Investigating Glioblastoma Multiforme Angiogenesis in In Vitro Three-Dimensional Microwell Platform



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Cancer is a serious health and social issue, causing about 8.2 million deaths worldwide. Of the most common cancer treatments, chemotherapy has shown the most promise in treating widespread cancers. Angiogenesis – the development of new blood vessels from pre-existing microvasculature – is a trademark of cancer that requires endothelial cell proliferation, cell migration through extra-cellular matrix, and cell-cell interactions. Understanding the angiogenic mechanisms of tumors is therefore essential for the development of reliable and effective therapies for cancer treatment. Although several in vivo/in vitro models have been developed to study these mechanisms, they have had limited success. Therefore, there remains a significant need for a reliable, cost-effective, three-dimensional (3D), in vitro angiogenesis model to investigate tumor formation. To address this need, we have developed a novel 3D in vitro GelMA-based platform that supports the co-culture of Glioblastoma and endothelial cells, and thus better mimics the in vivo microenvironment. Recently, our lab has investigated the efficacy of a novel 3D PEG hydrogel microwell platform by treating GBM spheroids in vitro with two widely-used FDA-approved drugs, Pitavastatin and Irinotecan, at different concentrations, individually and in combination. Our results show that the 3D in vitro platform we developed can be used to test drug sensitivity in vitro, while also having the potential for application in angiogenesis studies. In this study, we modified this 3D platform to better mimic an in vivo like microenvironment by using GelMA instead of PEG hydrogel to support co-cultured Glioblastoma and endothelial cells. Our studies confirmed in vitro formation of microtubules during the angiogenesis process. In the second part of this study, we tested the effectiveness of the angiogenesis inhibitor, TNP-470, in slowing or inhibiting the anti-angiogenic process in the 3D in vitro GelMA platform. Our data confirmed that the angiogenesis drug, TNP-470, was effective in significantly reducing the angiogenic progression of the GBM spheroids in the in vitro platform. We believe that our GelMA hydrogel based platform provides a novel, closed-loop system, 3D in vitro cancer model of cancer spheroids feeding through blood vessels. This platform can also be used for testing the effectiveness of other anti-angiogenesis drugs.



GBM, GelMA, Microwell, Angiogenesis, TNP-470


Portions of this document appear in: Nguyen, Duong Thanh, Yantao Fan, Yasemin M. Akay, and Metin Akay. "Investigating glioblastoma angiogenesis using a 3D in vitro GelMA microwell platform." IEEE transactions on nanobioscience 15, no. 3 (2016): 289-293. And in: Akay, Metin, Duong T. Nguyen, Yantao Fan, and Yasemin M. Akay. "Engineering a Three-Dimensional In Vitro Drug Testing Platform for Glioblastoma." Journal of Nanotechnology in Engineering and Medicine 6, no. 4 (2015): 041002. And in: Fan, Yantao, Naze G. Avci, Duong T. Nguyen, Andrei Dragomir, Yasemin M. Akay, Feng Xu, and Metin Akay. "Engineering a High-Throughput 3D In Vitro Glioblastoma Model." IEEE J. Transl. Eng. Health Med 3 (2015): 1-8.