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Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):214-9. doi: 10.1073/pnas.1417115112. Epub 2014 Dec 18.

Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation.

Author information

1
Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
2
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;
3
Cell and Tissue Engineering Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Ortopedico Galeazzi, 20161 Milan, Italy; PhD School in Life Sciences, Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy;
4
Department of Chemistry, Materials and Chemical Engineering, Politecnico di Milano, 20133 Milan, Italy;
5
Charles Stark Draper Laboratory, Cambridge, MA 02139; and.
6
Cell and Tissue Engineering Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Ortopedico Galeazzi, 20161 Milan, Italy; matteo.moretti@grupposandonato.it rdkamm@mit.edu.
7
Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 matteo.moretti@grupposandonato.it rdkamm@mit.edu.

Abstract

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.

KEYWORDS:

breast cancer; extravasation; metastasis; microenvironment; microfluidics

PMID:
25524628
PMCID:
PMC4291627
DOI:
10.1073/pnas.1417115112
[Indexed for MEDLINE]
Free PMC Article

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