Metabolic fluxes can serve as specific biomarkers for detecting malignant transformations, tumor progression, and response to microenvironmental changes and treatment procedures. We present noninvasive hyperpolarized 13 C NMR investigations on the metabolic flux of pyruvate to lactate, in a well-controlled injection/ perfusion system using T47D human breast cancer cells. Initial rates of pyruvate-to-lactate conversion were obtained by fitting the hyperpolarized 13 C and ancillary 31 P NMR data to a model, yielding both kinetic parameters and mechanistic insight into this conversion. Transport was found to be the rate-limiting process for the conversion of extracellular pyruvate to lactate with Km ‫؍‬ 2.14 ؎ 0.03 mM, typical of the monocarboxylate transporter 1 (MCT1), and a Vmax ‫؍‬ 27.6 ؎ 1.1 fmol⅐min ؊1 ⅐cell ؊1 , in agreement with the high expression level of this transporter. Modulation of the environment to hypoxic conditions as well as suppression of cells' perfusion enhanced the rate of pyruvate-to-lactate conversion, presumably by up-regulation of the MCT1. Conversely, the addition of quercetin, a flavonoidal MCT1 inhibitor, markedly reduces the apparent rate of pyruvate-to-lactate conversion. These results suggest that hyperpolarized 13 C1-pyruvate may be a useful magnetic resonance biomarker of MCT regulation and malignant transformations in breast cancer.hyperpolarized NMR ͉ metabolic fluxes ͉ monocarboxylate transporters ͉ pyruvate/lactate conversion ͉ breast cancer metabolism I maging is an integral component in the detection and treatment of cancer. Continuous efforts are being invested to develop imaging techniques with the aim of earlier detection as well as for an improved ability to distinguish between malignant and benign growths and to rapidly assess the response of cancer to therapeutic treatments. Anatomical imaging techniques are limited by the inherent contrast between normal and tumor tissue. Therefore, emphasis has been shifted to the development of biomarkers of metabolic processes for functional and molecular imaging, in which contrast between normal and cancerous tissues arises because of their different metabolic properties. The strong homeostasis of living cells makes metabolic fluxes, rather than actual changes in metabolic concentrations, promising biomarkers for detecting malignant transformations-including tumor progressions and their response to therapy. One such process is the elevated rate of anaerobic glycolysis in cancers (1). This phenomenon has been demonstrated in numerous studies, both in vitro and in vivo, and it is used clinically to identify the location of tumors via positron emission tomography (2). Although the origin and mechanism of the enhanced glycolysis in cancers is still being debated (3-5), evidence exists that it reflects the up-regulation of glucose transporters in human malignancies, enhancing glucose influx into the proliferating cancer cells (6).It has been recently shown that NMR of hyperpolarized precursors, has the potential to become a suitable m...

The discovery of metabolic and molecular markers that help improving the detection and diagnosis of breast cancer is an important goal to be achieved. A high composite-choline signal in magnetic resonance spectra of breast lesions has been demonstrated to improve the accuracy of breast cancer diagnosis. In the present study we revealed the principal molecular and biochemical steps associated with the induction of choline metabolism and phosphocholine accumulation in human breast cancer cell-lines in comparison with normal human mammary epithelial cells. We found upregulation of the expression levels of specific choline transporters: organic cation transporter-2 and choline high affinity transporter-1, as well as of the enzyme choline kinase a in the cancerous cells in comparison with that in the normal mammary epithelial cells. The expression levels of choline transporter like-1, organic cation transporter-1 and choline kinase b were similar in normal and cancerous cells. We further showed that choline transport rates and choline kinase activity indeed increased by several fold in the cancer cells leading to the elevation of phosphocholine. The results strongly suggest that phosphocholine can serve as a biomarker of breast cancer reflecting upregulation of specific choline transporters and choline kinase genes. ' 2007 Wiley-Liss, Inc.

We suggest that augmentation of severely atrophied jaw bone through the placement of horizontal and/or vertical intraoral OBGs in combination with Bio-Oss saturated with PRP and covered by PPP should be considered a reliable, safe, and very effective surgical technique for obtaining high bone graft survival rate and high long-term implant survival rate.