High throughput drug screening platform utilizing capillary and artery cell layered models based on tumor-vascular cell interactions.

Abstract

Interactions between tumors and adjacent blood vessels are critical in the tumor microenvironment (TME) for influencing angiogenesis and hematogenous metastasis. Understanding these interactions within the native TME is vital for targeting various tumors, including brain tumors, due to the complexities of the blood-brain barrier. Developing an accurate tumor model that includes cell-cell and cell-matrix interactions, as well as blood flow-induced shear stress, is essential for high-throughput screening (HTS) of anti-cancer drugs. Here, we developed a glioblastoma (GBM) model surrounded by vascular cells. The arterial model was constructed by encapsulating GBM spheroids with layers of human smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs), while the capillary cell layered model used only HUVECs. Comparative analysis with tumors from different organs revealed the significant role for platelet endothelial cell adhesion molecule (PECAM) in GBM-blood vascular cell interactions. Cytokine secretion analysis demonstrated PECAM's impact on tumor-specific angiogenic potential. Testing with anti-cancer drugs revealed increased expression of PECAM-associated proteins, drug resistance cytokines, and genes associated with tumor progression and metastasis. Additionally, we developed a HTS platform by encapsulating these tumor models in hydrogels and subjecting them to media circulation, effectively mimicking the dynamic TME, suitable for cancer treatment research and drug development.