title: A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone.
abstract: Cancer metastases arise following extravasation of circulating tumor cells with certain tumors exhibiting high organ specificity. Here, we developed a 3D microfluidic model to analyze the specificity of human breast cancer metastases to bone, recreating a vascularized osteo-cell conditioned microenvironment with human osteo-differentiated bone marrow-derived mesenchymal stem cells and endothelial cells. The tri-culture system allowed us to study the transendothelial migration of highly metastatic breast cancer cells and to monitor their behavior within the bone-like matrix. Extravasation, quantified 24 h after cancer cell injection, was significantly higher in the osteo-cell conditioned microenvironment compared to collagen gel-only matrices (77.5 ± 3.7% vs. 37.6 ± 7.3%), and the migration distance was also significantly greater (50.8 ± 6.2 μm vs. 31.8 ± 5.0 μm). Extravasated cells proliferated to form micrometastases of various sizes containing 4 to more than 60 cells by day 5. We demonstrated that the breast cancer cell receptor CXCR2 and the bone-secreted chemokine CXCL5 play a major role in the extravasation process, influencing extravasation rate and traveled distance. Our study provides novel 3D in vitro quantitative data on extravasation and micrometastasis generation of breast cancer cells within a bone-like microenvironment and demonstrates the potential value of microfluidic systems to better understand cancer biology and screen for new therapeutics.
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano 20133, Italy; Cell and Tissue Engineering Lab, IRCCS Istituto Ortopedico Galeazzi, Milano, 20161 Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Bersini
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Jessie S
authors.initials: JS
authors.lastname: Jeon
authors.affiliation: Department of Chemistry, Materials and Chemical Engineering, Politecnico di Milano, Milano 20133, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dubini
authors.affiliation: Cell and Tissue Engineering Lab, Gruppo Ospedaliero San Donato Foundation, Milano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Arrigoni
authors.affiliation: School of Mechanical Engineering, Korea University, Seoul 136-705, South Korea.
authors.forename: Seok
authors.initials: S
authors.lastname: Chung
authors.affiliation: Charles Stark Draper Laboratory, Cambridge, MA 02139, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Charest
authors.affiliation: Cell and Tissue Engineering Lab, IRCCS Istituto Ortopedico Galeazzi, Milano, 20161 Italy. Electronic address: matteo.moretti@grupposandonato.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Moretti
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: rdkamm@mit.edu.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Kamm
mesh_terms: D001854:Bone Marrow Cells / Q000378:metabolism; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054365:Chemokine CXCL5 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D044085:Microfluidics / Q000379:methods*; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism
chemical_list: C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; D023063:Receptors, Interleukin-8B; D003094:Collagen
keywords: Bone; Breast cancer; Extravasation; Hydrogel; Metastasis; Microfluidics