylating of mammalian target of rapamycin (mTOR). Autophagy increased free glutamine in muscle cells, which utilized glutamine as energy source through glutaminolysis-tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Glutamine was also released into the blood and taken by cancer cells, which utilized glutamine as energy source through glutaminolysis-partial use of TCA cycle-lactate fermentation. Thus, HMGB1-induced dysregulation of metabolism in the muscle causes the alteration of the PFAA profile.