Engineering tumors with 3D scaffolds

ARTICLES

Engineering tumors with 3D scaffolds

Claudia Fischbach1,2, Ruth Chen1, Takuya Matsumoto3, Tobias Schmelzle4, Joan S Brugge4, Peter J Polverini5 &

David J Mooney1

Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells dependency on these conditions. We engineered three-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. We assessed the broad relevance of these ndings with 3D culture of other tumor cell lines in this same model, comparison with standard 3D Matrigel culture and in vivo experiments. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.

Microenvironmental conditions regulate tumorigenesis1,2, and

biomimetic model systems are necessary to study how cancer is dependent on these conditions. Altered 3D cell-cell and cell extracellular matrix interactions, together with the development of central hypoxia and signaling between cells residing within spatially distinct niches (for example, outer proliferative regions and cells situated inside tumors), may enhance tumor aggressiveness2,3, and these conditions are poorly reected by conventional two-dimensional (2D) cell culture systems. The 3D cell culture approaches (gel systems and spheroid cultures) have dramatically improved our understanding of the role of 3D culture on tumor cells1,4,5, but there still exists a need for innovative 3D tumor

models that are capable of recreating distinct tumor niches, and that allow for in vitro and in vivo tumor modeling under well-dened and reproducible conditions.

We established a 3D model of human oral cancer by culturing oral squamous cell carcinoma (OSCC-3) cells within highly porous scaffolds fabricated from synthetic poly(lactide-co-glycolide) (PLG). PLG scaffolds provide a biocompatible 3D culture system applicable both in vitro and in vivo, are easy to reproduce, are convenient to handle, and are amenable to large-scale use. After extensive characterization, we used these engineered tumors to

investigate the malignant potential of cancer...