No abstract

Cancer stem cells (CSCs) represent a small subpopulation of self-renewing oncogenic cells. As in many other stem cells, metabolic reprogramming has been implicated to be a key characteristic of CSCs. However, little is known about how the metabolic features of cancer cells are controlled to orchestrate their CSC-like properties. We recently demonstrated that hyaluronan (HA) overproduction allowed plastic cancer cells to revert to stem cell states. Here, we adopted stable isotope-assisted tracing and mass spectrometry profiling to elucidate the metabolic features of HA-overproducing breast cancer cells. These integrated approaches disclosed an acceleration of metabolic flux in the hexosamine biosynthetic pathway (HBP). A metabolic shift toward glycolysis was also evident by quantitative targeted metabolomics, which was validated by the expression profiles of key glycolytic enzymes. Forced expression of glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), an HBP rate-limiting enzyme, resembled the results of HA overproduction with regard to HIF-1α accumulation and glycolytic program, whereas GFAT1 inhibition significantly decreased HIF-1α protein level in HA-overproducing cancer cells. Moreover, inhibition of the HBP-HIF-1 axis abrogated HA-driven glycolytic enhancement and reduced the CSC-like subpopulation. Taken together, our results provide compelling evidence that HA production regulates the metabolic and CSC-like properties of breast cancer cells via HBP-coupled HIF-1 signaling.

. These results suggest that versican facilitates chondrogenesis and joint morphogenesis, by localizing TGF-␤ in the extracellular matrix and regulating its signaling.

We have developed an antibody-based method to assess plasma uptake of a proprietary Undaria-derived fucoidan galactofucan sulfate (GFS(TM)) after oral ingestion by human volunteers. Fucoidans have high-molecular-weights but exert biological effects in experimental animals after oral intake. By using a novel antibody raised against sulfated polysaccharides, we carried out a competitive ELISA to quantitate GFS in plasma samples from healthy volunteers who ingested 3 g/day of whole Undaria containing 10% GFS fucoidan, purified 75% GFS fucoidan, or 3 g of a nonsulfated placebo polysaccharide over 12 days. Increased reactivity to the novel antibody, as measured against preingestion levels, was detected at all time points. Assuming the measured material to be intact GFS, the concentration detected (median) was 4.002 and 12.989 mg/l when 3 g of 10% or 75% pure fucoidan was ingested orally over a period of 12 days, respectively. High-molecular-weight fucoidan can be detected in plasma using an ELISA competitive assay based on a novel antibody to sulfated polysaccharides.

Background: Hyaluronan overproduction is implicated in breast cancer progression. Results: Hyaluronan overproduction expands cancer stem-like cells through the up-regulation of Snail and Twist expression. Conclusion: Hyaluronan overproduction allows plastic cancer cells to revert to stem cell states via Twist and the transforming growth factor ␤-Snail signaling axis. Significance: These findings will help to understand the unique hyaluronan-dependent mechanisms that govern cancer cell plasticity and cancer stem cell expansion.