Jeon Jessie S, Bersini Simone, Gilardi Mara, Dubini Gabriele, Charest Joseph L, Moretti Matteo, Kamm Roger D
Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
Department of Electronics, Information and Bioengineering, Politecnico di Milano, 20133 Milan, Italy; Cell and Tissue Engineering Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Ortopedico Galeazzi, 20161 Milan, Italy;
Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):214-9. doi: 10.1073/pnas.1417115112. Epub 2014 Dec 18.
A key aspect of cancer metastases is the tendency for specific cancer cells to home to defined subsets of secondary organs. Despite these known tendencies, the underlying mechanisms remain poorly understood. Here we develop a microfluidic 3D in vitro model to analyze organ-specific human breast cancer cell extravasation into bone- and muscle-mimicking microenvironments through a microvascular network concentrically wrapped with mural cells. Extravasation rates and microvasculature permeabilities were significantly different in the bone-mimicking microenvironment compared with unconditioned or myoblast containing matrices. Blocking breast cancer cell A3 adenosine receptors resulted in higher extravasation rates of cancer cells into the myoblast-containing matrices compared with untreated cells, suggesting a role for adenosine in reducing extravasation. These results demonstrate the efficacy of our model as a drug screening platform and a promising tool to investigate specific molecular pathways involved in cancer biology, with potential applications to personalized medicine.
癌症转移的一个关键方面是特定癌细胞倾向于归巢至特定的次级器官亚群。尽管存在这些已知倾向，但其潜在机制仍知之甚少。在此，我们开发了一种微流控三维体外模型，以分析器官特异性人乳腺癌细胞通过与壁细胞同心包裹的微血管网络外渗至模拟骨和肌肉的微环境中。与未处理或含有成肌细胞的基质相比，在模拟骨的微环境中，外渗率和微血管通透性显著不同。与未处理的细胞相比，阻断乳腺癌细胞的A3腺苷受体导致癌细胞向含有成肌细胞的基质中的外渗率更高，这表明腺苷在减少外渗中发挥作用。这些结果证明了我们的模型作为药物筛选平台的有效性，以及作为研究癌症生物学中特定分子途径的有前景工具的有效性，具有在个性化医学中的潜在应用。
