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Integrated cancer tissue engineering models for precision medicine

Tumors are not merely cancerous cells that undergo mindless proliferation. Rather, they are highly organized and interconnected organ systems. Tumor cells reside in complex microenvironments in which they are subjected to a variety of physical and chemical stimuli that influence cell behavior and ultimately the progression and maintenance of the tumor. As cancer bioengineers, it is their responsibility to create physiologic models that enable accurate understanding of the multi-dimensional structure, organization, and complex relationships in diverse tumor microenvironments. Such models can greatly expedite clinical discovery and translation by closely replicating the physiological conditions while maintaining high tunability and control of extrinsic factors. In this review, they discuss the current models that target key aspects of the tumor microenvironment and their role in cancer progression. In order to address sources of experimental variation and model limitations, they also make recommendations for methods to improve overall physiologic reproducibility, experimental repeatability, and rigor within the field. Improvements can be made through an enhanced emphasis on mathematical modeling, standardized in vitro model characterization, transparent reporting of methodologies, and designing experiments with physiological metrics. Taken together these considerations will enhance the relevance of in vitro tumor models, biological understanding, and accelerate treatment exploration ultimately leading to improved clinical outcomes. Moreover, the development of robust, user-friendly models that integrate important stimuli will allow for the in-depth study of tumors as they undergo progression from non-transformed primary cells to metastatic disease and facilitate translation to a wide variety of biological and clinical studies.1



To develop an accurate multi-dimensional understanding of the structure, organization, and complex relationships in cancers, we need to consider the following factors. Heterogeneous cancer cells reside in a complex tumor microenvironment, which consists of mechanical stimuli, non-malignant cell-cancer cell interactions, soluble signals, and extracellular matrix (ECM). The dimensionality of cell culture influences cancer cell motility and cellular interaction with the surrounding cells and ECM. Mechanical stimuli including shear, compressive, tensile, and viscoelastic forces, dynamically influence cancer cells as the tumor grows. Similarly, cellular interactions through direct contact with surrounding non-malignant cells and soluble signals alter communication and downstream signaling. Interactions between immune cells and cancerous cells are highly complex and can lead to immune evasion and support of tumor progression. All of these characteristics play an integral role in tumor progression and are critical to forming a complete picture of the ‘cancer-organ’ system.
Components of the ‘Cancer-Organ’ model.

Summarized here are the state-of-the-art cancer bioengineering models that we discuss in this review. Each model has inherent benefits and drawbacks that are discussed in more detail within the following sections. We have listed the components of the ‘cancer-organ’ system which can be probed with the specific model in the figure.
Various engineering tools can help construct the complex picture of the ‘cancer-organ’ system.
  1. Bregenzer, M. E., Horst, E. N., Mehta, P., Novak, C. M., Raghavan, S., Snyder, C. S., & Mehta, G. (2019). Integrated cancer tissue engineering models for precision medicine. PloS one, 14(5), e0216564. https://doi.org/10.1371/journal.pone.0216564