Overweight and obesity are associated with increased risk of developing metabolic disorders such as diabetes and cardiovascular diseases. However, besides these metabolic diseases, excess body weight is also associated with different cancers, including gastrointestinal cancers, such as liver, pancreatic and colon cancers. Inflammation is a common feature of both obesity and cancer; however, the origin of this inflammation has been largely debated. Over the past decade, growing evidence has shown that the composition of the gut microbiota and its activity might be associated not only with the onset of inflammation but also with metabolic disorders and cancer. Here, we review the links between the gut microbiota, gut barrier function and the onset of low-grade inflammation in the development of gastrointestinal cancer. We also describe the mechanisms by which specific microorganism-associated molecular patterns crosstalk with the immune system and how the metabolic activity of bacteria induces specific signalling pathways beyond the gut that eventually trigger carcinogenesis.

Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) represents an attractive therapeutic strategy but may stimulate glucose consumption by oxidative cancer cells. We report here that inhibition of mitochondrial pyruvate carrier (MPC) activity fulfils the tasks of blocking lactate use while preventing glucose oxidative metabolism. Using in vitro 13C-glucose and in vivo hyperpolarized 13C-pyruvate, we identify 7ACC2 as a potent inhibitor of mitochondrial pyruvate transport which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation. Also, while in spheroids MCT1 inhibition leads to cytostatic effects, MPC activity inhibition induces cytotoxic effects together with glycolysis stimulation and uncompensated inhibition of mitochondrial respiration. Hypoxia reduction obtained with 7ACC2 is further shown to sensitize tumor xenografts to radiotherapy. This study positions MPC as a control point for lactate metabolism and expands on the anticancer potential of MPC inhibition.

Tumor hypoxia is recognized as a limiting factor for the efficacy of radiotherapy, because it enhances tumor radioresistance. It is strongly suggested that assessing tumor oxygenation could help to predict the outcome of cancer patients undergoing radiation therapy. Strategies have also been developed to alleviate tumor hypoxia in order to radiosensitize tumors. In addition, oxygen mapping is critically needed for intensity modulated radiation therapy (IMRT), in which the most hypoxic regions require higher radiation doses and the most oxygenated regions require lower radiation doses. However, the assessment of tumor oxygenation is not yet included in day-to-day clinical practice. This is due to the lack of a method for the quantitative and non-invasive mapping of tumor oxygenation. To fully integrate tumor hypoxia parameters into effective improvements of the individually tailored radiation therapy protocols in cancer patients, methods allowing non-invasively repeated, safe, and robust mapping of changes in tissue oxygenation are required. In this review, non-invasive methods dedicated to assessing tumor oxygenation with the ultimate goal of predicting outcome in radiation oncology are presented, including positron emission tomography used with nitroimidazole tracers, magnetic resonance methods using endogenous contrasts (R1 and R2*-based methods), and electron paramagnetic resonance oximetry; the goal is to highlight results of studies establishing correlations between tumor hypoxic status and patients’ outcome in the preclinical and clinical settings.

Targeted chemotherapeutic agents often do not result in tumor shrinkage, so new biomarkers that correlate with clinical efficacy are needed. In this study, we investigated noninvasive imaging protocols to monitor responses to sorafenib, a multikinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma. Healthy cells are impermeable to fumarate, so conversion of this metabolite to malate as detected by 13C-magnetic resonance spectroscopy (MRS) has been suggested as one marker for cell death and treatment response in tumors. Diffusion MRI also has been suggested as a measure of therapy-induced cytotoxic edema because viable cells act as a diffusion barrier in tissue. For these reasons, we assessed sorafenib responses using hyperpolarized 13C-fumarate, diffusion-weighted MRI (DW-MRI) in a xenograft model of human breast cancer in which daily administration of sorafenib was sufficient to stabilize tumor growth. We detected signals from fumarate and malate following intravenous administration of hyperpolarized fumarate with a progressive increase in the malate-to-fumarate (MA/FA) ratio at days 2 to 5 after sorafenib infusion. The apparent diffusion coefficient (ADC) measured by DW-MRI increased in the treated group consistent with cytotoxic edema. However, the MA/FA ratio was a more sensitive marker of therapeutic response than ADC, with 2.8-fold versus 1.3-fold changes, respectively, by day 5 of drug treatment. Histologic analyses confirmed cell death in the sorafenib-treated cohort. Notably, 13C-pyruvate-to-lactate conversion was not affected by sorafenib in the breast cancer model examined. Our results illustrate how combining hyperpolarized substrates with DW-MRI can allow noninvasive monitoring of targeted therapeutic responses at relatively early times after drug administration.

This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (FNRS-PDR Convention T.0077.14, grant Télévie No. 7.6515.16 F to DDM and grant 5/4/150/5 awarded to MMD and CAA is research associate, FRS-FNRS), Fonds Spéciaux de Recherche, Fondation St Luc, and Foundation Against Cancer, and donations from the Ferrero family.