A Three-Dimensional Dense Collagen Hydrogel to Model Cancer Cell/Osteoblast Interactions.

Mark James-Bhasin,Showan Nazhat,Peter Siegel

doi:10.3390/jfb9040072

Mark James-Bhasin, Showan Nazhat + Show 1 more

Open Access

https://doi.org/10.3390/jfb9040072

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Abstract

No curative treatment options exist once breast cancer metastasizes to bone. This is due, in part, to an incomplete understanding of how osteolytic cancers interact with bone. Presented here is a novel approach to study the interactions between triple negative breast cancer cells and osteoblasts within a 3D collagenous environment. More specifically, a dense collagen hydrogel was employed to model interactions between MDA-MB-231 breast cancer cells and MC3T3-E1 pre-osteoblasts. Co-cultures with these two cell types, or MDA-MB-231-derived conditioned medium applied to MC3T3-E1 cells, were established in the context of plastically compressed dense collagen gel matrices. Importantly, breast cancer-derived conditioned medium or the establishment of breast cancer/osteoblast co-cultures did not negatively influence MC3T3-E1 cell viability. The inclusion of either conditioned medium or the presence of MDA-MB-231 cells resulted in impaired MC3T3-E1 differentiation into osteoblasts, which coincided with reduced osteoblast-mediated mineralization. The results presented here demonstrate that dense collagen gels provide a model environment to examine the effect of osteolytic breast cancer cells on osteoblast differentiation and subsequent mineralization of the collagen scaffold.

Highlights

The “seed and soil” hypothesis first described by Stephen Paget still governs our view of cancer metastasis [1]
Breast cancers can be sub-divided into several intrinsic subtypes, which include Luminal A, Luminal B, human epidermal growth factor receptor 2 (HER2+), and basal breast cancer, and show a high propensity to spread to bone [4]
Basal breast cancers, which include triple negative breast cancer (TNBC), are a poor-prognosis subtype, and limited treatment responses and relapse are of grave clinical concern [5,6]

Summary

Introduction

The “seed and soil” hypothesis first described by Stephen Paget still governs our view of cancer metastasis [1]. The central tenant of this hypothesis is that the metastatic cancer cells must possess a compatibility with the microenvironment to enable successful colonization and the formation of metastases [2,3]. Breast cancers can be sub-divided into several intrinsic subtypes, which include Luminal A, Luminal B, human epidermal growth factor receptor 2 (HER2+), and basal breast cancer, and show a high propensity to spread to bone [4]. Luminal A breast cancer spreads primarily to the bone only, whereas Luminal B, HER2+, and basal breast cancers metastasize to bone and soft tissue sites. Basal breast cancers, which include triple negative breast cancer (TNBC), are a poor-prognosis subtype, and limited treatment responses and relapse are of grave clinical concern [5,6]. Progression to palliative care and subsequent morbidity are associated with a patient diagnosis of metastatic osteolytic TNBC [7,8]

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