Bioinspired Hydrogels to Engineer Cancer Microenvironments

Abstract

Recent research has demonstrated that tumor microenvironments play pivotal roles in tumor development and metastasis through various physical, chemical, and biological factors, including extracellular matrix (ECM) composition, matrix remodeling, oxygen tension, pH, cytokines, and matrix stiffness. An emerging trend in cancer research involves the creation of engineered three-dimensional tumor models using bioinspired hydrogels that accurately recapitulate the native tumor microenvironment. With recent advances in materials engineering, many researchers are developing engineered tumor models, which are promising platforms for the study of cancer biology and for screening of therapeutic agents for better clinical outcomes. In this review, we discuss the development and use of polymeric hydrogel materials to engineer native tumor ECMs for cancer research, focusing on emerging technologies in cancer engineering that aim to accelerate clinical outcomes.

Keywords: cancer research; engineered tumor models; polymeric hydrogels; tumor microenvironments.

Figure 1

Cancerous pathways affected by accumulation of hypoxia-inducible factor (HIF). Abbreviations: ALDA, aldolase A; ANG-1, angiopoietin 1; ANG-2, angiopoietin 2; BMDSC, bone marrow–derived stem cell; CCND1, cyclin D1; CTGF, connective tissue growth factor; CXCR-4, C-X-C chemokine receptor type 4; ECM, extracellular matrix; ENO1, enolase 1; EPO, erythropoietin; FLK1, VEGF receptor 2; FLT-1, VEGF receptor 1; GLUT, glucose transporter; HK, hexokinase; IGF-2, insulin growth factor 2; IGF-BP2, insulin-like growth factor–binding protein 2; LDHA, lactate dehydrogenase A; LOX, lysyl oxidase; miRNA, microRNA; LOXL, lysyl oxidase homolog 1; MMP, matrix metalloproteinase; MXI-1, max interactor 1; P4HA, prolyl 4-hydroxylase subunit α1; PAI-1, plasminogen activator inhibitor 1; PDGF-B, platelet-derived growth factor B; PDK1, pyruvate dehydrogenase kinase 1; PFKL, phosphofructokinase L; PGK1, phosphoglycerate kinase 1; PLOD, procollagen-lysine 2-oxoglutarate 5-dioxygenase; SDF-1, stromal cell–derived factor 1; TF, transcription factor; TGF-α, transforming growth factor α; TIE-2, angiopoietin receptor 2; UPAR, urokinase plasminogen activator receptor; VEGF, vascular endothelial growth factor. Modified from Reference .

Figure 2

Tumor angiogenesis, in which certain growth and environmental factors lead to the recruitment of endothelial cells (70). Abbreviations: ECM, extracellular matrix; EPC, endothelial progenitor cell; MMP, matrix metalloproteinase.

Figure 3

In situ cross-linkable hydrogels as an artificial cellular microenvironment. Cross-linking strategies are detailed for each hydrogel system. Abbreviations: CD-HA, β-cyclodextrin-modified hyaluronic acid; FA, ferulic acid; GelMA, methacrylated gelatin; GtnFA, gelatin grafted with ferulic acid; HA, hyaluronic acid; MMP, matrix metalloproteinase; PEG, poly(ethylene glycol); PEG-diNHS, poly(ethylene glycol) conjugated to di(succinic acid N-hydroxysuccinimide ester).

Figure 4

Emerging techniques to create three-dimensional (3D) tumor microenvironments. (a) Strategy for studying vascular cell invasion into tumor microenvironments. (b) A microfluidic system consisting of three independently addressable media channels separated from extracellular matrix (ECM)-mimicking hydrogel matrices. (c) The printing process used to create 3D HeLa–hydrogel matrices. Abbreviations: ECFC, endothelial colony-forming cell; SDF-1, stromal cell–derived factor 1; S1P, sphingosine-1-phosphate; 2D, two-dimensional. Panel a modified from Reference . Panel b modified from Reference . Panel c modified from Reference .