The Multifaceted Role of Connexins in Tumor Microenvironment Initiation and Maintenance

Kutova, Olga M.; Pospelov, Anton D.; Balalaeva, Irina V.

doi:10.3390/biology12020204

Cited by 16 publications

(19 citation statements)

References 230 publications

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“…Moreover, low-dose IR induced mitochondrial translocation of connexin-43 and siRNA-mediated depletion of connexin-43 stimulated pro-apoptotic mitochondrial events suggesting a cytoprotective role of connexin-43 in tumor cells through mitochondrial functions. Connexin-43 plays an important role in cancer and cancer progression [181,182]. For example, the in vitro mesenchymal-epithelial transition (MET) in NIH353 fibroblasts initiated low-dose HRS coupled with an attenuated connexin-43 response [183].…”

Section: Involvement Of Mitochondriamentioning

confidence: 99%

Low-Dose Non-Targeted Effects and Mitochondrial Control

Averbeck

2023

IJMS

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Non-targeted effects (NTE) have been generally regarded as a low-dose ionizing radiation (IR) phenomenon. Recently, regarding long distant abscopal effects have also been observed at high doses of IR) relevant to antitumor radiation therapy. IR is inducing NTE involving intracellular and extracellular signaling, which may lead to short-ranging bystander effects and distant long-ranging extracellular signaling abscopal effects. Internal and “spontaneous” cellular stress is mostly due to metabolic oxidative stress involving mitochondrial energy production (ATP) through oxidative phosphorylation and/or anaerobic pathways accompanied by the leakage of O2− and other radicals from mitochondria during normal or increased cellular energy requirements or to mitochondrial dysfunction. Among external stressors, ionizing radiation (IR) has been shown to very rapidly perturb mitochondrial functions, leading to increased energy supply demands and to ROS/NOS production. Depending on the dose, this affects all types of cell constituents, including DNA, RNA, amino acids, proteins, and membranes, perturbing normal inner cell organization and function, and forcing cells to reorganize the intracellular metabolism and the network of organelles. The reorganization implies intracellular cytoplasmic-nuclear shuttling of important proteins, activation of autophagy, and mitophagy, as well as induction of cell cycle arrest, DNA repair, apoptosis, and senescence. It also includes reprogramming of mitochondrial metabolism as well as genetic and epigenetic control of the expression of genes and proteins in order to ensure cell and tissue survival. At low doses of IR, directly irradiated cells may already exert non-targeted effects (NTE) involving the release of molecular mediators, such as radicals, cytokines, DNA fragments, small RNAs, and proteins (sometimes in the form of extracellular vehicles or exosomes), which can induce damage of unirradiated neighboring bystander or distant (abscopal) cells as well as immune responses. Such non-targeted effects (NTE) are contributing to low-dose phenomena, such as hormesis, adaptive responses, low-dose hypersensitivity, and genomic instability, and they are also promoting suppression and/or activation of immune cells. All of these are parts of the main defense systems of cells and tissues, including IR-induced innate and adaptive immune responses. The present review is focused on the prominent role of mitochondria in these processes, which are determinants of cell survival and anti-tumor RT.

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Section: Involvement Of Mitochondriamentioning

confidence: 99%

Low-Dose Non-Targeted Effects and Mitochondrial Control

Averbeck

2023

IJMS

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“…By exploring the hypoxia biomarkers like HIF-1, GLUT-1, miRNA, and lactate, we seek to unravel the mechanisms through which hypoxia shapes the aggressive phenotype of HNC. Additionally, this review delves into the potential implications of hypoxia on therapeutic resistance, prognosis, and overall treatment outcomes [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor hypoxia and role of hypoxia-inducible factor in oral cancer

Singh,

Rajput,

Pandey

2024

World J Surg Onc

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Background Head and neck cancer (HNC) is one of the most frequent malignancies in Asian males with a poor prognosis. Apart from well-known prognostic indicators, markers of tumor hypoxia can help us predict response to treatment and survival. Methods A review of the literature on the present evidence and potential clinical importance of tumor hypoxia in head and neck cancer was carried out. The data obtained from the literature search is presented as a narrative review. Results The literature shows possible associations between prognosis and low tumor oxygenation. Intermediate hypoxia biomarkers like HIF-1, GLUT-1, miRNA, and lactate, can help in predicting the response to therapy and survival as their altered expression is related to prognosis. Conclusions Hypoxia is common in HNC and can be detected by use of biomarkers. The tumors that show expression of hypoxia biomarkers have poor prognosis except for patients with human papilloma virus-associated or VHL-associated cancers. Therapeutic targeting of hypoxia is emerging; however, it is still in its nascent stage, with increasing clinical trials hypoxia is set to emerge as an attractive therapeutic target in HNC.

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“…The tumor microenvironment includes cells of different origin and functions: stromal cells, immune cells, endotheliocytes, etc., and non-cellular component—the extracellular matrix (ECM). ECM is intricately involved in the maintenance of tissue-specific homeostasis [ 1 , 2 ]. The chemical composition of ECM, that is, the type and the ratio of proteins, polysaccharides, and water, and its physical properties arising from the organization of these components, are optimal to each tissue or organ.…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer Cell Type and Biomechanical Properties of Decellularized Mouse Organs Drives Tumor Cell Colonization

Pospelov,

Kutova,

Efremov

et al. 2023

Cells

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Tissue engineering has emerged as an indispensable tool for the reconstruction of organ-specific environments. Organ-derived extracellular matrices (ECM) and, especially, decellularized tissues (DCL) are recognized as the most successful biomaterials in regenerative medicine, as DCL preserves the most essential organ-specific ECM properties such as composition alongside biomechanics characterized by stiffness and porosity. Expansion of the DCL technology to cancer biology research, drug development, and nanomedicine is pending refinement of the existing DCL protocols whose reproducibility remains sub-optimal varying from organ to organ. We introduce a facile decellularization protocol universally applicable to murine organs, including liver, lungs, spleen, kidneys, and ovaries, with demonstrated robustness, reproducibility, high purification from cell debris, and architecture preservation, as confirmed by the histological and SEM analysis. The biomechanical properties of as-produced DCL organs expressed in terms of the local and total stiffness were measured using our facile methodology and were found well preserved in comparison with the intact organs. To demonstrate the utility of the developed DCL model to cancer research, we engineered three-dimensional tissue constructs by recellularization representative decellularized organs and collagenous hydrogel with human breast cancer cells of pronounced mesenchymal (MDA-MB-231) or epithelial (SKBR-3) phenotypes. The biomechanical properties of the DCL organs were found pivotal to determining the cancer cell fate and progression. Our histological and scanning electron microscopy (SEM) study revealed that the larger the ECM mean pore size and the smaller the total stiffness (as in lung and ovary), the more proliferative and invasive the mesenchymal cells became. At the same time, the low local stiffness ECMs (ranged 2.8–3.6 kPa) did support the epithelial-like SKBR-3 cells’ viability (as in lung and spleen), while stiff ECMs did not. The total and local stiffness of the collagenous hydrogel was measured too low to sustain the proliferative potential of both cell lines. The observed cell proliferation patterns were easily interpretable in terms of the ECM biomechanical properties, such as binding sites, embedment facilities, and migration space. As such, our three-dimensional tissue engineering model is scalable and adaptable for pharmacological testing and cancer biology research of metastatic and primary tumors, including early metastatic colonization in native organ-specific ECM.

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The Multifaceted Role of Connexins in Tumor Microenvironment Initiation and Maintenance

Cited by 16 publications

References 230 publications

Low-Dose Non-Targeted Effects and Mitochondrial Control

Low-Dose Non-Targeted Effects and Mitochondrial Control

Tumor hypoxia and role of hypoxia-inducible factor in oral cancer

Breast Cancer Cell Type and Biomechanical Properties of Decellularized Mouse Organs Drives Tumor Cell Colonization

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