A cell-instructive hydrogel to regulate malignancy of 3D tumor spheroids with matrix rigidity

Liang, Yong; Jeong, Jae-Hyun; DeVolder, Ross J.; Cha, Chaenyung; Wang, Fei; Tong, Yen Wah; Kong, Hyunjoon

doi:10.1016/j.biomaterials.2011.08.045

Cited by 137 publications

(120 citation statements)

References 20 publications

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“…From the perspective of cancer malignancy, cross-linked collagen 3D hydrogel constructs have shown a relationship between stiffness and cancer phenotype. Hepatocarcinoma spheroids interacting in softer constructs showed an increase in malignancy, whereas stiffer hydrogels caused hepatocarcinoma spheroid compaction and suppressed malignancy [72]. Similar behavior has been observed using in vitro glioblastoma models, correlating with increased malignancy within brain tissue [73,74].…”

Section: Animal-free 3d Gel Platformsupporting

confidence: 61%

Three-Dimensional Cell Culture Models for Biomarker Discoveries and Cancer Research

CE¹,

Q²,

A³

2012

Translational

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Novel biomarker discovery requires high quality biospecimens and proper maintenance of cell phenotype. However, patient samples have reduced availability rendering not practical for large-scale drug screening and biomarker discovery. This impracticality has stimulated the use of cell lines in many "-omics" research studies to discover biomarkers. In addition, cells in these in vitro models are typically grown on 2-dimensional (2D) culture dishes, which is obviously different from native in vivo microenvironments. Data extraction from cells grown in 2D has less relevance, and thus, the biomarkers derived from studies using 2D platforms will likely have less clinical value. Thus, implementation of in vitro models that take into account primary patient samples and in vivo-like factor represent a paradigm shift in cancer biomarker discovery. This review emphasizes on current 3D cell culture platforms used to recreate in vivo conditions and their ability to adapt towards demanding conditions of biological relevance. OverviewSince the discovery of the cell as the basic unit of tissues, cell culture has been traditionally defined by simple approximations. The most common are two-dimensional (2D) cell culture and separating disease cells from their native microenvironment. Because these limitations result in challenges for the discovery of clinically relevant biomarkers, many 3-dimensional (3D) cell culture methods have been introduced over the past decades. Models that have recently been used in tissue engineering include 3D geometry and cell co-culture to better represent tissue homeostasis in in vitro settings [1]. Adopting the success of Tissue Engineering models, the same principles can also be used for biomarker discovery projects for cancer. As mounting evidence indicates that gene expression and signaling pathways of tumor tissues depend on context or their native microenvironment, these 3D co-culture models more closely resemble cancers [2]. In the tumor microenvironment, normal and cancer cells interact in a 3D setting and influence each other to positively enhance oncogenic potential [3]. For example, during cancer progression and metastasis, tumor cells up regulate oncogenes to increase proliferation while actively modify their cellular microenvironment to control angiogenesis, extracellular matrix (ECM) stiffness, proliferation, and oxygen levels [4][5][6]. This highly orchestrated sequence of events defines the innate plasticity of cancer cells that allows them to exert control at molecular and tissue levels to maintain a malignant phenotype [7][8][9]. Clearly, the conditions that surround tumor cells must be replicated in an in vitro setting to resemble the tumor microenvironment, and the traditional 2D tumor cell culture method is an oversimplified in vitro cell-based model that cannot recreate the environment of cancer homeostasis [10]. As a consequence, biomarkers identified in 2D culture often lack critical in vivo signatures, whereas biomarkers identified in 3D culture are more likely to ult...

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Section: Animal-free 3d Gel Platformsupporting

confidence: 61%

Three-Dimensional Cell Culture Models for Biomarker Discoveries and Cancer Research

CE¹,

Q²,

A³

2012

Translational

View full text Add to dashboard Cite

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“…61 In another study, it was shown that the proliferation and sphere size of hepatocellular carcinoma cells encapsulated in PEG-collagen gels increased with decreasing elastic modulus from 4 kPa (corresponding to the modulus of healthy liver) to 0.7 kPa. 70 A decrease in sphere size and cell number for gel moduli > 5.3 kPa can be attributed to a decrease in mesh size and increase in retractive force of the gel network, leading to a negative contribution on the cell proliferation and sphere formation. 71 The average pore size or the mesh size of the hydrogel can affect diffusion of nutrients and oxygen and tumor cell motility.…”

Section: Discussionmentioning

confidence: 99%

Three-Dimensional-Engineered Matrix to Study Cancer Stem Cells and Tumorsphere Formation: Effect of Matrix Modulus

Yang

Sarvestani²,

Moeinzadeh³

et al. 2013

Tissue Engineering Part A

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Maintenance of cancer stem cells (CSCs) is regulated by the tumor microenvironment. Synthetic hydrogels provide the flexibility to design three-dimensional (3D) matrices to isolate and study individual factors in the tumor microenvironment. The objective of this work was to investigate the effect of matrix modulus on tumorsphere formation by breast cancer cells and maintenance of CSCs in an inert microenvironment without the interference of other factors. In that regard, 4T1 mouse breast cancer cells were encapsulated in inert polyethylene glycol diacrylate hydrogels and the effect of matrix modulus on tumorsphere formation and expression of CSC markers was investigated. The gel modulus had a strong effect on tumorsphere formation and the effect was bimodal. Tumorsphere formation and expression of CSC markers peaked after 8 days of culture. At day 8, as the matrix modulus was increased from 2.5 kPa to 5.3, 26.1, and 47.1 kPa, the average tumorsphere size changed from 37 -6 mm to 57 -6, 20 -4, and 12 -2 mm, respectively; cell number density in the gel changed from 0.8 -0.1 · 10 5 cells/mL to 1.7 -0.2 · 10 5 , 0.4 -0.1 · 10 5 , and 0.2 -0.1 · 10 5 cells/mL after initial encapsulation of 0.14 · 10 5 cells/mL; and the expression of CD44 breast CSC marker changed from 17 -4-fold to 38 -9-, 3 -1-, and 2 -1-fold increase compared with the initial level. Similar results were obtained with MCF7 human breast carcinoma cells. Mouse 4T1 and human MCF7 cells encapsulated in the gel with 5.3 kPa modulus formed the largest tumorspheres and highest density of tumorspheres, and had highest expression of breast CSC markers CD44 and ABCG2. The inert polyethylene glycol hydrogel can be used as a model-engineered 3D matrix to study the role of individual factors in the tumor microenvironment on tumorigenesis and maintenance of CSCs without the interference of other factors.

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“…PEG-diNHS can cross-link collagen-I fibrils by forming amide bonds to tether collagen molecules together, mimicking the physiological cross-links formed in vivo (23). These collagen-I PEG-diNHS hydrogels have been previously used in studies of tumor spheroid formation and in tissue engineering, and show good biocompatibility (24,25).…”

Section: Introductionmentioning

confidence: 94%

Palladin Mediates Stiffness-Induced Fibroblast Activation in the Tumor Microenvironment

McLane

Ligon

2015

Biophysical Journal

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Mechanical properties of the tumor microenvironment have emerged as key factors in tumor progression. It has been proposed that increased tissue stiffness can transform stromal fibroblasts into carcinoma-associated fibroblasts. However, it is unclear whether the three to five times increase in stiffness seen in tumor-adjacent stroma is sufficient for fibroblast activation. In this study we developed a three-dimensional (3D) hydrogel model with precisely tunable stiffness and show that a physiologically relevant increase in stiffness is sufficient to lead to fibroblast activation. We found that soluble factors including CC-motif chemokine ligand (CCL) chemokines and fibronectin are necessary for this activation, and the combination of C-C chemokine receptor type 4 (CCR4) chemokine receptors and β1 and β3 integrins are necessary to transduce these chemomechanical signals. We then show that these chemomechanical signals lead to the gene expression changes associated with fibroblast activation via a network of intracellular signaling pathways that include focal adhesion kinase (FAK) and phosphoinositide 3-kinase (PI3K). Finally, we identify the actin-associated protein palladin as a key node in these signaling pathways that result in fibroblast activation.

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A cell-instructive hydrogel to regulate malignancy of 3D tumor spheroids with matrix rigidity

Cited by 137 publications

References 20 publications

Three-Dimensional Cell Culture Models for Biomarker Discoveries and Cancer Research

Three-Dimensional Cell Culture Models for Biomarker Discoveries and Cancer Research

Three-Dimensional-Engineered Matrix to Study Cancer Stem Cells and Tumorsphere Formation: Effect of Matrix Modulus

Palladin Mediates Stiffness-Induced Fibroblast Activation in the Tumor Microenvironment

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