Tumor engineering: the other face of tissue engineering

Abstract

Advances in tissue engineering have been accomplished for years by employing biomimetic strategies to provide cells with aspects of their original microenvironment necessary to reconstitute a unit of both form and function for a given tissue. We believe that the most critical hallmark of cancer is loss of integration of architecture and function; thus, it stands to reason that similar strategies could be employed to understand tumor biology. In this commentary, we discuss work contributed by Fischbach-Teschl and colleagues to this special issue of Tissue Engineering in the context of 'tumor engineering', that is, the construction of complex cell culture models that recapitulate aspects of the in vivo tumor microenvironment to study the dynamics of tumor development, progression, and therapy on multiple scales. We provide examples of fundamental questions that could be answered by developing such models, and encourage the continued collaboration between physical scientists and life scientists not only for regenerative purposes, but also to unravel the complexity that is the tumor microenvironment.

FIG. 1.

Dynamically reciprocal and cooperative interactions occur within the tumor microenvironment. This schematic demonstrates just a subset of the complex interactions that should be considered when engineering tumor models. In this case, a loss of myoepithelial tumor suppressive functions results in mammary carcinoma penetrating the surrounding basement membrane sheath that separates the epithelium from stroma. As tumor cells invade in response to an oxygen/nutrient gradient, they not only generate proteolytic fragments that influence cell behavior (not shown), but also secrete a variety of factors that activate mesenchymal cells to a myofibroblast phenotype (darker mesenchymal cells), recruit and alter blood vessels, and attract and activate leukocytes (e.g., macrophages). In turn, soluble and insoluble factors generated from the now active stroma greatly influence receptor ligation and clustering on the surface of tumor cells (see zoomed-in depiction). These changes and others (such as those resulting from physical interactions with ECM and other cells) are transduced via signaling molecules and cytoskeletal components to the nucleus to alter gene expression. Transcriptional changes within the tumor cell affect production and secretion of ECM components and ECM remodeling enzymes (e.g., matrix metalloproteinases) and alter cytoskeletal tension. Resulting short- and long-range signaling could further sustain activation and recruitment of stromal components (e.g., through physical forces, F), perpetuating this cycle and ultimately resulting in tumor growth and/or dissemination. Not shown here are the systemic effects caused by remodeling of the primary tumor microenvironment that also influence secondary tumor sites in other organs. ECM, extracellular matrix.