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A Tissue Engineered Three Dimensional Vascularized Platform to Investigate Metastatic Behavior
Rachel C. Hooper, MD, Adam Jacoby, BA, Ope A. Asanbe, MD, Wilmina N. Landford, BA, Peipei Zhang, PhD, Hector L. Osoria, BS, Jason A. Spector, MD, FACS.
Weill Cornell Medical College, New York, NY, USA.

BACKGROUND: Transendothelial migration and metastasis are critical processes in the progression of most cancers, yet these processes remain poorly understood. Previously, we utilized a sacrificial microfiber technique to fabricate a tissue-engineered scaffold containing a functional vascularized microchannel for microsurgical anastomosis and in vivo perfusion. Here, we design a novel, three-dimensional (3D) platform to investigate breast cancer behavior in the presence of an engineered neovessel 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 MDAMB231 breast 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. Additional constructs with MDAMB231 breast cancer cells encapsulated in collagen without microchannel seeding (MDAMBbulk) were also fabricated. 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, α-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 to have migrated into the lumen. Cell density measurements confirmed MDAMBbulk constructs demonstrated a diffuse distribution of MDAMB231 cells without appreciable transendothelial migration. 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 expression decreased with time.
CONCLUSION: We successfully fabricated a 3D biomimetic platform for in vitro analysis of factors that drive neoangiogenesis, tumor invasion, metastasis and ultimately tumor progression. This model more closely recapitulates the in vivo tumor microenvironment by placing cells within 3D culture and in proximity to a functional small vessel. Using our platform, we successfully demonstrated that signaling between tumor cells and vascular cells plays a critical role in tumor progression and metastatic potential. Such a model can be utilized to further characterize tumor activity as well as to examine the efficacy of therapeutic interventions in the treatment of various malignancies.

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