Brett Elizabeth, Sauter Matthias, Timmins Éadaoin, Azimzadeh Omid, Rosemann Michael, Merl-Pham Juliane, Hauck Stefanie M, Nelson Peter J, Becker Karl Friedrich, Schunn Ilse, Lowery Aoife, Kerin Michael J, Atkinson Michael, Krüger Achim, Machens Hans-Günther, Duscher Dominik
Department of Plastic and Hand Surgery, Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany.
Department of Anatomy, National University of Ireland, Galway, Newcastle Road, H91 YR71 Galway, Ireland.
J Clin Med. 2020 Apr 2;9(4):991. doi: 10.3390/jcm9040991.
The triple-negative breast tumor boundary is made of aligned, linear collagen. The pro-oncogenic impact of linear collagen is well established; however, its mechanism of formation is unknown. An in vitro analogue of the tumor border is created by a co-culture of MDA-MB-231 cells, adipose derived stem cells, and dermal fibroblasts. Decellularization of this co-culture after seven days reveals an extracellular matrix that is linear in fashion, high in pro-oncogenic collagen type VI, and able to promote invasion of reseeded cells. Further investigation revealed linear collagen VI is produced by fibroblasts in response to a paracrine co-culture of adipose derived stem cells and MDA-MB-231, which together secrete high levels of the chemokine CCL5. The addition of monoclonal antibody against CCL5 to the co-culture results in an unorganized matrix with dramatically decreased collagen VI. Importantly, reseeded cells do not exhibit pro-oncogenic behavior. These data illustrate a cellular mechanism, which creates linear extracellular matrix (ECM) in vitro, and highlight a potential role of CCL5 for building striated tumor collagen in vivo.
三阴性乳腺癌的肿瘤边界由排列成线性的胶原蛋白构成。线性胶原蛋白的促癌作用已得到充分证实；然而，其形成机制尚不清楚。通过将MDA-MB-231细胞、脂肪来源干细胞和真皮成纤维细胞共培养，创建了肿瘤边界的体外类似物。7天后对这种共培养物进行脱细胞处理，揭示出一种呈线性、富含促癌的VI型胶原蛋白且能够促进重新接种细胞侵袭的细胞外基质。进一步研究发现，线性胶原蛋白VI是成纤维细胞在脂肪来源干细胞和MDA-MB-231的旁分泌共培养作用下产生的，这两种细胞共同分泌高水平的趋化因子CCL5。向共培养物中添加抗CCL5单克隆抗体，会导致基质变得无序，胶原蛋白VI显著减少。重要的是，重新接种的细胞不表现出促癌行为。这些数据阐明了一种在体外产生线性细胞外基质（ECM）的细胞机制，并突出了CCL5在体内构建横纹状肿瘤胶原蛋白中的潜在作用。
