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

Soliman, Faris 2021. The therapeutic potential of targeting hyaluronic acid to prevent peritoneal metastatic dissemination in colorectal cancer. MD Thesis, Cardiff University. Item availability restricted.

Preview	PDF - Accepted Post-Print Version Download (35MB) | Preview
	PDF (Cardiff University Electronic Publication Form) - Supplemental Material Restricted to Repository staff only Download (165kB)

Abstract

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=<0.0001) in CRC. Whereas, in non-HA-dependent adhesion molecules showed eithersignificant downregulation or no expression difference. In vitro adhesion assays saw significantly reduced cellular adhesion of HT115, HRT-18 and Caco-2 cell lines when treated with either HAi or excess exogenous HA in peritoneal mimicking plate coated models. Free-floating CRC cells in suspension demonstrated, firstly, significantly decreased viability at 24-hours when compared to controls (HAi p=0.0040, HA312ug/ml p= 0.0039 and HA624ug/ml p= 0.0019). Secondly, treatment groups exhibited reduced aggregation when compared to controls (HAi p=0.0015, HA312ug/ml p=0.0027 and HA624ug/ml p=0.0017). In vivo experimentation demonstrated no difference in weight or subcutaneous tumour size growth between groups. However, a significant reduction in the number of PM was seen for both treatment groups, compared to controls (HAi p=0.0094, HA p=0.0009). Interestingly, there was no significant difference in average peritoneal tumour nodule size between the groups compared to controls (HAi p=0.7976, HA p=0.4536). Conclusions Expression of HA-dependent adhesion molecules is increased in CRC. Targeting HAdependent adhesion potentially affects CRC cells’ ability to survive in the peritoneal environment and may have a potential therapeutic use in treatment or prevention of PM in CRC. Further in vitro and in vivo modelling is needed.

Item Type:	Thesis (MD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	14 November 2022
Last Modified:	08 Nov 2023 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/154039

Actions (repository staff only)

Edit Item