Publications by authors named "Vasiliki Gkretsi"

39 Publications

The focal adhesion protein Integrin-Linked Kinase (ILK) as an important player in breast cancer pathogenesis.

Cell Adh Migr 2020 12;14(1):204-213

Department of Life Sciences, School of Sciences, European University Cyprus , Nicosia, Cyprus.

Cell-extracellular matrix interactions, or focal adhesions (FA), are crucial for tissue homeostasis but are also implicated in cancer. Integrin-Linked Kinase (ILK) is an abundantly expressed FA protein involved in multiple signaling pathways. Here, we reviewed the current literature on the role of ILK in breast cancer (BC). Articles included in vitro and in vivo experiments as well as studies in human BC samples. ILK attenuation via silencing or pharmaceutical inhibition, leads to apoptosis or inhibition of epithelial-to-mesenchymal transition, and cell invasion whereas ILK overexpression suppresses anoikis and promotes tumor growth and metastasis. Finally, ILK is upregulated in BC tumors and its expression is associated with grade, and metastasis. Therefore, ILK should be evaluated as a potential anti-cancer pharmaceutical target.
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http://dx.doi.org/10.1080/19336918.2020.1829263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553581PMC
December 2020

Ras Suppressor-1 (RSU1) in Cancer Cell Metastasis: A Tale of a Tumor Suppressor.

Int J Mol Sci 2020 Jun 7;21(11). Epub 2020 Jun 7.

Biomedical Sciences Program, Department of Life Sciences, School of Sciences, European University Cyprus, 1516 Nicosia, Cyprus.

Cancer is a multifactorial disease responsible for millions of deaths worldwide. It has a strong genetic background, as mutations in oncogenes or tumor suppressor genes contribute to the initiation of cancer development. Integrin signaling as well as the signaling pathway of oncogene, have been long implicated both in carcinogenesis and disease progression. Moreover, they have been involved in the promotion of metastasis, which accounts for the majority of cancer-related deaths. was identified as a suppressor of induced transformation and was shown to localize to cell-extracellular matrix adhesions. Recent findings indicate that its expression is elevated in various cancer types, while its role in regulating metastasis-related cellular processes remains largely unknown. Interestingly, there is no in vivo work in the field to date, and thus, all relevant knowledge stems from in vitro studies. In this review, we summarize recent studies using breast, liver and brain cancer cell lines and highlight the role of RSU1 in regulating cancer cell invasion.
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http://dx.doi.org/10.3390/ijms21114076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312364PMC
June 2020

ILK silencing inhibits migration and invasion of more invasive glioblastoma cells by downregulating ROCK1 and Fascin-1.

Mol Cell Biochem 2020 Aug 6;471(1-2):143-153. Epub 2020 Jun 6.

Biomedical Sciences Program, Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenous Street, Egkomi, 1516, Nicosia, Cyprus.

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor and it is associated with poor survival. Integrin-linked kinase (ILK) is a serine/threonine protein pseudo-kinase that binds to the cytoplasmic domains of β1 and β3 integrins and has been previously shown to promote invasion and metastasis in many cancer types, including GBM. However, little is known regarding the exact molecular mechanism implicating ILK in GBM aggressiveness. In this study, we used two brain cell lines, the non-invasive neuroglioma H4 cells, and the highly invasive glioblastoma A172 cells, which express ILK in much higher levels than H4. We studied the effect of ILK silencing on the metastatic behavior of glioblastoma cells in vitro and elucidate the underlying molecular mechanism. We showed that siRNA-mediated silencing of ILK inhibits cell migration and invasion of the highly invasive A172 cells while it does not affect the migratory and invasive capacity of H4 cells. These data were also supported by respective changes in the expression of Rho-associated kinase 1 (ROCK1), fascin actin-bundling protein 1 (FSCN1), and matrix metalloproteinase 13 (MMP13), which are known to regulate cell migration and invasion. Our findings were further corroborated by analyzing the Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) dataset. We conclude that ILK promotes glioblastoma cell invasion through activation of ROCK1 and FSCN1 in vitro, providing a more exact molecular mechanism for its action.
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http://dx.doi.org/10.1007/s11010-020-03774-yDOI Listing
August 2020

Growth differentiation factor 15 (GDF15) in cancer cell metastasis: from the cells to the patients.

Clin Exp Metastasis 2020 08 5;37(4):451-464. Epub 2020 Jun 5.

Biomedical Sciences Program, Department of Life Sciences, School of Sciences, European University Cyprus, 6, Diogenis Str, Engomi, 2404, Nicosia, Cyprus.

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor β superfamily, has been postulated to be implicated in cancer cell metastasis although its role has not been fully elucidated yet. The purpose of this review is to clarify the role of GDF-15 in cancer cell metastasis based on current advances in the field. The studies were divided into those involving evaluation of GDF15 expression in the serum or tissue of cancer patients, and those involving in vitro experiments in cancer cell lines or in vivo experiments in animal models. GDF15 was shown to be elevated in the serum or tissues of cancer patients with its expression being correlated with decreased survival. Moreover, most in vitro and in vivo studies also corroborated a metastasis-promoting role for GDF15. However, there were a few studies, where GDF15 was shown to suppress the metastatic properties of cells. As, GDF15 has been known for its pleiotropic effects, it is not surprising to behave differently in different types of cancer. Thus, GDF15 has the potential of not only being a useful metastasis biomarker, but also a promising therapeutic target against cancer cell metastasis in many cancer types.
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http://dx.doi.org/10.1007/s10585-020-10041-3DOI Listing
August 2020

Silencing of Growth Differentiation Factor-15 Promotes Breast Cancer Cell Invasion by Down-regulating Focal Adhesion Genes.

Anticancer Res 2020 Mar;40(3):1375-1385

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus

Background/aim: As metastasis accounts for most breast cancer (BC)-related deaths, identifying key players becomes research priority. Growth differentiation factor-15 (GDF15), a member of the transforming growth factor-β superfamily, is affected by the actin cytoskeleton and has been associated with cancer. However, its exact role in BC cell invasiveness is vague.

Materials And Methods: GDF15 short-hairpin (shRNA)-mediated silencing was used to inhibit GDF15 expression in MCF-7 and MDA-MB-231 BC cells and gene expression of relevant focal adhesion (FA) genes, cell migration, invasion and tumor spheroid invasion were subsequently analyzed.

Results: GDF15 silencing promoted cell migration, cell invasion as well as tumor spheroid invasion and up-regulated urokinase plasminogen activator (uPA) and FA genes, integrin-linked kinase (ILK), LIM zinc finger domain containing 1 (LIMS1), α-parvin (PARVA), and RAS suppressor-1 (RSU1). Computational analysis of Cancer Genome Atlas BC dataset however, revealed no significant correlation between GDF15 expression and metastasis pointing towards a more complex molecular interplay between GDF15, actin cytoskeleton and FA-related genes which ultimately affects their expression pattern, in vivo.

Conclusion: GDF15 suppresses BC cell invasion in vitro through down-regulation of FA genes but its role in BC is more complicated in vivo and warrants further investigation.
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http://dx.doi.org/10.21873/anticanres.14079DOI Listing
March 2020

Coordinated Expression of Ras Suppressor 1 (RSU-1) and Growth Differentiation Factor 15 (GDF15) Affects Glioma Cell Invasion.

Cancers (Basel) 2019 Aug 13;11(8). Epub 2019 Aug 13.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678 Nicosia, Cyprus.

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor due to its invasive phenotype. Ras suppressor 1 (RSU-1) is a cell-extracellular matrix adhesion protein and we recently found that it promotes cell invasion in aggressive cells and inhibits it in non-invasive. Growth differentiation factor-15 (GDF15) is known to be involved in actin cytoskeleton reorganization and metastasis. In this study, we used three brain cell lines (H4, SW1088 and A172) with increasing expression levels and invasive capacity and decreasing levels to investigate the interplay between RSU-1 and GDF15 with regard to cell invasion. Four experimental approaches were used: (a) GDF15 treatment, (b) silencing, (c) silencing, and (d) combined GDF15 treatment and silencing. We found that the differential expression of and in H4 and A172 cells leading to inhibition of cell invasion in H4 cells and promotion in A172 through respective changes in , and expression. Interestingly SW1088, with intermediate and expression, were not affected by any treatment. We conclude that there is a strong connection between RSU-1 and GDF15 in H4, SW1088 and A172 cells and the relative expression of these two proteins is fundamental in affecting their invasive fate.
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http://dx.doi.org/10.3390/cancers11081159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721804PMC
August 2019

Depletion of Ras Suppressor-1 (RSU-1) promotes cell invasion of breast cancer cells through a compensatory upregulation of a truncated isoform.

Sci Rep 2019 07 11;9(1):10050. Epub 2019 Jul 11.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.

Extracellular matrix (ECM)-adhesion proteins and actin cytoskeleton are pivotal in cancer cell invasion. Ras Suppressor-1 (RSU-1), a cell-ECM adhesion protein that interacts with PINCH-1, thus being connected to Integrin Linked Kinase (ILK), alpha-parvin (PARVA), and actin cytoskeleton, is up-regulated in metastatic breast cancer (BC) samples. Apart from the originally-identified gene (RSU-1L), an alternatively-spliced isoform (RSU-1-X1) has been reported. We used non-invasive MCF-7 cells, expressing only RSU-1L, and highly invasive MDA-MB-231-LM2 expressing both isoforms and generated stable shRNA-transduced cells lacking RSU-1L, while the truncated RSU-1-X1 isoform was depleted by siRNA-mediated silencing. RSU-1L depletion in MCF-7 cells resulted in complete abrogation of tumor spheroid invasion in three-dimensional collagen gels, whereas it promoted MDA-MB-231-LM2 invasion, through a compensatory upregulation of RSU-1-X1. When RSU-1-X1 was also eliminated, RSU-1L-depletion-induced migration and invasion were drastically reduced being accompanied by reduced urokinase plasminogen activator expression. Protein expression analysis in 23 human BC samples corroborated our findings showing RSU-1L to be upregulated and RSU-1-X1 downregulated in metastatic samples. We demonstrate for the first time, that both RSU-1 isoforms promote invasion in vitro while RSU-1L elimination induces RSU-1-X1 upregulation to compensate for the loss. Hence, we propose that both isoforms should be blocked to effectively eliminate metastasis.
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http://dx.doi.org/10.1038/s41598-019-46575-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624310PMC
July 2019

Ras suppressor-1 (RSU-1) promotes cell invasion in aggressive glioma cells and inhibits it in non-aggressive cells through STAT6 phospho-regulation.

Sci Rep 2019 05 23;9(1):7782. Epub 2019 May 23.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.

Most gliomas are invasive tumors formed from glial cells and associated with high mortality rates. In this study, we characterized four glioma cell lines of varying degree of aggressiveness (H4, SW1088, A172 and U87-MG) in terms of morphology, cytoskeleton organization and stiffness, and evaluated their invasive potential by performing invasion, colony forming and spheroid invasion assays. Cells were divided into two distinct groups: aggressive cell lines (A172 and U87-MG) with more elongated, softer and highly invasive cells and less aggressive cells (H4 and SW088). Interestingly, we found that Ras Suppressor-1 (RSU-1), a cell-matrix adhesion protein involved in cancer cell invasion, was significantly upregulated in more aggressive glioma cells compared to less aggressive. Importantly, RSU-1 silencing had opposing effects on glioma cell invasion depending on their aggressiveness, inhibiting migration and invasion of aggressive cells and promoting those of less aggressive cells. Finally, we found that RSU-1 silencing in aggressive cells led to decreased Signal Transducer and Activator of Transcription6 (STAT6) phosphorylation and Matrix Metalloproteinase13 (MMP13) expression in contrast to less invasive cells. Our study demonstrates that RSU-1 promotes invasion of aggressive glioma cells and inhibits it in the non-aggressive cells, indicating that it could serve as a predictor of gliomas progression.
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http://dx.doi.org/10.1038/s41598-019-44200-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533309PMC
May 2019

Collagen content and extracellular matrix cause cytoskeletal remodelling in pancreatic fibroblasts.

J R Soc Interface 2019 05;16(154):20190226

1 Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus , Nicosia 1678 , Cyprus.

In many solid tumours a desmoplastic reaction takes place, which results in tumour tissue stiffening due to the extensive production of extracellular matrix (ECM) proteins, such as collagen, by stromal cells, mainly fibroblasts (FBs) and cancer-associated fibroblasts (CAFs). In this study, we investigated the effect of collagen stiffness on pancreatic FBs and CAFs, particularly on specific cytoskeleton properties and gene expression involved in tumour invasion. We found that cells become stiffer when they are cultured on stiff substrates and express higher levels of alpha-smooth muscle actin (α-SMA). Also, it was confirmed that on stiff substrates, CAFs are softer than FBs, while on soft substrates they have comparable Young's moduli. Furthermore, the number of spread FBs and CAFs was higher in stiffer substrates, which was also confirmed by Ras-related C3 botulinum toxin substrate 1 ( RAC1) mRNA expression, which mediates cell spreading. Although stress fibres in FBs become more oriented on stiff substrates, CAFs have oriented stress fibres regardless of substrate stiffness. Subsequently, we demonstrated that cells' invasion has a differential response to stiffness, which was associated with regulation of Ras homologue family member ( RhoA) and Rho-associated, coiled-coil containing protein kinase 1 ( ROCK-1) mRNA expression. Overall, our results demonstrate that collagen stiffness modulates FBs and CAFs cytoskeleton remodelling and alters their invasion properties.
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http://dx.doi.org/10.1098/rsif.2019.0226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544883PMC
May 2019

Editorial: Metastasis: From Cell Adhesion and Beyond.

Front Oncol 2019 2;9:214. Epub 2019 Apr 2.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.

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http://dx.doi.org/10.3389/fonc.2019.00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454140PMC
April 2019

Inhibition of Breast Cancer Cell Invasion by Ras Suppressor-1 (RSU-1) Silencing Is Reversed by Growth Differentiation Factor-15 (GDF-15).

Int J Mol Sci 2019 01 4;20(1). Epub 2019 Jan 4.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678 Nicosia, Cyprus

Extracellular matrix (ECM)-related adhesion proteins are important in metastasis. Ras suppressor-1 (RSU-1), a suppressor of -transformation, is localized to cell⁻ECM adhesions where it interacts with the Particularly Interesting New Cysteine-Histidine rich protein (PINCH-1), being connected to Integrin Linked Kinase (ILK) and alpha-parvin (PARVA), a direct actin-binding protein. was also found upregulated in metastatic breast cancer (BC) samples and was recently demonstrated to have metastasis-promoting properties. In the present study, we transiently silenced in BC cells, MCF-7 and MDA-MB-231. We found that silencing leads to downregulation of Growth Differentiation Factor-15 (), which has been associated with both actin cytoskeleton reorganization and metastasis. silencing also reduced the mRNA expression of and cell division control protein-42 (), while increasing that of and regardless of the presence of GDF-15. However, the downregulation of actin-modulating genes , , Rho associated kinase-1 (), and following depletion was completely reversed by GDF-15 treatment in both cell lines. Moreover, complete rescue of the inhibitory effect of silencing on cell invasion was achieved by GDF-15 treatment, which also correlated with matrix metalloproteinase-2 expression. Finally, using a graph clustering approach, we corroborated our findings. This is the first study providing evidence of a functional association between and with regard to cancer cell invasion.
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http://dx.doi.org/10.3390/ijms20010163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337329PMC
January 2019

The role of fibroblast growth factors and their receptors in gliomas: the mutations involved.

Rev Neurosci 2019 07;30(5):543-554

Biomedical Sciences Program, Department of Life Sciences, School of Sciences, European University of Cyprus, 6, Diogenis Str, Engomi 2404, Nicosia, Cyprus.

The central nervous system (CNS) comprises of neurons, which are responsible for impulse transmission, and glial cells, which surround neurons providing protection and nutrition. Glial cells are categorized into astrocytes, oligodendrocytes, microglial cells, and ependymal cells. Tumors forming from glial cells are called gliomas, and they are classified accordingly into astrocytomas, oligodendrogliomas, and ependymomas. Gliomas are characterized by high mortality rates and degree of malignancy, heterogeneity, and resistance to treatment. Among the molecular players implicated in glioma pathogenesis are members of the fibroblast growth factor (FGF) superfamily as well as their receptors (FGFRs). In the present study, we provide a review of the literature on the role of FGFs and FGFRs in glioma pathogenesis. We also demonstrate that FGFs, and particularly FGF1 and FGF2, bear a variety of mutations in gliomas, while FGFRs are also crucially involved. In fact, several studies show that in gliomas, FGFRs bear mutations, mainly in the tyrosine kinase domains. Specifically, it appears that FGFR1-TACC1 and FGFR3-TACC3 fusions are common in these receptors. A better understanding of the mutations and the molecular players involved in glioma formation will benefit the scientific community, leading to the development of more effective and innovative therapeutic approaches.
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http://dx.doi.org/10.1515/revneuro-2018-0051DOI Listing
July 2019

Atomic force microscopy nano-characterization of 3D collagen gels with tunable stiffness.

MethodsX 2018 22;5:503-513. Epub 2018 May 22.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, P.O. Box 20537, Nicosia, 1678, Cyprus.

As extracellular matrix (ECM) nano-characteristics play a crucial role in cell behavior, including cancer development and metastasis, several ECM in vitro models have been used in order to study cells behavior under different biochemical and mechanical conditions. Among the ECM constituents, collagen (especially collagen type I) has been extensively used as an essential component of ECM models, since it is one of the most abundant ECM protein. Use of three-dimensional (3D) collagen gels provides the advantage of allowing the cells to grow in a 3D environment that bears strong similarities to their natural, in vivo setting. Thus, the ability to form collagen gels with tunable stiffness and well defined naturally occurring nano-characteristics is crucial for these studies. Atomic Force Microscopy (AFM) is a unique tool that is ideal for the complete characterization of such models, in terms of morphology and mechanical properties without destroying the collagen fiber structure. In this protocol, the development and the AFM nano-scale characterization of 3D collagen type I gels is presented. The protocol includes: •The formation of 3D collagen type I gels with tunable stiffness•The preparation of histological sections from collagen gels•The AFM-based morphological and mechanical nano-characterization of the gels.
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http://dx.doi.org/10.1016/j.mex.2018.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046612PMC
May 2018

Cell Adhesion and Matrix Stiffness: Coordinating Cancer Cell Invasion and Metastasis.

Front Oncol 2018 4;8:145. Epub 2018 May 4.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.

Metastasis is a multistep process in which tumor extracellular matrix (ECM) and cancer cell cytoskeleton interactions are pivotal. ECM is connected, through integrins, to the cell's adhesome at cell-ECM adhesion sites and through them to the actin cytoskeleton and various downstream signaling pathways that enable the cell to respond to external stimuli in a coordinated manner. Cues from cell-adhesion proteins are fundamental for defining the invasive potential of cancer cells, and many of these proteins have been proposed as potent targets for inhibiting cancer cell invasion and thus, metastasis. In addition, ECM accumulation is quite frequent within the tumor microenvironment leading in many cases to an intense fibrotic response, known as desmoplasia, and tumor stiffening. Stiffening is not only required for the tumor to be able to displace the host tissue and grow in size but also contributes to cell-ECM interactions and can promote cancer cell invasion to surrounding tissues. Here, we review the role of cell adhesion and matrix stiffness in cancer cell invasion and metastasis.
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http://dx.doi.org/10.3389/fonc.2018.00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945811PMC
May 2018

Transforming growth factor-β modulates pancreatic cancer associated fibroblasts cell shape, stiffness and invasion.

Biochim Biophys Acta Gen Subj 2018 Jul 15;1862(7):1537-1546. Epub 2018 Mar 15.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 1678, Cyprus. Electronic address:

Background: Tumor microenvironment consists of the extracellular matrix (ECM), stromal cells, such as fibroblasts (FBs) and cancer associated fibroblasts (CAFs), and a myriad of soluble factors. In many tumor types, including pancreatic tumors, the interplay between stromal cells and the other tumor microenvironment components leads to desmoplasia, a cancer-specific type of fibrosis that hinders treatment. Transforming growth factor beta (TGF-β) and CAFs are thought to play a crucial role in this tumor desmoplastic reaction, although the involved mechanisms are unknown.

Methods: Optical/fluorescence microscopy, atomic force microscopy, image processing techniques, invasion assay in 3D collagen I gels and real-time PCR were employed to investigate the effect of TGF-β on normal pancreatic FBs and CAFs with regard to crucial cellular morphodynamic characteristics and relevant gene expression involved in tumor progression and metastasis.

Results: CAFs present specific myofibroblast-like characteristics, such as α-smooth muscle actin expression and cell elongation, they also form more lamellipodia and are softer than FBs. TGF-β treatment increases cell stiffness (Young's modulus) of both FBs and CAFs and increases CAF's (but not FB's) elongation, cell spreading, lamellipodia formation and spheroid invasion. Gene expression analysis shows that these morphodynamic characteristics are mediated by Rac, RhoA and ROCK expression in CAFs treated with TGF-β.

Conclusions: TGF-β modulates CAFs', but not FBs', cell shape, stiffness and invasion.

General Significance: Our findings elucidate on the effects of TGF-β on CAFs' behavior and stiffness providing new insights into the mechanisms involved.
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http://dx.doi.org/10.1016/j.bbagen.2018.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957271PMC
July 2018

Solid Stress Facilitates Fibroblasts Activation to Promote Pancreatic Cancer Cell Migration.

Ann Biomed Eng 2018 May 22;46(5):657-669. Epub 2018 Feb 22.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, P.O. Box 20537, 1678, Nicosia, Cyprus.

Pancreatic fibroblasts are continuously gaining ground as an important component of tumor microenvironment that dynamically interact with cancer cells to promote tumor progression. In addition, these tumor-infiltrated fibroblasts can acquire an activated phenotype and produce excessive amounts of extracellular matrix creating a highly dense stroma, a situation known as desmoplasia. Desmoplasia, along with the uncontrolled proliferation of cancer cells, leads to the development of compressive forces within the tumor, generating the so-called solid stress. Solid stress is previously shown to affect cancer cell proliferation and migration, however there is no pertinent study taking into account the effects of solid stress on fibroblasts and whether these effects contribute to tumor progression. In this work, we applied a defined compressive stress on pancreatic fibroblasts, similar in magnitude to that experienced by cells in native pancreatic tumors. Our results suggest that solid stress stimulates fibroblasts activation and strongly upregulates Growth Differentiation Factor-15 (GDF15) expression. Moreover, co-culture of compression-induced activated fibroblasts with pancreatic cancer cells significantly promotes cancer cell migration, which is inhibited by shRNA-mediated silencing of GDF15 in fibroblasts. Conclusively, our findings highlight the involvement of biophysical factors, such as solid stress, in tumor progression and malignancy revealing a novel role for GDF15.
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http://dx.doi.org/10.1007/s10439-018-1997-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951267PMC
May 2018

Targeting Inflammation to Improve Tumor Drug Delivery.

Trends Cancer 2017 09 23;3(9):621-630. Epub 2017 Aug 23.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. Electronic address:

Inefficient delivery of drugs is a main cause of chemotherapy failure in hypoperfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness, and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on anti-angiogenic drugs, whereas stress alleviation is based on stroma-depleting agents. We present here an alternative approach to normalize tumor vasculature, taking into account that malignant tumors tend to develop at sites of chronic inflammation. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyperpermeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or inflammation resolution mediators, as an alternative means to increase tumor drug delivery might prove promising.
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http://dx.doi.org/10.1016/j.trecan.2017.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614424PMC
September 2017

Exploring the Nano-Surface of Collagenous and Other Fibrotic Tissues with AFM.

Methods Mol Biol 2017 ;1627:453-489

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus, Greece.

Atomic force microscope (AFM) is a powerful and invaluable tool for imaging and probing the mechanical properties of biological samples at the nanometric scale. The importance of nano-scale characterization and nanomechanics of soft biological tissues is becoming widely appreciated, and AFM offers unique advantages in this direction. In this chapter, we describe the procedure to collect data sets (imaging and mechanical properties measurement) of collagen gels and tumor tissues. We provide step-by-step instructions throughout the procedure, from sample preparation to cantilever calibration, data acquisition, analysis, and visualization, using two commercial AFM systems (PicoPlus and Cypher ES) and software that accompanied the AFM systems and/or are freeware available (WSxM, AtomicJ). Our protocols are written specifically for these two systems and the mentioned software; however, most of the general concepts can be readily translated to other AFM systems and software.
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http://dx.doi.org/10.1007/978-1-4939-7113-8_29DOI Listing
May 2018

Identification of Ras suppressor-1 (RSU-1) as a potential breast cancer metastasis biomarker using a three-dimensional in vitro approach.

Oncotarget 2017 Apr;8(16):27364-27379

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.

Breast cancer (BC) is the most common malignant disease in women, with most patients dying from metastasis to distant organs, making discovery of novel metastasis biomarkers and therapeutic targets imperative. Extracellular matrix (ECM)-related adhesion proteins as well as tumor matrix stiffness are important determinants for metastasis. As traditional two-dimensional culture does not take into account ECM stiffness, we employed 3-dimensional collagen I gels of increasing concentration and stiffness to embed BC cells of different invasiveness (MCF-7, MDA-MB-231 and MDA-MB-231-LM2) or tumor spheroids. We tested the expression of cell-ECM adhesion proteins and found that Ras Suppressor-1 (RSU-1) is significantly upregulated in increased stiffness conditions. Interestingly, RSU-1 siRNA-mediated silencing inhibited Urokinase Plasminogen Activator, and metalloproteinase-13, whereas tumor spheroids formed from RSU-1-depleted cells lost their invasive capacity in all cell lines and stiffness conditions. Kaplan-Meier survival plot analysis corroborated our findings showing that high RSU-1 expression is associated with poor prognosis for distant metastasis-free and remission-free survival in BC patients. Taken together, our results indicate the important role of RSU-1 in BC metastasis and set the foundations for its validation as potential BC metastasis marker.
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http://dx.doi.org/10.18632/oncotarget.16062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432341PMC
April 2017

Vasodilator-Stimulated Phosphoprotein (VASP) depletion from breast cancer MDA-MB-231 cells inhibits tumor spheroid invasion through downregulation of Migfilin, β-catenin and urokinase-plasminogen activator (uPA).

Exp Cell Res 2017 03 14;352(2):281-292. Epub 2017 Feb 14.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Cyprus. Electronic address:

A hallmark of cancer cells is their ability to invade surrounding tissues and form metastases. Cell-extracellular matrix (ECM)-adhesion proteins are crucial in metastasis, connecting tumor ECM with actin cytoskeleton thus enabling cells to respond to mechanical cues. Vasodilator-stimulated phosphoprotein (VASP) is an actin-polymerization regulator which interacts with cell-ECM adhesion protein Migfilin, and regulates cell migration. We compared VASP expression in MCF-7 and MDA-MB-231 breast cancer (BC) cells and found that more invasive MDA-MB-231 cells overexpress VASP. We then utilized a 3-dimensional (3D) approach to study metastasis in MDA-MB-231 cells using a system that considers mechanical forces exerted by the ECM. We prepared 3D collagen I gels of increasing concentration, imaged them by atomic force microscopy, and used them to either embed cells or tumor spheroids, in the presence or absence of VASP. We show, for the first time, that VASP silencing downregulated Migfilin, β-catenin and urokinase plasminogen activator both in 2D and 3D, suggesting a matrix-independent mechanism. Tumor spheroids lacking VASP demonstrated impaired invasion, indicating VASP's involvement in metastasis, which was corroborated by Kaplan-Meier plotter showing high VASP expression to be associated with poor remission-free survival in lymph node-positive BC patients. Hence, VASP may be a novel BC metastasis biomarker.
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http://dx.doi.org/10.1016/j.yexcr.2017.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349498PMC
March 2017

Ras Suppressor-1 (RSU-1) in Cancer Cell Metastasis: Friend or Foe?

Crit Rev Oncog 2017 ;22(3-4):249-253

Biomedical Sciences Program, Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus.

Metastasis to distant organs and not the primary tumor itself is usually the cause of death for cancer patients. Hence, studying the key molecules and molecular pathways involved in metastasis are essential. Metastasis is a complex process in which cancer cells detach from the original tumor, migrate, and invade through surrounding tissues and metastasize to other sites of the body through the circulation. The cell-extracellular matrix (ECM) adhesion proteins play a fundamental role in this process as cancer cells need to weaken their adhesions to dissociate from the ECM as well as the neighboring cells within the tumor and finally form new adhesions and invade surrounding tissues. Ras suppressor-1 (RSU-1) was originally identified as a suppressor of Ras-dependent oncogenic transformation and found to be localized to cell-ECM adhesions where it binds to PINCH-1, a focal adhesion involved in cell survival. Although RSU-1 was connected to cancer early on, little is known about its expression in various cancer types or its role in metastasis. In this article, we review the recent literature regarding the expression of RSU-1 in various cancer types and its potential role in metastasis, discussing interesting findings and issues that still need to be addressed.
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http://dx.doi.org/10.1615/CritRevOncog.2018024231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985951PMC
April 2019

Hyaluronan-Derived Swelling of Solid Tumors, the Contribution of Collagen and Cancer Cells, and Implications for Cancer Therapy.

Neoplasia 2016 Dec 22;18(12):732-741. Epub 2016 Nov 22.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. Electronic address:

Despite the important role that mechanical forces play in tumor growth and therapy, the contribution of swelling to tumor mechanopathology remains unexplored. Tumors rich in hyaluronan exhibit a highly negative fixed charge density. Repulsive forces among these negative charges as well as swelling of cancer cells due to regulation of intracellular tonicity can cause tumor swelling and development of stress that might compress blood vessels, compromising tumor perfusion and drug delivery. Here, we designed an experimental strategy, using four orthotopic tumor models, to measure swelling stress and related swelling to extracellular matrix components, hyaluronan and collagen, as well as to tumor perfusion. Subsequently, interventions were performed to measure tumor swelling using matrix-modifying enzymes (hyaluronidase and collagenase) and by repurposing pirfenidone, an approved antifibrotic drug. Finally, in vitro experiments on cancer cell spheroids were performed to identify their contribution to tissue swelling. Swelling stress was measured in the range of 16 to 75 mm Hg, high enough to cause vessel collapse. Interestingly, while depletion of hyaluronan decreased swelling, collagen depletion had the opposite effect, whereas the contribution of cancer cells was negligible. Furthermore, histological analysis revealed the same linear correlation between tumor swelling and the ratio of hyaluronan to collagen content when data from all tumor models were combined. Our data further revealed an inverse relation between tumor perfusion and swelling, suggesting that reduction of swelling decompresses tumor vessels. These results provide guidelines for emerging therapeutic strategies that target the tumor microenvironment to alleviate intratumoral stresses and improve vessel functionality and drug delivery.
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http://dx.doi.org/10.1016/j.neo.2016.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122704PMC
December 2016

Remodeling Components of the Tumor Microenvironment to Enhance Cancer Therapy.

Front Oncol 2015 14;5:214. Epub 2015 Oct 14.

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus , Nicosia , Cyprus.

Solid tumor pathophysiology is characterized by an abnormal microenvironment that guides tumor progression and poses barriers to the efficacy of cancer therapies. Most common among tumor types are abnormalities in the structure of the tumor vasculature and stroma. Remodeling the tumor microenvironment with the aim to normalize any aberrant properties has the potential to improve therapy. In this review, we discuss structural abnormalities of the tumor microenvironment and summarize the therapeutic strategies that have been developed to normalize tumors as well as their potential to enhance therapy. Finally, we present different in vitro models that have been developed to analyze and better understand the effects of the tumor microenvironment on cancer cell behavior.
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http://dx.doi.org/10.3389/fonc.2015.00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604307PMC
November 2015

Experimental evidence of Migfilin as a new therapeutic target of hepatocellular carcinoma metastasis.

Exp Cell Res 2015 Jun 12;334(2):219-27. Epub 2015 Mar 12.

Department of Biomedical Research and Technology, Institute for Research and Technology-Thessaly, Centre for Research and Technology-Hellas (CE.R.T.H.), Larissa 41222, Greece; Department of Rheumatology, School of Medicine, University of Thessaly, University Hospital of Larissa, 41110 Larissa, Greece; Institute of Liver Studies, King׳s College Hospital, Denmark Hill, London SE5 9RS, UK.

Migfilin is a novel cell-matrix adhesion protein known to interact with Vasodilator Stimulated Phosphoprotein (VASP) and be localized both at cell-matrix and cell-cell adhesions. To date there is nothing known about its role in hepatocellular carcinoma (HCC). As matrix is important in metastasis, we aimed to investigate the Migfilin׳s role in HCC metastasis using two human HCC cell lines that differ in their metastatic potential; non-invasive Alexander cells and the highly invasive HepG2 cells. We silenced Migfilin by siRNA and studied its effect on signaling and metastasis-related cellular properties. We show that Migfilin׳s expression is elevated in HepG2 cells and its silencing leads to upregulation of actin reorganization-related proteins, namely phosphor-VASP (Ser157 and Ser239), Fascin-1 and Rho-kinase-1, promoting actin polymerization and inhibiting cell invasion. Phosphor-Akt (Ser473) is decreased contributing to the upregulation of free and phosphor-β-catenin (Ser33/37Thr41) and inducing proliferation. Migfilin elimination upregulates Extracellular Signal-regulated kinase, which increases cell adhesion in HepG2 and reduces invasiveness. This is the first study to reveal that Migfilin inhibition can halt HCC metastasis in vitro, providing the molecular mechanism involved and presenting Migfilin as potential therapeutic target against HCC metastasis.
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http://dx.doi.org/10.1016/j.yexcr.2015.03.002DOI Listing
June 2015

Elimination of Ras Suppressor-1 from hepatocellular carcinoma cells hinders their in vitro metastatic properties.

Anticancer Res 2015 Mar;35(3):1509-12

Department of Biomedical Research and Technology, Institute for Research and Technology-Thessaly, Centre for Research and Technology-Hellas (CE.R.T.H.), Larissa, Greece Department of Rheumatology, School of Medicine, University of Thessaly, University Hospital of Larissa, Larissa, Greece Institute of Liver Studies, King's College Hospital, London, U.K.

Background/aim: Extracellular matrix (ECM) is of great significance for homeostasis in the liver. In fact, one of the stages leading to hepatocellular carcinoma (HCC) includes accumulation of excess ECM. Ras Suppressor-1 (RSU-1) is localized in the cell-ECM adhesions but its role in HCC is unexplored.

Materials And Methods: We investigated the expression and role of RSU-1 in two HCC cell lines that differ in aggressiveness; non-invasive Alexander cells and highly invasive HepG2 cells.

Results: Our results showed that RSU-1 expression is elevated in HepG2 cells both at the mRNA and protein level, while its silencing leads to increased cell proliferation in both cell lines. Interestingly, RSU-1 depletion from highly invasive HepG2 cells reduces cell adhesion and invasion.

Conclusion: This is the first study to provide in vitro evidence for the involvement of RSU-1 in HCC cell invasive behavior.
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March 2015

Ras suppressor-1 promotes apoptosis in breast cancer cells by inhibiting PINCH-1 and activating p53-upregulated-modulator of apoptosis (PUMA); verification from metastatic breast cancer human samples.

Clin Exp Metastasis 2015 Mar 3;32(3):255-65. Epub 2015 Feb 3.

Centre for Research and Technology-Hellas (CE.R.T.H.), Institute for Research and Technology-Thessaly, 51 Papanastasiou Street, 41222, Larissa, Greece.

Metastasis, responsible for most deaths from breast cancer (BC), is a multistep process leading to cancer cell spread. Extracellular matrix (ECM)-related adhesion and apoptosis resistance play pivotal role in metastasis. Ras suppressor-1 (RSU-1) localizes to cell-ECM adhesions and binds to pro-survival adhesion protein PINCH-1. Little is known about the role of RSU-1 in BC. In the present study, we investigated the role of RSU-1 in BC metastasis using two BC cell lines that differ in terms of their metastatic potential and a set of 32 human BC samples from patients with or without lymph node metastasis. We show that RSU-1 is upregulated in the aggressive MDA-MB-231 cells compared to MCF-7 and that its silencing by siRNA leads to upregulation of PINCH-1, induction of proliferation and reduction of apoptosis through downregulation of the pro-apoptotic gene p53-upregulated-modulator-of-apoptosis (PUMA). Our findings in the cell lines were further validated in the human BC tissues where normal adjacent tissues were used as controls. We demonstrate for the first time, that RSU-1 expression is upregulated in metastatic BC samples and downregulated in non-metastatic while it is negatively correlated with PINCH-1 and positively correlated with PUMA expression, suggesting that a pro-apoptotic mechanism is in place in metastatic BC samples and identifying RSU-1 as a potentially interesting molecule that needs to be evaluated further as a novel BC metastasis biomarker.
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http://dx.doi.org/10.1007/s10585-015-9701-xDOI Listing
March 2015

Mitogen-inducible Gene-2 (MIG2) and migfilin expression is reduced in samples of human breast cancer.

Anticancer Res 2013 May;33(5):1977-81

Department of Biomedical Research and Technology, Institute for Research and Technology-Thessaly (I.RE.TE.TH), 51 Papanastasiou street, Larissa 41222, Greece.

Background: Cell adhesion proteins that connect each cell to neighboring cells and the extracellular matrix play a fundamental role in metastasis. Mitogen-inducible gene-2 (MIG2), is a cell-matrix adhesion protein, which through migfilin, interacts with filamin-A, being linked to actin cytoskeleton.

Aim: Recent studies have implicated both MIG2 and migfilin in cancer, but little is known regarding their expression in breast cancer. In this study, we investigated this topic.

Materials And Methods: mRNA and protein expression was examined in 30 breast cancer samples and compared to that of normal adjacent tissue using real time-polymerase chain reaction (PCR) and western blotting.

Results: Our results showed that expression of MIG2 and migfilin was significantly reduced in the majority of the breast cancer tissues compared to normal tissues regardless of metastatic status and disease stage.

Conclusion: Both MIG2 and migfilin are down-regulated in breast cancer.
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May 2013

Migfilin's elimination from osteoarthritic chondrocytes further promotes the osteoarthritic phenotype via β-catenin upregulation.

Biochem Biophys Res Commun 2013 Jan 10;430(2):494-9. Epub 2012 Dec 10.

Center for Research and Technology-Thessaly (CE.RE.TE.TH), Department of Biomedical Research and Technology, Larissa 41222, Greece.

Osteoarthritis (OA) is a debilitating disease of the joints characterized by cartilage degradation but to date there is no available pharmacological treatment to inhibit disease progression neither is there any available biomarker to predict its development. In the present study, we examined the expression level and possible involvement of novel cell-ECM adhesion-related molecules such as Iintegrin Linked Kinase (ILK), PINCH, parvin, Mig-2 and Migfilin in OA pathogenesis using primary human articular chondrocytes from healthy individuals and OA patients. Our findings show that only ILK and Migfilin were upregulated in OA compared to the normal chondrocytes. Interestingly, Migfilin silencing in OA chondrocytes rather exacerbated than ameliorated the osteoarthritic phenotype, as it resulted in even higher levels of catabolic and hypertrophic markers while at the same time induced reduction in ECM molecules such as aggrecan. Furthermore, we also provide a link between Migfilin and β-catenin activation in OA chondrocytes, showing Migfilin to be inversely correlated with β-catenin. Thus, the present study emphasizes for the first time to our knowledge the role of Migfilin in OA and highlights the importance of cell-ECM adhesion proteins in OA pathogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2012.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764434PMC
January 2013

Central role of SREBP-2 in the pathogenesis of osteoarthritis.

PLoS One 2012 25;7(5):e35753. Epub 2012 May 25.

Department of Cytogenetics and Molecular Genetics, University of Thessaly School of Medicine, Larissa, Greece.

Background: Recent studies have implied that osteoarthritis (OA) is a metabolic disease linked to deregulation of genes involved in lipid metabolism and cholesterol efflux. Sterol Regulatory Element Binding Proteins (SREBPs) are transcription factors regulating lipid metabolism with so far no association with OA. Our aim was to test the hypothesis that SREBP-2, a gene that plays a key role in cholesterol homeostasis, is crucially involved in OA pathogenesis and to identify possible mechanisms of action.

Methodology/principal Findings: We performed a genetic association analysis using a cohort of 1,410 Greek OA patients and healthy controls and found significant association between single nucleotide polymorphism (SNP) 1784G>C in SREBP-2 gene and OA development. Moreover, the above SNP was functionally active, as normal chondrocytes' transfection with SREBP-2-G/C plasmid resulted in interleukin-1β and metalloproteinase-13 (MMP-13) upregulation. We also evaluated SREBP-2, its target gene 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR), phospho-phosphoinositide3-kinase (PI3K), phospho-Akt, integrin-alphaV (ITGAV) and transforming growth factor-β (TGF-β) mRNA and protein expression levels in osteoarthritic and normal chondrocytes and found that they were all significantly elevated in OA chondrocytes. To test whether TGF-β alone can induce SREBP-2, we treated normal chondrocytes with TGF-β and found significant upregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13. We also showed that TGF-β activated aggrecan (ACAN) in chondrocytes only through Smad3, which interacts with SREBP-2. Finally, we examined the effect of an integrin inhibitor, cyclo-RGDFV peptide, on osteoarthritic chondrocytes, and found that it resulted in significant upregulation of ACAN and downregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13 expression levels.

Conclusions/significance: We demonstrated, for the first time, the association of SREBP-2 with OA pathogenesis and provided evidence on the molecular mechanism involved. We suggest that TGF-β induces SREBP-2 pathway activation through ITGAV and PI3K playing a key role in OA and that integrin blockage may be a potential molecular target for OA treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035753PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360703PMC
December 2012

Lipid metabolism and osteoarthritis: lessons from atherosclerosis.

Prog Lipid Res 2011 Apr 27;50(2):133-40. Epub 2010 Nov 27.

Institute of Biomedical Research and Technology, Center for Research and Technology, Thessaly (CE.RE.TE.TH), 51 Papanastasiou Street, 41222 Larissa, Greece.

Osteoarthritis (OA) is an age-related degenerative disease comprising the main reason of handicap in the Western world. Interestingly, to date, there are neither available biomarkers for early diagnosis of the disease nor any effective therapy other than symptomatic treatment and joint replacement surgery. OA has long been associated with obesity, mainly due to mechanical overload exerted on the joints. Recent studies however, point to the direction that OA is a metabolic disease, as it also involves non-weight bearing joints. In fact, altered lipid metabolism may be the underlying cause. First, adipokines have been shown to be key regulators of OA pathogenesis. Second, epidemiological studies have shown serum cholesterol to be a risk factor for OA development. Third, lipid deposition in the joint is observed at the early stages of OA before the occurrence of histological changes. Fourth, proteomic analyses have shown an important connection between OA and lipid metabolism. Finally, recent gene expression studies reveal a deregulation of cholesterol influx and efflux and in the expression of lipid metabolism-related genes. Interestingly, lipids and lipid metabolism are known to be implicated in the development and progression of another age-related degenerative disease, atherosclerosis (ATH). Thus, although it is tempting to speculate that the osteoarthritic chondrocyte has been transformed to foam cell, it has not been proven yet. However, this may be an intriguing theory linking ATH and OA, which may open new avenues to novel therapeutic interventions for OA taking advantage of previous knowledge from ATH.
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http://dx.doi.org/10.1016/j.plipres.2010.11.001DOI Listing
April 2011