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.
Overview
- The study focuses on developing a glioblastoma (GBM) model surrounded by vascular cells to understand interactions between tumors and adjacent blood vessels, essential for targeting various tumors, including brain tumors.
- The model was constructed by encapsulating GBM spheroids with layers of human smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs), mimicking the native tumor microenvironment.
- The study aims to develop an accurate tumor model for high-throughput screening (HTS) of anti-cancer drugs and understand the role of platelet endothelial cell adhesion molecule (PECAM) in GBM-blood vascular cell interactions.
Comparative Analysis & Findings
- Comparative analysis with tumors from different organs revealed the significant role of PECAM in GBM-blood vascular cell interactions.
- Cytokine secretion analysis demonstrated PECAM's impact on tumor-specific angiogenic potential and increased expression of PECAM-associated proteins, drug resistance cytokines, and genes associated with tumor progression and metastasis.
- Testing with anti-cancer drugs revealed changes in the tumor microenvironment, including increased expression of PECAM-associated proteins and cytokines, indicating a potential mechanism for drug resistance and tumor progression.
Implications and Future Directions
- The study highlights the importance of PECAM in GBM-blood vascular cell interactions and its potential role in tumor progression and metastasis.
- Future studies should aim to investigate the specific molecular mechanisms underlying PECAM's impact on tumor angiogenesis and metastasis.
- The HTS platform developed in this study can be used for testing anti-cancer drugs and identifying potential targets for brain tumor treatment, a critical step in developing effective therapies for glioblastoma patients.