Preferential, enhanced breast cancer cell migration on biomimetic electrospun nanofiber 'cell highways'.
BACKGROUND
Aggressive metastatic breast cancer cells seemingly evade surgical resection and current therapies, leading to colonization in distant organs and tissues and poor patient prognosis. Therefore, high-throughput in vitro tools allowing rapid, accurate, and novel anti-metastatic drug screening are grossly overdue. Conversely, aligned nanofiber constitutes a prominent component of the late-stage breast tumor margin extracellular matrix. This parallel suggests that the use of a synthetic ECM in the form of a nanoscale model could provide a convenient means of testing the migration potentials of cancer cells to achieve a long-term goal of providing clinicians an in vitro platform technology to test the efficacy of novel experimental anti-metastatic compounds.


METHODS
Electrospinning produces highly aligned, cell-adhesive nanofiber matrices by applying a strong electric field to a polymer-containing solution. The resulting fibrous microstructure and morphology closely resembles in vivo tumor microenvironments suggesting their use in analysis of migratory potentials of metastatic cancer cells. Additionally, a novel interface with a gel-based delivery system creates CXCL12 chemotactic gradients to enhance CXCR4-expressing cell migration.


RESULTS
Cellular dispersions of MCF-10A normal mammary epithelial cells or human breast cancer cells (MCF-7 and MDA-MB-231) seeded on randomly-oriented nanofiber exhibited no significant differences in total or net distance traveled as a result of the underlying topography. Cells traveled ~2-5 fold greater distances on aligned fiber. Highly-sensitive MDA-MB-231 cells displayed an 82% increase in net distance traversed in the presence of a CXCL12 gradient. In contrast, MCF-7 cells exhibited only 31% increase and MCF-10A cells showed no statistical difference versus control or vehicle conditions. MCF-10A cells displayed little sensitivity to CXCL12 gradients, while MCF-7 cells displayed early sensitivity when CXCL12 concentrations were higher. MDA-MB-231 cells displayed low relative expression levels of CXCR4, but high sensitivity resulting in 55-fold increase at late time points due to CXCL12 gradient dissipation.


CONCLUSIONS
This model could create clinical impact as an in vitro diagnostic tool for rapid assessment of tumor needle biopsies to confirm metastatic tumors, their invasiveness, and allow high-throughput drug screening providing rapid development of personalized therapies.
Mark Tyler
MT
Nelson
Aaron
A
Short
Sara L
SL
Cole
Amy C
AC
Gross
Jessica
J
Winter
Tim D
TD
Eubank
Department of Materials Science and Engineering, Ohio State University, 143 Fontana Labs, 116 W 19th Ave, Columbus, OH 43210-1179, USA. lannutti.1@osu.edu.
John J
JJ
Lannutti
D040761:Biomimetic Materials / Q000138:chemical synthesis; D001943:Breast Neoplasms / Q000737:chemistry / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002630:Chemotactic Factors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000648:ultrastructure; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D061986:MCF-7 Cells; D057139:Nanofibers / Q000648:ultrastructure*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000032:analysis; D019718:Receptors, CXCR4 / Q000235:genetics; D059016:Tumor Microenvironment
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D002630:Chemotactic Factors; D012333:RNA, Messenger; D019718:Receptors, CXCR4