Engineering Approaches for Investigating Tumor Angiogenesis: Exploiting the Role of the Extracellular Matrix

Hielscher, Abigail; Gerecht, Sharon

doi:10.1158/0008-5472.can-12-2773

Cited by 34 publications

(18 citation statements)

References 64 publications

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“…This is partly due to the high cost of developing a new anti-cancer drug, as well as the need to better understand cancer development and the tumour microenvironment (TME), including the roles of inflammation, different effectors and suppressors of immune responses, the heterogeneity of tumour stroma, and the function of tumour vasculature. To make significant improvements in cancer therapy, it is necessary to develop more effective approaches to screen anti-cancer drug leads and to have a better understanding of TME using advanced technologies, including the organs-on-chips technology [1][2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

Tsai

Trubelja

Shen

et al. 2017

J. R. Soc. Interface.

179

133

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Cancer remains one of the leading causes of death, albeit enormous efforts to cure the disease. To overcome the major challenges in cancer therapy, we need to have a better understanding of the tumour microenvironment (TME), as well as a more effective means to screen anti-cancer drug leads; both can be achieved using advanced technologies, including the emerging tumour-on-a-chip technology. Here, we review the recent development of the tumour-on-a-chip technology, which integrates microfluidics, microfabrication, tissue engineering and biomaterials research, and offers new opportunities for building and applying functional three-dimensional in vitro human tumour models for oncology research, immunotherapy studies and drug screening. In particular, tumour-on-a-chip microdevices allow well-controlled microscopic studies of the interaction among tumour cells, immune cells and cells in the TME, of which simple tissue cultures and animal models are not amenable to do. The challenges in developing the next-generation tumour-on-a-chip technology are also discussed.

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Section: Introductionmentioning

confidence: 99%

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

Tsai

Trubelja

Shen

et al. 2017

J. R. Soc. Interface.

179

133

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“…Among various 3D models, tumor aggregates, often referred to as spheroids or microtumors, are multicellular structures that have been widely used to study (1) cell-cell interactions, 7,8 (2) microenvironmental cues important for tumor growth, 5 (3) to understand complex phenomena such as angiogenesis, [9][10][11][12][13][14] and (4) to test drug penetration, tumor responses, and drug resistance. 15,16 Microtumors have been shown to recapitulate various aspects of solid tumors in vivo, including their responses to cancer drugs (e.g., development of multidrug resistance), and can serve as good models for preclinical drug testing.…”

mentioning

confidence: 99%

Production of Uniform 3D Microtumors in Hydrogel Microwell Arrays for Measurement of Viability, Morphology, and Signaling Pathway Activation

Singh

Mukundan

et al. 2015

ASSAY and Drug Development Technologies

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Despite significant investments in cancer research and drug discovery/development, the rate of new cancer drug approval is £5% and most cases of metastatic cancer remain incurable. Ninety-five percent of new cancer drugs fail in clinical development because of a lack of therapeutic efficacy and/or unacceptable toxicity. One of the major factors responsible for the low success rate of anticancer drug development is the failure of preclinical models to adequately recapitulate the complexity and heterogeneity of human cancer. For throughput and capacity reasons, high-throughput screening growth inhibition assays almost exclusively use two-dimensional (2D) monolayers of tumor cell lines cultured on tissue culture-treated plastic/glass surfaces in serum-containing medium. However, these 2D tumor cell line cultures fail to recapitulate the three-dimensional (3D) context of cells in solid tumors even though the tumor microenvironment has been shown to have a profound effect on anticancer drug responses. Tumor spheroids remain the best characterized and most widely used 3D models; however, spheroid sizes tend to be nonuniform, making them unsuitable for high-throughput drug testing. To circumvent this challenge, we have developed defined size microwell arrays using nonadhesive hydrogels that are applicable to a wide variety of cancer cell lines to fabricate sizecontrolled 3D microtumors. We demonstrate that the hydrogel microwell array platform can be applied successfully to generate hundreds of uniform microtumors within 3-6 days from many cervical and breast, as well as head and neck squamous cell carcinoma (HNSCC) cells. Moreover, controlling size of the microwells in the hydrogel array allows precise control over the size of the microtumors. Finally, we demonstrate the application of this platform technology to probe activation as well as inhibition of epidermal growth factor receptor (EGFR) signaling in 3D HNSCC microtumors in response to EGF and cetuximab treatments, respectively. We believe that the ability to generate large numbers of HNSCC microtumors of uniform size and 3D morphology using hydrogel arrays will provide more physiological in vitro 3D tumor models to investigate how tumor size influences signaling pathway activation and cancer drug efficacy.

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“…Three-dimensional (3D) cell culture models recapitulate aspects of the in vivo extracellular matrix (ECM) microenvironment, allowing the study of tumor development and progression under pathologically relevant culture conditions [1–5]. Specifically, hydrogels are structurally and mechanically similar to the native ECM of many tissues and have been utilized as matrices to study cellular responses to a range of microenvironmental signals [6–8].…”

mentioning

confidence: 99%

Hyaluronic acid hydrogel stiffness and oxygen tension affect cancer cell fate and endothelial sprouting

et al. 2014

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Three-dimensional (3D) tissue culture models may recapitulate aspects of the tumorigenic microenvironment in vivo, enabling the study of cancer progression in vitro. Both hypoxia and matrix stiffness are known to regulate tumor growth. Using a modular culture system employing an acrylated hyaluronic acid (AHA) hydrogel, three hydrogel matrices with distinctive degrees of viscoelasticity — soft (78±16 Pa), medium (309± 57 Pa), and stiff (596± 73 Pa) — were generated using the same concentration of adhesion ligands. Oxygen levels within the hydrogel in atmospheric (21 %), hypoxic (5 %), and severely hypoxic (1 %) conditions were assessed with a mathematical model. HT1080 fibrosarcoma cells, encapsulated within the AHA hydrogels in high densities, generated nonuniform oxygen distributions, while lower cell densities resulted in more uniform oxygen distributions in the atmospheric and hypoxic environments. When we examined how varying viscoelasticity in atmospheric and hypoxic environments affects cell cycles and the expression of BNIP3 and BNIP3L (autophagy and apoptosis genes), and GLUT-1 (a glucose transport gene), we observed that HT1080 cells in 3D hydrogel adapted better to hypoxic conditions than those in a Petri dish, with no obvious correlation to matrix viscoelasticity, by recovering rapidly from possible autophagy/apoptotic events and alternating metabolism mechanisms. Further, we examined how HT1080 cells cultured in varying viscoelasticity and oxygen tension conditions affected endothelial sprouting and invasion. We observed that increased matrix stiffness reduced endothelial sprouting and invasion in atmospheric conditions; however, we observed increased endothelial sprouting and invasion under hypoxia at all levels of matrix stiffness with the upregulation of vascular endothelial growth factor (VEGF) and angiopoeitin-1 (ANG-1). Overall, HT1080 cells encapsulated in the AHA hydrogels under hypoxic stress recovered better from apoptosis and demonstrated greater angiogenic induction. Thus, we propose that oxygen tension more profoundly influences cell fate and the angiogenic potential of 3D cultured HT1080 fibrosarcoma cells than does matrix stiffness.

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Engineering Approaches for Investigating Tumor Angiogenesis: Exploiting the Role of the Extracellular Matrix

Cited by 34 publications

References 64 publications

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

Production of Uniform 3D Microtumors in Hydrogel Microwell Arrays for Measurement of Viability, Morphology, and Signaling Pathway Activation

Hyaluronic acid hydrogel stiffness and oxygen tension affect cancer cell fate and endothelial sprouting

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