Editorial

2 pages, 154 KiB

Open AccessEditorial

Application of Biophysical Techniques to Cellular and Molecular Oncology

by Diane S. Lidke, Jennifer M. Gillette and Alessandra Cambi

Cancers 2023, 15(11), 2919; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15112919 - 26 May 2023

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Dysregulated cellular processes drive malignant transformation, tumor progression, and metastasis, and affect responses to therapies [...] Full article

(This article belongs to the Special Issue Application of Biophysical Techniques to Cellular and Molecular Oncology)

Research

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22 pages, 4048 KiB

Open AccessArticle

Effect of Collagen Matrix on Doxorubicin Distribution and Cancer Cells’ Response to Treatment in 3D Tumor Model

by Irina Druzhkova, Elena Nikonova, Nadezhda Ignatova, Irina Koryakina, Mikhail Zyuzin, Artem Mozherov, Dmitriy Kozlov, Dmitry Krylov, Daria Kuznetsova, Uliyana Lisitsa, Vladislav Shcheslavskiy, Evgeny A. Shirshin, Elena Zagaynova and Marina Shirmanova

Cancers 2022, 14(22), 5487; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14225487 - 08 Nov 2022

Cited by 5 | Viewed by 1709

Abstract

The extracellular matrix (ECM) plays an important role in regulation of many aspects of tumor growth and response to therapies. However, the specifics of the interaction of chemotherapeutic agents with cancer cells in the presence of collagen, the major component of ECM, is [...] Read more.

The extracellular matrix (ECM) plays an important role in regulation of many aspects of tumor growth and response to therapies. However, the specifics of the interaction of chemotherapeutic agents with cancer cells in the presence of collagen, the major component of ECM, is still poorly investigated. In this study, we explored distribution of doxorubicin (DOX) and its effects on cancer cells’ metabolism in the presence of collagen with different structures in 3D models. For this, a combination of second harmonic generation imaging of collagen and multiphoton fluorescence microscopy of DOX, and metabolic cofactor NAD(P)H was used. It was found that collagen slowed down the diffusion of DOX and thus decreased the cellular drug uptake. Besides nuclei, DOX also targeted mitochondria leading to inhibition of oxidative phosphorylation, which was more pronounced in the cells growing in the absence of collagen. As a result, the cells in collagen displayed better viability upon treatment with DOX. Taken together, our data illustrate that tumor collagen contributes to heterogeneous and sub-optimal response to DOX and highlight the challenges in improving drug delivery and efficacy. Full article

(This article belongs to the Special Issue Application of Biophysical Techniques to Cellular and Molecular Oncology)

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16 pages, 2376 KiB

Open AccessArticle

Tunneling Nanotubes between Cells Migrating in ECM Mimicking Fibrous Environments

by Aniket Jana, Katherine Ladner, Emil Lou and Amrinder S. Nain

Cancers 2022, 14(8), 1989; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081989 - 14 Apr 2022

Cited by 8 | Viewed by 3235

Abstract

Tunneling nanotubes (TNTs) comprise a unique class of actin-rich nanoscale membranous protrusions. They enable long-distance intercellular communication and may play an integral role in tumor formation, progression, and drug resistance. TNTs are three-dimensional, but nearly all studies have investigated them using two-dimensional cell [...] Read more.

Tunneling nanotubes (TNTs) comprise a unique class of actin-rich nanoscale membranous protrusions. They enable long-distance intercellular communication and may play an integral role in tumor formation, progression, and drug resistance. TNTs are three-dimensional, but nearly all studies have investigated them using two-dimensional cell culture models. Here, we applied a unique 3D culture platform consisting of crosshatched and aligned fibers to fabricate synthetic suspended scaffolds that mimic the native fibrillar architecture of tumoral extracellular matrix (ECM) to characterize TNT formation and function in its native state. TNTs are upregulated in malignant mesothelioma; we used this model to analyze the biophysical properties of TNTs in this 3D setting, including cell migration in relation to TNT dynamics, rate of TNT-mediated intercellular transport of cargo, and conformation of TNT-forming cells. We found that highly migratory elongated cells on aligned fibers formed significantly longer but fewer TNTs than uniformly spread cells on crossing fibers. We developed new quantitative metrics for the classification of TNT morphologies based on shape and cytoskeletal content using confocal microscopy. In sum, our strategy for culturing cells in ECM-mimicking bioengineered scaffolds provides a new approach for accurate biophysical and biologic assessment of TNT formation and structure in native fibrous microenvironments. Full article

(This article belongs to the Special Issue Application of Biophysical Techniques to Cellular and Molecular Oncology)

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36 pages, 7432 KiB

Open AccessArticle

Ion Channel Drugs Suppress Cancer Phenotype in NG108-15 and U87 Cells: Toward Novel Electroceuticals for Glioblastoma

by Juanita Mathews, Franz Kuchling, David Baez-Nieto, Miranda Diberardinis, Jen Q. Pan and Michael Levin

Cancers 2022, 14(6), 1499; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061499 - 15 Mar 2022

Cited by 12 | Viewed by 7463

Abstract

Glioblastoma is a lethal brain cancer that commonly recurs after tumor resection and chemotherapy treatment. Depolarized resting membrane potentials and an acidic intertumoral extracellular pH have been associated with a proliferative state and drug resistance, suggesting that forced hyperpolarization and disruption of proton [...] Read more.

Glioblastoma is a lethal brain cancer that commonly recurs after tumor resection and chemotherapy treatment. Depolarized resting membrane potentials and an acidic intertumoral extracellular pH have been associated with a proliferative state and drug resistance, suggesting that forced hyperpolarization and disruption of proton pumps in the plasma membrane could be a successful strategy for targeting glioblastoma overgrowth. We screened 47 compounds and compound combinations, most of which were ion-modulating, at different concentrations in the NG108-15 rodent neuroblastoma/glioma cell line. A subset of these were tested in the U87 human glioblastoma cell line. A FUCCI cell cycle reporter was stably integrated into both cell lines to monitor proliferation and cell cycle response. Immunocytochemistry, electrophysiology, and a panel of physiological dyes reporting voltage, calcium, and pH were used to characterize responses. The most effective treatments on proliferation in U87 cells were combinations of NS1643 and pantoprazole; retigabine and pantoprazole; and pantoprazole or NS1643 with temozolomide. Marker analysis and physiological dye signatures suggest that exposure to bioelectric drugs significantly reduces proliferation, makes the cells senescent, and promotes differentiation. These results, along with the observed low toxicity in human neurons, show the high efficacy of electroceuticals utilizing combinations of repurposed FDA approved drugs. Full article

(This article belongs to the Special Issue Application of Biophysical Techniques to Cellular and Molecular Oncology)

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24 pages, 2188 KiB

Open AccessArticle

Anandamide-Modulated Changes in Metabolism, Glycosylation Profile and Migration of Metastatic Melanoma Cells

by Anna Sobiepanek, Małgorzata Milner-Krawczyk, Paulina Musolf, Tomasz Starecki and Tomasz Kobiela

Cancers 2022, 14(6), 1419; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061419 - 10 Mar 2022

Cited by 4 | Viewed by 2547

Abstract

An effective therapy for advanced melanoma, a skin cancer with the highest mortality, has not yet been developed. The endocannabinoid system is considered to be an attractive target for cancer treatment. The use of endocannabinoids, such as anandamide (AEA), is considered to be [...] Read more.

An effective therapy for advanced melanoma, a skin cancer with the highest mortality, has not yet been developed. The endocannabinoid system is considered to be an attractive target for cancer treatment. The use of endocannabinoids, such as anandamide (AEA), is considered to be much greater than as a palliative agent. Thus, we checked its influence on various signaling pathways in melanoma cells. Our investigation was performed on four commercial cell lines derived from different progression stages (radial WM35 and vertical WM115 growth phases, lymph node WM266-4 metastasis, solid tumor A375-P metastasis). Cell viability, glucose uptake, quantification of reactive oxygen species production, expression of selected genes encoding glycosyltransferases, quantification of glycoproteins production and changes in the glycosylation profile and migration, as well as in cell elastic properties were analyzed. The cell glycosylation profile was investigated using the biophysical profiling method—the quartz crystal microbalance with dissipation monitoring (QCM-D). Anandamide treatment of only metastatic cells resulted in: an increase in the cell metabolism, a decrease in GFAT-1 and DPM1 expression, followed by a decrease in L1-CAM glycoprotein production, which further influenced the reduction in the cell glycosylation profile and migration. Considering our results, AEA usage is highly recommended in the combined therapy of advanced melanoma. Full article

(This article belongs to the Special Issue Application of Biophysical Techniques to Cellular and Molecular Oncology)

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18 pages, 6778 KiB

Open AccessArticle

The Role of Plasma Membrane Viscosity in the Response and Resistance of Cancer Cells to Oxaliplatin

by Liubov Shimolina, Alexander Gulin, Nadezhda Ignatova, Irina Druzhkova, Margarita Gubina, Maria Lukina, Ludmila Snopova, Elena Zagaynova, Marina K. Kuimova and Marina Shirmanova

Cancers 2021, 13(24), 6165; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246165 - 07 Dec 2021

Cited by 17 | Viewed by 3175

Abstract

Maintenance of the biophysical properties of membranes is essential for cell survival upon external perturbations. However, the links between a fluid membrane state and the drug resistance of cancer cells remain elusive. Here, we investigated the role of membrane viscosity and lipid composition [...] Read more.

Maintenance of the biophysical properties of membranes is essential for cell survival upon external perturbations. However, the links between a fluid membrane state and the drug resistance of cancer cells remain elusive. Here, we investigated the role of membrane viscosity and lipid composition in the responses of cancer cells to oxaliplatin and the development of chemoresistance. Plasma membrane viscosity was monitored in live colorectal cancer cells and tumor xenografts using two-photon excited fluorescence lifetime imaging microscopy (FLIM) using the fluorescent molecular rotor BODIPY 2. The lipid profile was analyzed using time-of-flight secondary ion mass spectrometry (ToF-SIMS). It was found that the plasma membrane viscosity increased upon oxaliplatin treatment, both in vitro and in vivo, and that this correlated with lower phosphatidylcholine and higher cholesterol content. The emergence of resistance to oxaliplatin was accompanied by homeostatic adaptation of the membrane lipidome, and the recovery of lower viscosity. These results suggest that maintaining a constant plasma membrane viscosity via remodeling of the lipid profile is crucial for drug resistance in cancer. Full article

(This article belongs to the Special Issue Application of Biophysical Techniques to Cellular and Molecular Oncology)

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Review

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22 pages, 3436 KiB

Open AccessReview

Collagen-Based Biomimetic Systems to Study the Biophysical Tumour Microenvironment

by Alessandra Cambi and Maurizio Ventre

Cancers 2022, 14(23), 5939; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235939 - 30 Nov 2022

Cited by 1 | Viewed by 1956

Abstract

The extracellular matrix (ECM) is a pericellular network of proteins and other molecules that provides mechanical support to organs and tissues. ECM biophysical properties such as topography, elasticity and porosity strongly influence cell proliferation, differentiation and migration. The cell’s perception of the biophysical [...] Read more.

The extracellular matrix (ECM) is a pericellular network of proteins and other molecules that provides mechanical support to organs and tissues. ECM biophysical properties such as topography, elasticity and porosity strongly influence cell proliferation, differentiation and migration. The cell’s perception of the biophysical microenvironment (mechanosensing) leads to altered gene expression or contractility status (mechanotransduction). Mechanosensing and mechanotransduction have profound implications in both tissue homeostasis and cancer. Many solid tumours are surrounded by a dense and aberrant ECM that disturbs normal cell functions and makes certain areas of the tumour inaccessible to therapeutic drugs. Understanding the cell-ECM interplay may therefore lead to novel and more effective therapies. Controllable and reproducible cell culturing systems mimicking the ECM enable detailed investigation of mechanosensing and mechanotransduction pathways. Here, we discuss ECM biomimetic systems. Mainly focusing on collagen, we compare and contrast structural and molecular complexity as well as biophysical properties of simple 2D substrates, 3D fibrillar collagen gels, cell-derived matrices and complex decellularized organs. Finally, we emphasize how the integration of advanced methodologies and computational methods with collagen-based biomimetics will improve the design of novel therapies aimed at targeting the biophysical and mechanical features of the tumour ECM to increase therapy efficacy. Full article

(This article belongs to the Special Issue Application of Biophysical Techniques to Cellular and Molecular Oncology)

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9 pages, 1660 KiB

Open AccessReview

Differential Intracellular Protein Distribution in Cancer and Normal Cells—Beta-Catenin and CapG in Gynecologic Malignancies

by Maria Kristha Fernandez, Molika Sinha and Malte Renz

Cancers 2022, 14(19), 4788; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194788 - 30 Sep 2022

Cited by 2 | Viewed by 1406

Abstract

It is well-established that cancer and normal cells can be differentiated based on the altered sequence and expression of specific proteins. There are only a few examples, however, showing that cancer and normal cells can be differentiated based on the altered distribution of [...] Read more.

It is well-established that cancer and normal cells can be differentiated based on the altered sequence and expression of specific proteins. There are only a few examples, however, showing that cancer and normal cells can be differentiated based on the altered distribution of proteins within intracellular compartments. Here, we review available data on shifts in the intracellular distribution of two proteins, the membrane associated beta-catenin and the actin-binding protein CapG. Both proteins show altered distributions in cancer cells compared to normal cells. These changes are noted (i) in steady state and thus can be visualized by immunohistochemistry—beta-catenin shifts from the plasma membrane to the cell nucleus in cancer cells; and (ii) in the dynamic distribution that can only be revealed using the tools of quantitative live cell microscopy—CapG shuttles faster into the cell nucleus of cancer cells. Both proteins may play a role as prognosticators in gynecologic malignancies: beta-catenin in endometrial cancer and CapG in breast and ovarian cancer. Thus, both proteins may serve as examples of altered intracellular protein distribution in cancer and normal cells. Full article

(This article belongs to the Special Issue Application of Biophysical Techniques to Cellular and Molecular Oncology)

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31 pages, 2678 KiB

Open AccessReview

It Takes More than Two to Tango: Complex, Hierarchal, and Membrane-Modulated Interactions in the Regulation of Receptor Tyrosine Kinases

by Tamas Kovacs, Florina Zakany and Peter Nagy

Cancers 2022, 14(4), 944; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040944 - 14 Feb 2022

Cited by 13 | Viewed by 2579

Abstract

The search for an understanding of how cell fate and motility are regulated is not a purely scientific undertaking, but it can also lead to rationally designed therapies against cancer. The discovery of tyrosine kinases about half a century ago, the subsequent characterization [...] Read more.

The search for an understanding of how cell fate and motility are regulated is not a purely scientific undertaking, but it can also lead to rationally designed therapies against cancer. The discovery of tyrosine kinases about half a century ago, the subsequent characterization of certain transmembrane receptors harboring tyrosine kinase activity, and their connection to the development of human cancer ushered in a new age with the hope of finding a treatment for malignant diseases in the foreseeable future. However, painstaking efforts were required to uncover the principles of how these receptors with intrinsic tyrosine kinase activity are regulated. Developments in molecular and structural biology and biophysical approaches paved the way towards better understanding of these pathways. Discoveries in the past twenty years first resulted in the formulation of textbook dogmas, such as dimerization-driven receptor association, which were followed by fine-tuning the model. In this review, the role of molecular interactions taking place during the activation of receptor tyrosine kinases, with special attention to the epidermal growth factor receptor family, will be discussed. The fact that these receptors are anchored in the membrane provides ample opportunities for modulatory lipid–protein interactions that will be considered in detail in the second part of the manuscript. Although qualitative and quantitative alterations in lipids in cancer are not sufficient in their own right to drive the malignant transformation, they both contribute to tumor formation and also provide ways to treat cancer. The review will be concluded with a summary of these medical aspects of lipid–protein interactions. Full article

(This article belongs to the Special Issue Application of Biophysical Techniques to Cellular and Molecular Oncology)

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