Abstract LB-045: A tissue-engineered vascularized tumor microenvironment for preclinical testing of anticancer therapeutics

Abstract

Abstract Despite significant advances in cancer research the most aggressive breast cancers remain incurable. Better methods are necessary to predict efficacy of therapeutic regimes and are critical to improving clinical outcomes. Drug screens using conventional 2D and 3D in vitro tissue culture assays are relatively inexpensive, yet are often insufficient in predicting patient response to drugs. This is likely due to the inability of conventional tissue culture to recapitulate the complex tissue architecture and physiological cues required for cellular interactions. A particularly critical shortcoming of these models is the lack of tumor vasculature within the tissue. Although mouse models remain the gold standard for clinical drug development, they are expensive, of ethical concern, and importantly, do not reliably predict clinical outcome. Thus, promising drug candidates in preclinical trials often fail in expensive clinical studies. In response to these limitations, a number of groups are beginning to develop microfluidic approaches to studying cancer biology. Nortis provides microfluidic systems for the in vitro generation of living 3D perfused tissue microenvironments. At the heart of Nortis’ microfluidic chip is a small 25-ul culture chamber in which a lumenally perfused microvessel is formed by casting extracellular matrix around a thin glass fiber. Removal of the fiber creates a single tubular void in line with a fluidic circuit. With this method users can create complex microenvironments with perfusable vascular networks. The chip design also facilitates high-quality brightfield and fluorescence imaging, histology, and collection of fluids for downstream analysis. Using this technology, we developed a vascularized breast cancer model. Vascular networks were created by tissue-engineering perfusable ‘parent’ endothelial vessels within a collagen matrix. The quiescent cell tubes were cultured for up to 60 days and could be induced to sprout directionally in response to growth factors. The sprouting vessels responded to flow, underwent anastomosis, and eventually established perfusable vascular networks. When co-cultured with tumor cells the sprouts invaded the tumor tissue yielding vascularized tumor microenvironments. The perfusable vasculature recapitulates a key feature of the tumor microenvironment, enables preclinical testing of drugs that target both tumor cells and vasculature, and allows controlled in vivo-like delivery of test agents. Using this model we tested different antiangiogenic therapeutics and were able to successfully demonstrate anti-angiogenic effects in our chips and with this, have a platform available to routinely test antiangiogenic and thus, novel anti-cancer drugs in a human in vitro tumor microenvironment. Citation Format: Henning Mann, Anne Grosse-Wilde. A tissue-engineered vascularized tumor microenvironment for preclinical testing of anticancer therapeutics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-045.