Abstract
Cancer is characterized by cell heterogeneity and the development of 3D invitro assays that can distinguish more invasive or migratory phenotypes could enhance diagnosis or drug discovery. 3D collagen scaffolds have been used to develop analogues of complex tissues invitro and are suited to routine biochemical and immunological assays. We sought to increase 3D model tractability and modulate the migration rate of seeded cells using an ice-templating technique to create either directional/anisotropic or non-directional/isotropic porous architectures within cross-linked collagen scaffolds. Anisotropic scaffolds supported the enhanced migration of an invasive breast cancer cell line MDA-MB-231 with an altered spatial distribution of proliferative cells in contrast to invasive MDA-MB-468 and non-invasive MCF-7cells lines. In addition, MDA-MB-468 showed increased migration upon epithelial-to-mesenchymal transition (EMT) in anisotropic scaffolds. The provision of controlled architecture in this system may act both to increase assay robustness and as a tuneable parameter to capture detection of a migrated population within a set time, with consequences for primary tumour migration analysis. The separation of invasive clones from a cancer biomass with invitro platforms could enhance drug development and diagnosis testing by contributing assay metrics including migration rate, as well as modelling cell-cell and cell-matrix interaction in a system compatible with routine histopathological testing.
Highlights
The process of metastasis, whereby cancer cells are able to disengage from a primary tumour and seed and colonise distant sites of the body, remains the primary key contributor to cancer lethality
Together with the ability to degrade extracellular matrix is a critical requirement for invasion [1] and could form a potential metric for assessing drug potency alongside indices of cell death
The fabrication of 3D collagen scaffolds combining functional internal anisotropic architecture with a defined funnel feature for repeatable cell seeding was confirmed by microecomputed tomography and scanning electron microscopy (SEM) (Fig. 3)
Summary
The process of metastasis, whereby cancer cells are able to disengage from a primary tumour and seed and colonise distant sites of the body, remains the primary key contributor to cancer lethality. Together with the ability to degrade extracellular matrix is a critical requirement for invasion [1] and could form a potential metric for assessing drug potency alongside indices of cell death. Cellular heterogeneity is a defining feature of the cancer microenvironment, and in vitro test systems that can distinguish or even separate cell types dependent on their migratory or invasive ability could contribute enhanced platforms for diagnosis or aid drug development [3]. In vitro cellular assays for examining cancer invasiveness and migratory potential within 3D extracellular matrices remain potent tools for examining features of this process [4,5], such models need adaptation into standardized and reproducible formats suitable for high-throughput applications [6]. If migration is to form a useful parameter for studies of cell behaviour and drug efficacy in this context, 3D models should be consistent with regard to fabrication and incorporate deterministic architecture to minimise random cell migration patterns
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