Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors

Yata, Teerapong; Lee, Eugene L. Q.; Suwan, Keittisak; Syed, Nelofer; Asavarut, Paladd; Hajitou, Amin

doi:10.1186/s12943-015-0383-4

Cited by 21 publications

(22 citation statements)

References 54 publications

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“…Therapies that target the ECM provide a promising approach to overcome chemoresistance either by preventing ECM-conferred chemoresistance or by altering the ECM such that current therapies can overcome physical treatment limits [ 200 , 201 , 202 , 203 , 204 ]. It has been shown that the dense ECM can inhibit therapeutic drug penetration, diffusion and transport, thus the ECM acts as a barrier to drug delivery [ 205 , 206 , 207 , 208 , 209 , 210 , 211 ].…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…However, the phage has evolved to infect bacteria only, with no optimized strategies to deliver genes to mammalian cells. We have investigated various steps of gene delivery upon RGD4C/AAVP vector treatment of cells and found that the main extracellular limiting steps are vector diffusion through the extracellular matrix (ECM) and binding to the cell surface receptors caused by repulsion between the negatively charged phage capsid and mammalian cell surface membranes [ 21 , 22 ]. Following internalization, we reported the endosome/lysosome degradative pathway and proteasome degradation as major intracellular barriers to gene delivery by the vector [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors

Tsafa

Bentayebi

Topanurak

et al. 2020

IJMS

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Merging targeted systemic gene delivery and systemic chemotherapy against cancer, chemovirotherapy, has the potential to improve chemotherapy and gene therapy treatments and overcome cancer resistance. We introduced a bacteriophage (phage) vector, named human adeno-associated virus (AAV)/phage or AAVP, for the systemic targeting of therapeutic genes to cancer. The vector was designed as a hybrid between a recombinant adeno-associated virus genome (rAAV) and a filamentous phage capsid. To achieve tumor targeting, we displayed on the phage capsid the double-cyclic CDCRGDCFC (RGD4C) ligand that binds the alpha-V/beta-3 (αvβ3) integrin receptor. Here, we investigated a combination of doxorubicin chemotherapeutic drug and targeted gene delivery by the RGD4C/AAVP vector. Firstly, we showed that doxorubicin boosts transgene expression from the RGD4C/AAVP in two-dimensional (2D) cell cultures and three-dimensional (3D) tumor spheres established from human and murine cancer cells, while preserving selective gene delivery by RGD4C/AAVP. Next, we confirmed that doxorubicin does not increase vector attachment to cancer cells nor vector cell entry. In contrast, doxorubicin may alter the intracellular trafficking of the vector by facilitating nuclear accumulation of the RGD4C/AAVP genome through destabilization of the nuclear membrane. Finally, a combination of doxorubicin and RGD4C/AAVP-targeted suicide gene therapy exerts a synergistic effect to destroy human and murine tumor cells in 2D and 3D tumor sphere settings.

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“…Having shown that chemical modification of phage vectors with either CaPi or PEI increases gene delivery efficiency; we next sought to determine whether incorporation of genetic targeting into the vector complexes would lead to further enhancement of gene transfer. Our previously reported phage vectors, AAVP, were initially designed to enter mammalian cells and allow gene expression by ligand display on the phage capsid to bind to specific mammalian receptors [ 23 , 24 ]. The targeting peptide ligand, cyclic RGD4C, was engineered to be displayed on the pIII minor coat protein of phage to allow the vector (RGD4C-phage) to enter mammalian cells expressing αv integrin receptors [ 13 ].…”

Section: Resultsmentioning

confidence: 99%

Bacteriophage Mediates Efficient Gene Transfer in Combination with Conventional Transfection Reagents

Donnelly

Yata

Bentayebi

et al. 2015

Viruses

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The development of commercially available transfection reagents for gene transfer applications has revolutionized the field of molecular biology and scientific research. However, the challenge remains in ensuring that they are efficient, safe, reproducible and cost effective. Bacteriophage (phage)-based viral vectors have the potential to be utilized for general gene transfer applications within research and industry. Yet, they require adaptations in order to enable them to efficiently enter cells and overcome mammalian cellular barriers, as they infect bacteria only; furthermore, limited progress has been made at increasing their efficiency. The production of a novel hybrid nanocomplex system consisting of two different nanomaterial systems, phage vectors and conventional transfection reagents, could overcome these limitations. Here we demonstrate that the combination of cationic lipids, cationic polymers or calcium phosphate with M13 bacteriophage-derived vectors, engineered to carry a mammalian transgene cassette, resulted in increased cellular attachment, entry and improved transgene expression in human cells. Moreover, addition of a targeting ligand into the nanocomplex system, through genetic engineering of the phage capsid further increased gene expression and was effective in a stable cell line generation application. Overall, this new hybrid nanocomplex system (i) provides enhanced phage-mediated gene transfer; (ii) is applicable for laboratory transfection processes and (iii) shows promise within industry for large-scale gene transfer applications.

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Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors

Cited by 21 publications

References 54 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

Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors

Bacteriophage Mediates Efficient Gene Transfer in Combination with Conventional Transfection Reagents

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