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- 2019
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Tidskriftsartikel (refereegranskat)
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- Karalis, Theodoros T, et al.
(författare)
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Salicylate suppresses the oncogenic hyaluronan network in metastatic breast cancer cells.
- 2020
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Ingår i: Matrix biology plus. - : Elsevier BV. - 2590-0285. ; 6-7
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Tidskriftsartikel (refereegranskat)abstract
- The oncogenic role of hyaluronan in several aspects of tumor biology has been well established. Recent studies by us and others suggest that inhibition of hyaluronan synthesis could represent an emerging therapeutic approach with significant clinical relevance in controlling different breast cancer subtypes, including triple-negative breast cancer. Epidemiological and preclinical studies have revealed the therapeutic potential of aspirin (acetyl salicylate), a classical anti-inflammatory drug, in patients with cancer. However, the underlying molecular mechanisms remain unknown. The present study demonstrates that salicylate, a break down product of aspirin in vivo, alters the organization of hyaluronan matrices by affecting the expression levels of hyaluronan synthesizing (HAS1, 2, 3) and degrading (HYAL-1, -2) enzymes, and that of hyaluronan receptor CD44. In particular, salicylate was found to potently activate AMPK, a kinase known to inhibit HAS2 activity, and caused a dose-dependent decrease of cell associated (intracellular and membrane-bound) as well as secreted hyaluronan, followed by the down-regulation of HAS2 and the induction of HYAL-2 and CD44 in metastatic breast cancer cells. These salicylate-mediated effects were associated with the redistribution of CD44 and actin cytoskeleton that resulted in a less motile cell phenotype. Interestingly, salicylate inhibited metastatic breast cancer cell proliferation and growth by inducing cell growth arrest without signs of apoptosis as evidenced by the substantial decrease of cyclin D1 protein and the absence of cleaved caspase-3, respectively. Collectively, our study offers a possible direction for the development of new matrix-based targeted treatments of metastatic breast cancer subtypes via inhibition of hyaluronan, a pro-angiogenic, pro-inflammatory and tumor promoting glycosaminoglycan.
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- Karalis, Theodoros T., et al.
(författare)
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Tumor-suppressive functions of 4-MU on breast cancer cells of different ER status : Regulation of hyaluronan/HAS2/CD44 and specific matrix effectors
- 2019
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Ingår i: Matrix Biology. - : ELSEVIER SCIENCE BV. - 0945-053X .- 1569-1802. ; 78-79, s. 118-138
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Tidskriftsartikel (refereegranskat)abstract
- The malignant phenotype of various cancers is linked to enhanced expression of hyaluronan, a proangiogenic glycosaminoglycan whose expression is suppressed by 4-methylumbelliferone (4-MU), a non-toxic oral agent used as a dietary supplement to improve health and combat prostate cancer. In this study, we investigated the role of 4-MU in mammary carcinoma cells with distinct malignant phenotypes and estrogen receptor (ER) status, a major prognostic factor in the clinical management of breast cancers. We focused on two breast cancer cell lines, the low metastatic and ER alpha+ MCF-7 cells, and the highly-aggressive and ER alpha-MDA-MB-231 cells. Treatment with 4-MU caused a dose-dependent decrease of hyaluronan accumulation in the extracellular matrix as well as within the breast cancer cells, most prevalent in cells lacking ER alpha. This decrease in hyaluronan was accompanied by suppression of Hyaluronan Synthase 2 (HAS2), the major enzyme responsible for the synthesis of hyaluronan, and by induction of hyaluronidases (HYALs) -1 and -2. Moreover, 4-MU induced intense phenotypic changes and substantial loss of CD44, a major hyaluronan receptor, from cell protrusions. Importantly, 4-MU evoked differential effects depending on the absence or presence of ER alpha. Only the ER alpha+ cells showed signs of apoptosis, as determined by cleaved PARP-1, and anoikis as shown by concurrent loss of E-cadherin and beta-catenin. Interestingly, 4-MU significantly reduced migration, adhesion and invasion of ER alpha- breast cancer cells, and concurrently reduced the expression and activity of several matrix degrading enzymes and pro-inflammatory molecules with tumor-promoting functions. Collectively, our findings suggest that 4-MU could represent a novel therapeutic for specific breast cancer subtypes with regard to their ER status via suppression of hyaluronan synthesis and regulation of HAS2, CD44, matrix-degrading enzymes and inflammatory mediators.
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- Karamanos, T. K., et al.
(författare)
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A Population Shift between Sparsely Populated Folding Intermediates Determines Amyloidogenicity
- 2016
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 138:19, s. 6271-6280
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Tidskriftsartikel (refereegranskat)abstract
- The balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of nonuniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and nonamyloidogenic variants of beta(2)-microglobulin (beta(2)m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the aggregation-prone I-Trans state and population of a less stable, more dynamic species ablate amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding.
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- Korpetinou, Angeliki, et al.
(författare)
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Serglycin Is Implicated in the Promotion of Aggressive Phenotype of Breast Cancer Cells
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- Serglycin is a proteoglycan expressed by some malignant cells. It promotes metastasis and protects some tumor cells from complement system attack. In the present study, we show for the first time the in situ expression of serglycin by breast cancer cells by immunohistochemistry in patients' material. Moreover, we demonstrate high expression and constitutive secretion of serglycin in the aggressive MDA-MB-231 breast cancer cell line. Serglycin exhibited a strong cytoplasmic staining in these cells, observable at the cell periphery in a thread of filaments near the cell membrane, but also in filopodia-like structures. Serglycin was purified from conditioned medium of MDA-MB-231 cells, and represented the major proteoglycan secreted by these cells, having a molecular size of similar to 250 kDa and carrying chondroitin sulfate side chains, mainly composed of 4-sulfated (similar to 87%), 6-sulfated (similar to 10%) and non-sulfated (similar to 3%) disaccharides. Purified serglycin inhibited early steps of both the classical and the lectin pathways of complement by binding to C1q and mannose-binding lectin. Stable expression of serglycin in less aggressive MCF-7 breast cancer cells induced their proliferation, anchorage-independent growth, migration and invasion. Interestingly, over-expression of serglycin lacking the glycosaminoglycan attachment sites failed to promote these cellular functions, suggesting that glycanation of serglycin is a pre-requisite for its oncogenic properties. Our findings suggest that serglycin promotes a more aggressive cancer cell phenotype and may protect breast cancer cells from complement attack supporting their survival and expansion.
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- Labropoulou, V. T., et al.
(författare)
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Pathophysiology and Pharmacological Targeting of Tumor-Induced Bone Disease : Current Status and Emerging Therapeutic Interventions
- 2011
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Ingår i: Current Medicinal Chemistry. - 0929-8673 .- 1875-533X. ; 18:11, s. 1584-1598
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Forskningsöversikt (refereegranskat)abstract
- Bone disease is a common complication of metastatic solid tumors but also of primary hematological malignancies such as multiple myeloma. Our understanding of the molecular mechanisms underlying the development of bone disease by solid tumors and multiple myeloma has been significantly improved. A complex inter-dependence exists between bone disease and malignant cell growth, creating a vicious cycle of extensive bone destruction and tumor progression. Although myeloma and solid tumors share a number of common molecular pathogenetic mechanisms, they involve distinct pathophysiological pathways, resulting in osteoclastic bone resorption and inhibition of bone formation. In this review, we analyze the molecular mechanisms, involved in tumor-induced bone disease and discuss the current therapeutic approaches and the most recent clinical developments of emerging targeted therapies.
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- Skandalis, Spyros S, et al.
(författare)
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Hyaluronan-CD44 axis orchestrates cancer stem cell functions.
- 2019
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Ingår i: Cellular Signalling. - : Elsevier BV. - 0898-6568 .- 1873-3913. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- The prominent role of CD44 in tumor cell signaling together with its establishment as a cancer stem cell (CSC) marker for various tumor entities imply a key role for CD44 in CSC functional properties. Hyaluronan, the main ligand of CD44, is a major constituent of CSC niche and, therefore, the hyaluronan-CD44 signaling axis is of functional importance in this special microenvironment. This review aims to provide recent advances in the importance of hyaluronan-CD44 interactions in the acquisition and maintenance of a CSC phenotype. Hyaluronan-CD44 axis has a substantial impact on stemness properties of CSCs and drug resistance through induction of EMT program, oxidative stress resistance, secretion of extracellular vesicles/exosomes and epigenetic control. Potential therapeutic approaches targeting CSCs based on the hyaluronan-CD44 axis are also presented.
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| 10. |
- Skandalis, Spyros S., et al.
(författare)
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Versican but not decorin accumulation is related to malignancy in mammographically detected high density and malignant-appearing microcalcifications in non-palpable breast carcinomas
- 2011
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 11, s. 314-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mammographic density (MD) and malignant-appearing microcalcifications (MAMCs) represent the earliest mammographic findings of non-palpable breast carcinomas. Matrix proteoglycans versican and decorin are frequently over-expressed in various malignancies and are differently involved in the progression of cancer. In the present study, we have evaluated the expression of versican and decorin in non-palpable breast carcinomas and their association with high risk mammographic findings and tumor characteristics. Methods: Three hundred and ten patients with non-palpable suspicious breast lesions, detected during screening mammography, were studied. Histological examination was carried out and the expression of decorin, versican, estrogen receptor alpha (ER alpha), progesterone receptor (PR) and c-erbB2 (HER-2/neu) was assessed by immunohistochemistry. Results: Histological examination showed 83 out of 310 (26.8%) carcinomas of various subtypes. Immunohistochemistry was carried out in 62/83 carcinomas. Decorin was accumulated in breast tissues with MD and MAMCs independently of the presence of malignancy. In contrast, versican was significantly increased only in carcinomas with MAMCs (median +/- SE: 42.0 +/- 9.1) and MD (22.5 +/- 10.1) as compared to normal breast tissue with MAMCs (14.0 +/- 5.8), MD (11.0 +/- 4.4) and normal breast tissue without mammographic findings (10.0 +/- 2.0). Elevated levels of versican were correlated with higher tumor grade and invasiveness in carcinomas with MD and MAMCs, whereas increased amounts of decorin were associated with in situ carcinomas in MAMCs. Stromal deposition of both proteoglycans was related to higher expression of ER alpha and PR in tumor cells only in MAMCs. Conclusions: The specific accumulation of versican in breast tissue with high MD and MAMCs only in the presence of malignant transformation and its association with the aggressiveness of the tumor suggests its possible use as molecular marker in non-palpable breast carcinomas.
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