Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with α-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential.

Expression of estrogen-related receptor α (ERRα) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor α (ERα) and ERRα initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERα-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERα-ERRα cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERRα target genes, this study yielded the surprising result that most ERRα-regulated genes are unrelated to estrogen signaling. The relatively small number of genes regulated by both ERα and ERRα led us to expand our study to the more aggressive and less clinically treatable ERα-negative class of breast cancers. In this setting, we found that ERRα expression is required for the basal level of expression of many known and novel ERRα target genes. Introduction of a small interfering RNA directed to ERRα into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRα expression in MDA-MB-231 cells had no effect on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRα in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor–negative breast cancer. [Cancer Res 2008;68(21):8805–12]

Diet, nutritional status, and certain dietary supplements are postulated to influence the development and progression of prostate cancer. Angiogenesis and inflammation are central to tumor growth and progression, but the effect of diet on these processes remains uncertain. We explored changes in 50 plasma cytokines and angiogenic factors (CAF) in 145 men with prostate cancer enrolled in a preoperative, randomized controlled phase II trial with four arms: control (usual diet), low-fat (LF) diet, flaxseed-supplemented (FS) diet, and FS+LS diet. The mean duration of dietary intervention was 30 to 31 days. Among the individual arms, the largest number of significant changes (baseline vs. preoperative follow-up) was observed in the LF arm, with 19 CAFs decreasing and one increasing (P < 0.05). Compared with the control arm, 6 CAFs—including proangiogenic factors (stromal-cell derived-1α) and myeloid factors (granulocyte-colony-stimulating factor, macrophage colony-stimulating factor)—all decreased in the LF arm compared with controls; three and four CAFs changed in the FS and FS+LF arms, respectively. Weight loss occurred in the LF arms and significantly correlated with VEGF decreases (P < 0.001). The CAFs that changed in the LF arm are all known to be regulated by NF-κB, and a pathway analysis identified NF-κB as the most likely regulatory network associated with these changes in the LF arm but not in the FS-containing arms. These results suggest that a LF diet without flaxseed may reduce levels of specific inflammatory CAFs and suggests that the NF-κB pathway may be a mediator of these changes. Cancer Prev Res; 4(10); 1590–8. ©2011 AACR.

2-Deoxy-2-[18F]fluoro-D-glucose PET/CT is a well-established imaging method for staging, restaging and therapy-control in human medicine. In veterinary medicine, this imaging method could prove to be an attractive and innovative alternative to conventional imaging in order to improve staging and restaging. The aim of this study was both to evaluate the effectiveness of this image-guided method in canine patients with spontaneously occurring cancer as well as to illustrate the dog as a well-suited animal model for comparative oncology. Ten dogs with various malignant tumors were included in the study and underwent a whole body FDG PET/CT. One patient has a second PET-CT 5 months after the first study. Patients were diagnosed with histiocytic sarcoma (n = 1), malignant lymphoma (n = 2), mammary carcinoma (n = 4), sertoli cell tumor (n = 1), gastrointestinal stromal tumor (GIST) (n = 1) and lung tumor (n = 1). PET/CT data were analyzed with the help of a 5-point scale in consideration of the patients’ medical histories. In seven of the ten dogs, the treatment protocol and prognosis were significantly changed due to the results of FDG PET/CT. In the patients with lymphoma (n = 2) tumor extent could be defined on PET/CT because of increased FDG uptake in multiple lymph nodes. This led to the recommendation for a therapeutic polychemotherapy as a treatment. In one of the dogs with mammary carcinoma (n = 4) and in the patient with the lung tumor (n = 1), surgery was cancelled due to the discovery of multiple metastasis. Consequently no treatment was recommended. FDG PET/CT offers additional information in canine patients with malignant disease with a potential improvement of staging and restaging. The encouraging data of this clinical study highlights the possibility to further improve innovative diagnostic and staging methods with regard to comparative oncology. In the future, performing PET/CT not only for staging but also in therapy control could offer a significant improvement in the management of dogs with malignant tumors.