Abstract
Previous indirect 2D co-culture studies have demonstrated that mesenchymal stem cells (MSCs) promote breast cancer (BC) progression through secretion of paracrine factors including growth factors, cytokines and chemokines. In order to investigate this aspect of the tumour microenvironment in a more relevant 3D co-culture model, spheroids incorporating breast cancer cells (BCCs), both cell lines and primary BCCs expanded as patient-derived xenografts, and MSCs were established. MSCs in co-cultures were shown to enhance proliferation of estrogen receptor (ER)/progesterone receptor (PR)-positive BCCs. In addition, co-culture resulted in downregulation of E-cadherin in parallel with upregulation of the epithelial-mesenchymal transition (EMT)-relation transcription factor, SNAIL. Cytoplasmic relocalization of ski-related novel protein N (SnON), a negative regulator of transforming growth factor-beta (TGF-β) signalling, and of β-catenin, involved in a number of pathways including Wnt signalling, was also observed in BCCs in co-cultures in contrast to monocultures. In addition, the β-catenin inhibitor, 3-[[(4-methylphenyl)sulfonyl]amino]-benzoic acid methyl ester (MSAB), mediated reduced growth and invasion in the co-cultures. This study highlights the potential role for SnON as a biomarker for BC invasiveness, and the importance of interactions between TGF-β and Wnt signalling, involving SnON. Such pathways may contribute towards identifying possible targets for therapeutic intervention in BC patients.
Highlights
There is growing recognition of the importance of the tumour microenvironment (TME), especially cells within the stroma, in determining biological characteristics of cancer cells such as proliferation, Cancers 2020, 12, 2290; doi:10.3390/cancers12082290 www.mdpi.com/journal/cancersCancers 2020, 12, 2290 invasion and drug resistance [1,2,3,4,5,6]
To restore mesenchymal cell-driven signalling, we have established a co-culture model incorporating breast cancer cells (BCCs) together with mesenchymal stem cells (MSCs), using either breast cancer (BC) cell lines or BCCs isolated from patient-derived xenografts
We have shown that there is enhanced proliferation and invasion of Estrogen Receptor (ER)/progesterone receptor (PR)-positive BCCs in the co-culture models compared with the monocultures
Summary
There is growing recognition of the importance of the tumour microenvironment (TME), especially cells within the stroma, in determining biological characteristics of cancer cells such as proliferation, Cancers 2020, 12, 2290; doi:10.3390/cancers12082290 www.mdpi.com/journal/cancersCancers 2020, 12, 2290 invasion and drug resistance [1,2,3,4,5,6]. The presence of several growth factors and chemokines including hepatocyte growth factor (HGF), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), transforming growth factor-beta (TGF-β) and CCL-5 in MSC-conditioned medium in 2D suggests that, once within the TME, MSCs secrete growth factors that promote tumour growth, epithelial-mesenchymal transition (EMT) and invasion through direct paracrine actions and remodelling of extracellular matrix [8,9,10,11]; activated signalling axes identified in this way may provide therapeutic targets. In vivo xenograft models have been used [15] but cross-species interaction between human tumour and murine stromal cells [16] may mask the real signalling axes activated in cancer cells by human MSCs
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