Abstract 6312: Targeting HSPG is more efficient than using soluble heparin for interfering with cancer cell adhesion and migration

Abstract Given the relevance of heparan sulfate proteoglycans (HSPG) and of heparin binding ligands in the regulation of cancer cell adhesion, migration and invasiveness, drugs that may interfere with HSPG functions have been studied for decades for their possible use in oncology. In this view heparin analogues have been tested for their effectiveness not only in cancer associated thromboembolism but also for their potential effects on cancer growth and metastasis. Despite a number of promising preclinical results and clinical hypothesis, many different clinical trials on the use of heparin analogues in different cancers reported no significant benefits in tumor progression and overall survival, indicating that using heparin as a soluble decoy for the many HSPG ligands does not appear to be the best possible approach (1,2). Taking advantage of the tetra-branched peptide NT4, which is a specific ligand of HSPG sulfated glycosaminoglycan (GAG) chains (3, 4), we tested the effectiveness of targeting cell membrane HSPG, as a potential alternative approach for interfering with HSPG functions in cancer cell invasiveness. We had demonstrated that NT4 can either inhibit or increase oriented migration in respectively PANC-1 pancreas adenocarcinoma and TE671 rhabdomyosarcoma human cancer cells, indicating a crucial but diverse role of HSPGs in oriented cell migration in different cancer cells. NT4 and heparin were here compared for their effect on adhesion and migration of different cancer cell lines on extracellular matrix (ECM) supports, as well as for their effect on proliferation and in vitro invasiveness of the same cell lines. We found that inhibition of cancer cells adhesion to ECM proteins by NT4 varies in different cancer cell lines, ranging from 90% inhibition to as low as 20%, whereas heparin has no effect. Analogous results were obtained when testing cancer cell migration. NT4 inhibited migration and in vitro invasiveness of different human cancer cell lines, with the sole exception of TE671 cells. Heparin did not modify cell migration in any of the tested cancer cell lines. NT4 had no effect on cell proliferation, whereas, notably, heparin resulted to stimulate cell proliferation in some cancer cell lines. Differently from using heparin as an unspecific soluble decoy, targeting HSPG with well-defined ligands can result in an efficient tumor-specific treatment. Nevertheless, as for most cancer cellular targets, a detailed definition of cellular mechanisms and a related personalized approach is mandatory. 1) Schünemann HJ et al. Lancet Haematol. 2020;7(10):e746. 2) Posch F et al. ibid:e703. 3) Brunetti J et al. Sci. Rep. 2016,6,27174. 4) Depau L et al. J Med Chem 2020;63(24):15997. Citation Format: Lorenzo Depau, Elisabetta Mandarini, Jlenia Brunetti, Marta Zanchi, Chiara Falciani, Luisa Bracci. Targeting HSPG is more efficient than using soluble heparin for interfering with cancer cell adhesion and migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6312.