Cancer cells often have an increased amount of glycans, such as sialic acid (SA), on the cell surface, which normally play an important role in cell growth, proliferation and differentiation. In this study, SA expression is determined by fluorescent nanoprobes, molecularly imprinted polymers, SA-MIPs. The nanoprobes are synthesized with an imprinting approach to produce tailor-made fluorescent core-shell particles with high affinity for cell surface SA. Inflammation and cytokine production are well known tumor promoters, modulating the cellular microenvironment, including an aberrant cell surface glycan pattern. The recombinant cytokines IL-4, IL-6, IL-8 and a cocktail of cytokines collected from stimulated T leukemia Jurkat cells were used to induce in vitro inflammation in two cell lines, and thereafter analyzed with the use of SA-MIPs and flow cytometry. One of the cell lines showed a different binding pattern of SA-MIPs after treatment with recombinant cytokines and the cytokine cocktail. This study shows that SA-MIPs can be an important tool in the investigation of overexpressed glycans in the tumor microenvironment.

Aim: Lactate can signal through the endogenous lactate receptor, GPR81, which is expressed in some cancers. Lactate metabolism is altered by the metastasis-promoting process of epithelial-mesenchymal transition (EMT). This study examined the expression and function of GPR81 in breast cancer samples, and in receptor-positive epithelial vs. triple-negative post-EMT mesenchymal breast cancer cells.

Methods: GPR81 mRNA expression was examined by breast cancer microarray, and by a Kaplan-Meier survival curve. Using 3-dimensional culture conditions, GPR81 mRNA expression in epithelial and mesenchymal breast cancer cell lines was measured by qRT-PCR. GPR81 siRNA was used to assess the role of GPR81, alone or in conjunction with tamoxifen, in the regulation of MCT1 and MCT4 lactate transporters, intracellular lactate, and cell proliferation and survival.

Results: GPR81 mRNA levels were elevated in receptor-positive breast cancer, relative to non-tumor and triple-negative samples, and correlated with increased survival. GPR81 expression was elevated in the two epithelial breast cancer cell lines vs. the corresponding post-EMT mesenchymal cell lines. GPR81 knock-down in epithelial MCF7 cells caused: 1, selectively lower mRNA and protein expression of the MCT1 transporter, but not MCT2 or MCT4 transporters; 2, lower levels of intracellular lactate; and 3, decreased proliferation and survival in lactate only-containing conditions. GPR81 siRNA plus tamoxifen displayed additive suppressive effects on MCT1 expression and cell viability.

Conclusion: GPR81 promotes the ability of epithelial breast cancer cells to import lactate for energy use. As such, GPR81 represents a potential target for treatment of hormone-positive breast cancer cells, and may be prognostic for higher grade breast cancer.

Metabolism is defined as the collection of complex biochemical processes that living cells use to generate energy and maintain their growth and survival. Metabolism encompasses the synthesis and breakdown of glucose, fatty acids, and amino acids; the generation of energy (ATP); and oxidative phosphorylation. In cancer cells, metabolism can be commandeered to promote tumor growth and cellular proliferation. These alterations in metabolism have emerged as an additional hallmark of various cancers. In this review we focus on metabolic alterations in multiple myeloma (MM) - a malignancy of plasma cells - including derangements in glycolysis, gluconeogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid/amino acid synthesis and degradation. Particular focus is given to metabolic alterations that contribute to myeloma cell growth, proliferation and drug resistance. Finally, novel approaches that target metabolic pathways for the treatment of MM are discussed.

The carcinogenic mechanism proposed considers that stem cells committed to repair tissues and differentiated cells, acquire different metabolic properties, if there is an associated GABA deficiency suppressing a control system of the endocrine pancreas. This control system mediated by GABA, released with insulin, normally turns off glucagon and somatostatin release when insulin is released. A consequence of the GABA deficiency in pancreas and adrenals is a hybrid insulin-glucagon-somatostatin message, received by new mitotic stem cells displaying then a hybrid metabolic rewiring. This gives them a selective metabolic advantage over differentiated cells that become insulin resistant and only receive the glucagon- somatostatin part of the hormonal message. Indeed, their insulin receptors are desensitized by the persistent leakage of insulin resulting from the GABA deficiency that fails to close the insulin release mechanism. Thus differentiated cells are simply rewired to be plundered by stem cells. The metabolic advantage gained by stem cells blocks their own differentiation and maintains their mitotic capacity. Inevitable mutations of mitotic cells follow, the immune system is unable to eliminate a geometrically increasing number of altered stem cells, a selection of the most aggressive but metabolically successful population takes place when cancer is declared.