Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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A Novel 3D Platform to Investigate Neoangiogenesis, Transendothelial Migration and Metastasis of Breast Cancer Cells
Rachel C. Hooper, MD1, Karina A. Hernandez, DO1, Jeremiah Joyce, BA1, Adam Jacoby, BA1, Ope Asanbe, MD1, Ross Weinreb, BA Candidate1, Claudia Fischbach, PhD2.
1Weill Cornell Medical College, New York, NY, USA, 2Cornell University, Ithaca, NY, USA.

PURPOSE:
Breast cancer remains the most common cancer afflicting
women and is the second leading cause of death from cancer. A crucial step in the progression of this disease is the transendothelial migration of tumor cells into the blood stream or lymphatic system. The factors guiding this process remain poorly understood. The development an in vitro biomimetic platform to further investigate these factors is under intensive investigation. In previous work we synthesized a tissue-engineered scaffold containing an endothelialized internal loop microchannel for microsurgical anastomosis and in vivo perfusion utilizing a sacrificial microfiber technique. Here we design a novel 3D platform to investigate tumor cell behavior in the presence of vascular cells in order to better understand the cell-cell and cell-matrix interactions that drive neoangiogenesis, invasion, metastasis and ultimately tumor progression.
METHODS:
Pluronic F127 microfibers were sacrificed in neutralized type I collagen with 1 x106 cells/mL MDA-MB231 breast cancer cells suspended in the bulk of the hydrogel creating a central loop microchannel, 1.5 mm in
diameter. A 5 x106 cells/mL cell suspension of human umbilical vein
endothelial cells (HUVEC) or HUVEC and human aortic smooth muscle cells (HASMC) was seeded into the microchannel. Scaffolds without microchannel seeding served as controls. Following 7, 14, and 28 days of culture specimens were fixed and processed for histology.
RESULTS:
After 7, 14, and 28 days of culture, MDA-MB 231 cells had performed
significant matrix remodeling and migrated extensively toward the surface of the hydrogel or “lumen” of HUVEC/HASMC seeded microchannels. At 14 and 28 days dense MBA-MB231 tumor nests were seen within the collagen hydrogel bulk of HUVEC and HUVEC/HASMC-seeded microchannel constructs. After 7,14, and 28 days MDAMB demonstrated transendothelial migration into the central ‘neovessel’ of HUVEC-only seeded microchannels resulting in HUVEC apoptosis .
After 7, 14, and 28 days, the endothelial lining of HUVEC/HASMC appeared thinner and somewhat destabilized, without the elaboration of additional matrix proteins as had been seen in previous constructs without breast cancer cells in the bulk. Immunohistochemical staining demonstrated adherence of both CD31 and VWF expressing endothelial cells and α-SMA positive-smooth muscle cells along co-culture seeded microchannels. Epithelial cell adhesion molecule (EpCAM) positive staining of MDA-MB231 cells confirmed tumor cell migration toward HUVEC- and HASMC/HUVEC- seeded microchannels as well as breast cancer tumor aggregates within the bulk after 14 and 28 days. MDA-MB231 cells demonstrated no distinct pattern of tumor formation or transmigration
within the hydrogels containing unseeded microchannels.
CONCLUSION:
We have successfully created an in vitro 3D biomimetic platform to analyze the progression,transendothelial migration, and metastasis of MDA-MD231 breast cancer cells within tissue-engineered constructs containing endothelialized microchannels.Using our platform, we have demonstrated that signaling between tumor cells and endothelial cells plays a critical role in tumor invasiveness and metastatic potential. Such a model can be utilized to examine the efficacy of therapeutic interventions in the treatment of various malignancies and prevention of metastasis, shedding light on these incompletely understood phenomena.



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