Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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The Investigation of Transendothelial Migration and Breast Cancer Metastasis Utilizing A Tissue Engineered, Ex Vivo Three Dimensional Vascularized Platform
Rachel C. Hooper, MD1, Ope A. Asanbe, MD1, Wilmina N. Landford, BA1, Adam M. Jacoby, BA1, Peipei Zhang, PhD1, Hector L. Osoria, BS1, Claudia Fischbach, PhD2, Jason A. Spector, MD, FACS1.
1Weill Cornell Medical College, New York, NY, USA, 2Cornell University, Ithaca, NY, USA.

Purpose: Breast cancer is the second most common cancer afflicting women in the United States. Transendothelial migration and metastasis are critical processes in the progression of most cancers, yet these processes remain poorly understood. In previous work, we utilized a sacrificial microfiber technique to synthesize a tissue-engineered scaffold containing an endothelialized loop microchannel for microsurgical anastomosis and in vivo perfusion. Here, we design a novel, three-dimensional (3D) platform to investigate tumor cell behavior in the presence of vascular cells in order to better understand the factors that drive neoangiogenesis, invasion, metastasis and ultimately tumor progression.
Methods: U-shaped Pluronic F127 microfibers, 1.5 mm in diameter, were sacrificed in neutralized type I collagen with 1x106 cells/mL of encapsulated MDAMB231breast cancer cells (MDAMBe). Twenty four hours following fiber sacrifice, 5 x106 cells/mL of human aortic smooth muscle cells (HASMC) and 5 x106 cells/mL of human umbilical vein endothelial cells (HUVEC) were sequentially seeded (24 hours apart) into the microchannel. Scaffolds without encapsulated MDAMB (MDAMBneg) served as controls. After 7 and 14 days of culture, scaffolds were fixed and processed for histology.
Results: After 7 and 14 days, MDAMBneg constructs exhibited microchannels consisting of CD31+ HUVEC along the luminal surface, -SMA-expressing HASMC in the subendothelial plane and deposition of critical extracellular matrix proteins, including collagen IV and fibronectin. In addition, intact adherans junctions were evidenced by VE cadherin expression along the luminal surface. After 7 and 14 days, MDAMBe constructs revealed microchannels with aberrantly organized HUVEC and HASMC. Further, there was evidence of transendothelial migration, as cancer cells initially encapsulated in the bulk were seen within the lumen. Additionally, MDAMB performed extensive matrix remodeling, forming dense tumor nests within the collagen hydrogel. Deposition of collagen IV and fibronectin was also noted, however, their relative expressions decreased over time.
Conclusions: We successfully created an in vitro, 3D biomimetic platform to analyze the factors that drive neoangiogenesis, tumor invasion, metastasis and ultimately tumor progression. Using our platform, we demonstrated that signaling between tumor cells and vascular 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.


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