Hyaluronic Acid of Low Molecular Weight Triggers the Invasive “Hummingbird” Phenotype on Gastric Cancer Cells

The overproduction and deposition of hyaluronic acid (HA) of different sizes in the tumor microenvironment is associated with cancer metastasis. Here, the development of layer-by-layer (LbL) constructs containing HA of different molecular weights (i.e., 5.6, 618, and 1450 kDa) that mimic the HA-rich cancer extracellular matrix is described to study the effect of the HA's size on the behavior of gastric cancer cells (AGS). The results demonstrate that LbL constructs with short HA, i.e., 5.6 kDa, activate the cytoskeleton rearrangement leading to the "hummingbird" morphology, promote high cellular motility, and activate signaling pathways with increased expression of p-ERK1/2 and p-AKT. In addition, it is demonstrated that this malignant transformation involves an active participation of the HA coreceptor RHAMM in AGS cells.