Multilayer platform to model the bioactivity of hyaluronic acid in gastric cancer

Hyaluronic acid (HA) is a biopolymer that accumulates in the tumour microenvironment, especially around cancer cells. The accumulation is concomitant with changes of HA properties resulting in the generation of chains with different sizes. In this study, we developed a multilayer platform composed by HA of different molecular weights aiming to evaluate, in real time, the influence of HA on the biological response of gastric cancer cells. Here, we demonstrated that HA of low molecular weight triggers the formation of focal adhesion sites on MKN45 cells, with high expression of paxillin, responsible for the migration and activation of signalling cascades associated to the invasion and aggressiveness of cancer. In contrast, the surfaces containing HA of long chains inhibit the cellular adhesion, activating mechanisms of cellular apoptosis.

Authors and affiliations:
Sara Amorim (3B’s Research Group, I3Bs – Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal; ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal.)

Diana Soares da Costa (3B’s Research Group, I3Bs – Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal; ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal.)

Stefan Mereiter (Instituto de Investigação e Inovação em Saúde, , Universidade do Porto, Porto)

Iva Pashkuleva (3B’s Research Group, I3Bs – Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal; ICVS/3B’s - PT Government Associate Laboratory, Braga/, Portugal.)

Celso A. Reis (Instituto de Investigação e Inovação em Saúde, Universidade do Porto. IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto; Portugal; ICBAS, Universidade do Porto, Portugal; Faculdade Medicina, Universidade do Porto, Portugal)

Rui L. Reis (3B’s Research Group, I3Bs – Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal; ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal)

Ricardo A. Pires (3B’s Research Group, I3Bs – Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal; ICVS/3B’s - PT Government Associate Laboratory, Braga/, Portugal)

Abstract:
Hyaluronic acid (HA) has a key role in cancer progression. The HA's molecular weight (Mw) is altered in this pathological state: increased concentration of shorter fragments due to the overexpressed hyaluronidases and ROS. Aiming to mimic this microenvironment, we developed a Layer-by-Layer (LbL) platform presenting HA of different Mws, namely 6.4, 752 and 1500 kDa, to study the influence of HA Mw on the formation of focal adhesion sites (FAs), and the involvement of paxillin and CD44 in this process. High paxillin expression and formation of FAs, via CD44, is observed for MKN45 cells seeded on LbLs presenting HA 6.4 kDa, with the activation of the ERK1/2 pathway, responsible for cell motility and tumour progression. In contrast, activation of p38 pathway, usually related with cancer latency, is observed for cells seeded on LbLs with high Mw HA, i.e. 1500 kDa. Overall, we demonstrate the suitability of the developed platform to study cancer invasiveness.

Journal:
Materials Science and Engineering: C

Link: https://www.sciencedirect.com/science/article/pii/S0928493120335347