Bioreactor-Based Tumor Tissue Engineering

Abstract

This review focuses on modeling of cancer tumors using tissue engineering technology. Tumor tissue engineering (TTE) is a new method of three-dimensional (3D) simulation of malignant neoplasms. Design and development of complex tissue engineering constructs (TECs) that include cancer cells, cell-bearing scaffolds acting as the extracellular matrix, and other components of the tumor microenvironment is at the core of this approach. Although TECs can be transplanted into laboratory animals, the specific aim of TTE is the most realistic reproduction and long-term maintenance of the simulated tumor properties in vitro for cancer biology research and for the development of new methods of diagnosis and treatment of malignant neoplasms. Successful implementation of this challenging idea depends on bioreactor technology, which will enable optimization of culture conditions and control of tumor TECs development. In this review, we analyze the most popular bioreactor types in TTE and the emerging applications.

Keywords: bioreactors; cancer; models; tissue engineering.

Fig. 1

Malignant tumor structure (A) (a schematic view, adapted from [8])) and conditions for traditional 2D-tissue culture in vitro (B) (adapted from [9]). (A) The tumor is a 3D-structure. Due to abnormal local blood circulation and innervation, the tumor possesses multiple metabolic gradients which contribute to the genetic instability of malignant cells. Phenotype selection affects the dynamic responses of a cancer stem cell pool. In addition to the neoplastic cell population, resident cells of the affected organ and cells of the inflammatory infiltrate (including macrophages, lymphocytes, eosinophils, and sometimes plasma cells) are involved in the tumor. The extracellular matrix, blood vessels, and connective tissue inclusions are the second component, known as the stroma of the tumor. The degree of stroma development in malignant tumors varies notably and significantly affects the course of the disease and tumor drug resistance. Also, sites with active growth, necrotic zones, hemorrhages, and purulent pockets can occur within the tumor. (B) Changes observed in a 2D culture are induced by the selection of specific cellular phenotypes and abnormal interactions between cells and their micro- and macro-environments.

Fig. 2

Comparisons of histological structures of prostate (A, C, E) and colon (B, D, F) cancers observed in primary tumors (A, B) and the cancers propagated as model systems in mice (C-F). Tumors obtained by subcutaneous engraftment of suspensions of linear cells PC-3M (C) and Colo205 (D) have a homogenous structure with absence of specific glandular elements formed by cancer cells and the lack of a stromal component. Significant alterations of tumor-stroma ratio are also notable in the cases of subcutaneous grafting of surgical biopsy specimens of original human primary tumors (E, F). Adapted from [12] with changes.

Fig. 3

Principles of formation of tumor TECs. In order to create biomimetic tumor TECs the key components of the original tumor (as cancer cells and a scaffold, representing the extracellular matrix) should be included into the model. In addition, it is very important to reproduce the conditions of tumor growth by the inclusion of physical and chemical signalling factors. Adapted from [23] with changes.