How to Build a Better Bone Tumor

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Science Translational Medicine  07 May 2014:
Vol. 6, Issue 235, pp. 235ec81
DOI: 10.1126/scitranslmed.3009303

One of the highest hurdles in the race for the cancer cure is the lack of predictive models in which to test potential drug candidates. Animal models are far from perfect, as evidenced by the high numbers of apparent wonder drugs that fly through preclinical trials only to fail in patients. Benchtop models that use human cells have the potential to be more clinically relevant, but cancer cells behave quite differently when cultured in the lab as compared with native tumors. The cells lose many of the aggressive traits that make them so hard to kill in people, presumably because cultures lack signals that come from the microenvironment, such as cues from the extracellular matrix and neighboring cells. To coax human cancer cells into behaving more realistically in an artificial environment, Villasante and colleagues used advanced tissue-engineering methods to build a complex miniature ecosystem that mimics Ewing’s sarcoma, a particularly aggressive bone cancer that afflicts children and young adults.

The team grew human bone by differentiating human mesenchymal stem cells (hMSCs) into bone cells within a native cow-derived bone matrix that had been stripped of its cells by treatment with detergents. Over the course of a few weeks, the hMSCs gradually laid down their own human bone matrix, creating 3-dimensional (3D) structures that secreted signals found in native bone. The centers of the 3D constructs had low levels of oxygen tension, which is an important aspect of normal tumors that induces cancer cells to increase their metabolic activity in order to support their growth. When the researchers introduced cancer cells into the engineered tissues, they found that the cells regained many important characteristics of the typical cancer signature that they lost in 2D cultures. The investigators evaluated three different Ewing’s sarcoma cancer cell lines to build these disease models and found that one of them regained several key attributes of the native tumor. In particular, they re-expressed genes in the focal adhesion pathway, the response to hypoxia, and angiogenesis. They even showed evidence of vasculogenic mimicry, the strange and menacing hallmark of Ewing’s sarcoma in which tumor cells take on properties of endothelial cells to organize themselves into blood-filled vessels that supply nutrients to the growing tumor. This native-like behavior appeared to be linked to the response to hypoxia via hypoxia-inducible factor–1α, although further studies are required to decipher whether this gene product is the true culprit.

Although the model requires further validation, this work represents a major advance in the development of technology that allows us to investigate tumor biology and test new drugs in a system that more closely mimics the clinical situation. By using nature’s building blocks, we can build a better tumor.

A. Villasante et al., Bioengineered human tumor within a bone niche. Biomaterials 10.1016/j.biomaterials.2014.03.081 (2014). [Abstract]

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