Recreating complex pathophysiologies in vitro with extracellular matrix surrogates for anticancer therapeutics screening

Shologu, Naledi; Szegezdi, Éva; Lowery, Aoife; Kerin, Michael J.; Pandit, Abhay; Zeugolis, Dimitrios I.

doi:10.1016/j.drudis.2016.06.001

Cited by 29 publications

(32 citation statements)

References 198 publications

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“…This ultimately leads to incorrect and misleading claims when it comes to the efficacy of drug candidates. Such scenarios can be avoided by employing in vitro models that better recapitulate the in vivo tumor microenvironment [ 3 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. One important constituent of the tumor microenvironment is the extracellular matrix, a meshwork of proteins and glycosaminoglycans [ 3 , 17 , 18 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices

Senthebane

Jonker

Rowe

et al. 2018

IJMS

111

176

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Background: The functional interplay between tumor cells and their adjacent stroma has been suggested to play crucial roles in the initiation and progression of tumors and the effectiveness of chemotherapy. The extracellular matrix (ECM), a complex network of extracellular proteins, provides both physical and chemicals cues necessary for cell proliferation, survival, and migration. Understanding how ECM composition and biomechanical properties affect cancer progression and response to chemotherapeutic drugs is vital to the development of targeted treatments. Methods: 3D cell-derived-ECMs and esophageal cancer cell lines were used as a model to investigate the effect of ECM proteins on esophageal cancer cell lines response to chemotherapeutics. Immunohistochemical and qRT-PCR evaluation of ECM proteins and integrin gene expression was done on clinical esophageal squamous cell carcinoma biopsies. Esophageal cancer cell lines (WHCO1, WHCO5, WHCO6, KYSE180, KYSE 450 and KYSE 520) were cultured on decellularised ECMs (fibroblasts-derived ECM; cancer cell-derived ECM; combinatorial-ECM) and treated with 0.1% Dimethyl sulfoxide (DMSO), 4.2 µM cisplatin, 3.5 µM 5-fluorouracil and 2.5 µM epirubicin for 24 h. Cell proliferation, cell cycle progression, colony formation, apoptosis, migration and activation of signaling pathways were used as our study endpoints. Results: The expression of collagens, fibronectin and laminins was significantly increased in esophageal squamous cell carcinomas (ESCC) tumor samples compared to the corresponding normal tissue. Decellularised ECMs abrogated the effect of drugs on cancer cell cycling, proliferation and reduced drug induced apoptosis by 20–60% that of those plated on plastic. The mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK-ERK) and phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) signaling pathways were upregulated in the presence of the ECMs. Furthermore, our data show that concomitant addition of chemotherapeutic drugs and the use of collagen- and fibronectin-deficient ECMs through siRNA inhibition synergistically increased cancer cell sensitivity to drugs by 30–50%, and reduced colony formation and cancer cell migration. Conclusion: Our study shows that ECM proteins play a key role in the response of cancer cells to chemotherapy and suggest that targeting ECM proteins can be an effective therapeutic strategy against chemoresistant tumors.

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Section: Introductionmentioning

confidence: 99%

The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices

Senthebane

Jonker

Rowe

et al. 2018

IJMS

111

176

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“…cleave both proteins of the extracellular matrix and cell-surface receptors. By doing that, digestion irreversibly changes cellular signaling [193]. However, comparison of different cell-dissociating agents for stem cell isolation from glioma tumorspheres revealed that there was a difference in CD133 antigen retention: the worst result was obtained for nonenzymatic dissociation solution NECDS, while the minimal impact was observed in Libertase-TL-treated cells [194].…”

Section: D In Vitro Modelsmentioning

confidence: 99%

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

Stulpinas¹,

Imbrasaitė²,

Krestnikova³

et al. 2020

Tumor Progression and Metastasis

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Despite the advancements in biomarker-based personalized cancer therapy, the inadequacy of molecular and genetic profiling in identifying effective drug combinations was defined in most cases. Drug resistance remains a major limitation of the current predictive oncology. Emerging reports indicate that the success of anticancer therapy is usually limited by intratumoral heterogeneity which is not captured by the existing cancer cell biomarker-based approaches. Cell heterogeneity, not only genetic but also phenotypic, is considered to be the root cause of resistance to anticancer treatment, cancer progression, and the presence of cancer stem cells. Therefore, functional testing of live cells representing various cell types within the tumor exposed to potential therapies is needed for identification of effective drug combinations. Here we look at the different existing model systems, including ex vivo models of the patient's tumor cells, 2D/3D in vitro cultures/cocultures, patient-derived cellular organoids, single-cell models, ex vivo tumor platforms containing tumor microenvironment and extracellular matrix, etc., scoping at drug efficacy evaluation and solving the problem of cancer resistance.

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“…[s1]decellularized tissue grafts to mimic key factors of the extracellular matrix composition [6] or by recreating complex pathophysiologies using 3D tissue surrogates [7], there are still limitations because of the complexity, diversity and heterogeneity of the human tumor microenvironment. Also, in vivo animal models utilized as cancer models in the investigation of different human tumor types, such as zebrafish [8,9] that enable appropriate in vivo imaging and fast development, or humanized mouse models that have been shown promise [10], there are still limitations because zebrafish cannot accurately resemble a mammalian model and mouse biology does not present an appropriately authentic model of human tumors and is cost-inefficient when large numbers of animals are required [11].…”

Section: Introductionmentioning

confidence: 99%

Cell spheroids: the new frontiers in in vitro models for cancer drug validation

Chatzinikolaidou

2016

Drug Discovery Today

100

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Recreating complex pathophysiologies in vitro with extracellular matrix surrogates for anticancer therapeutics screening

Cited by 29 publications

References 198 publications

The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices

The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

Cell spheroids: the new frontiers in in vitro models for cancer drug validation

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