TY - JOUR
T1 - Microfluidic Tumor–Vascular Model to Study Breast Cancer Cell Invasion and Intravasation
AU - Nagaraju, Supriya
AU - Truong, Danh
AU - Mouneimne, Ghassan
AU - Nikkhah, Mehdi
N1 - Funding Information:
S.N. and D.T. contributed equally to this work. The authors would like to acknowledge National Science Foundation Award No. CBET 1510700. D.T. acknowledges the 2017–2018 Achievement Rewards for College Scientists (ARCS) Scholarship, and the 2016–2017 International Foundation for Ethical Research (IFER) Fellowship. The authors also acknowledge Harpinder Saini for advice and thoughtful discussions as well as Thai Nguyen for assistance with device preparation. Finally, CD-31 antibody was purchased from the Developmental Studies Hybridoma Bank, deposited to the DSHB by E. A. Wayner/G. Vercellotti, and maintained at The University of Iowa, Department of Biology, Iowa City, IA.
Publisher Copyright:
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2018/5/9
Y1 - 2018/5/9
N2 - Cancer is a major leading cause of disease-related death in the world. The severe impact of cancer can be attributed to poor understanding of the mechanisms involved in earliest steps of the metastatic cascade, specifically invasion into the surrounding stroma and intravasation into the blood capillaries. However, conducting integrated biological studies of invasion and intravasation have been challenging, within in vivo models and traditional in vitro assay, due to difficulties in establishing a precise tumor microenvironment. To that end, in this work, a novel 3D microfluidic platform comprised of concentric three-layer cell-laden hydrogels for simultaneous investigation of breast cancer cell invasion and intravasation as well as vasculature maturation influenced by tumor–vascular crosstalk is developed. It was demonstrated that the presence of spontaneously formed vasculature enhance MDA-MB-231 invasion into the 3D stroma. Following invasion, cancer cells are visualized intravasating into the outer vasculature. Additionally, invading cancer cells significantly reduce vessel diameter while increasing permeability, consistent with previous in vivo studies. Major signaling cytokines involved in tumor–vascular crosstalk that govern cancer cell invasion and intravasation are further identified. Taken together, this platform will enable unique insights of critical biological events within the metastatic cascade, with significant potential for developing efficient cancer therapeutics.
AB - Cancer is a major leading cause of disease-related death in the world. The severe impact of cancer can be attributed to poor understanding of the mechanisms involved in earliest steps of the metastatic cascade, specifically invasion into the surrounding stroma and intravasation into the blood capillaries. However, conducting integrated biological studies of invasion and intravasation have been challenging, within in vivo models and traditional in vitro assay, due to difficulties in establishing a precise tumor microenvironment. To that end, in this work, a novel 3D microfluidic platform comprised of concentric three-layer cell-laden hydrogels for simultaneous investigation of breast cancer cell invasion and intravasation as well as vasculature maturation influenced by tumor–vascular crosstalk is developed. It was demonstrated that the presence of spontaneously formed vasculature enhance MDA-MB-231 invasion into the 3D stroma. Following invasion, cancer cells are visualized intravasating into the outer vasculature. Additionally, invading cancer cells significantly reduce vessel diameter while increasing permeability, consistent with previous in vivo studies. Major signaling cytokines involved in tumor–vascular crosstalk that govern cancer cell invasion and intravasation are further identified. Taken together, this platform will enable unique insights of critical biological events within the metastatic cascade, with significant potential for developing efficient cancer therapeutics.
KW - cancer metastasis
KW - intravasation
KW - microfluidics
KW - tumor microenvironment
KW - tumor models
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U2 - 10.1002/adhm.201701257
DO - 10.1002/adhm.201701257
M3 - Article
C2 - 29334196
AN - SCOPUS:85040673882
SN - 2192-2640
VL - 7
JO - Advanced Healthcare Materials
JF - Advanced Healthcare Materials
IS - 9
M1 - 1701257
ER -