The therapeutic potential of targeting hyaluronic acid to prevent peritoneal metastatic dissemination in colorectal cancer

Background Peritoneal Metastasis (PM) in Colorectal Cancer (CRC) undoubtedly remains a challenge to treat and often portends a poor prognosis for patients. Hyaluronic acid (HA) is found throughout the body and is particularly found in abundance coating the mesothelial cells of the peritoneum. Interaction of HA with HA-dependent adhesion molecules can facilitate cell adhesion to the peritoneum. HA may play a role in spread of PM in CRC in association with known HA-receptor molecules CD44, RHAMM and ICAM-1. Methods Expression of HA-dependent and HA-independent adhesion molecules was examined in CRC using tissue microarray datasets and matched to clinicopathological data. In vitro peritoneal modelling tested CRC cellular adhesion when treated with either a small peptide competitive binding HA-inhibitor (HAi) or excess exogenous HA. Further in vitro testing assessed CRC ability to aggregate and survive when in suspension, evaluating the ability of cells both to survive and to aggregate at fixed time points. An in vivo Xenograft peritoneal model was used, using three groups of CD1 nude mice injected with CRC cells both intraperitoneally (IP) and subcutaneously to monitor tumour growth. Treatment groups received either a further IP injection of HAi or HA continuously for 5 days for the first week of treatment and biweekly for the remaining three weeks and compared to a control. (PPL: PE9445FC2). Results Tissue microarray data demonstrated a significant increase in RNA expression of the three HA-dependent adhesion molecules CD44 (p=<0.0001), RHAMM (p=0.0004) and ICAM-1 (p=