Molecular size-dependent specificity of hyaluronan on functional properties, morphology and matrix composition of mammary cancer cells.
Matrix Biol Plus
; 3: 100008, 2019 Aug.
Article
em En
| MEDLINE
| ID: mdl-33543007
ABSTRACT
High levels of hyaluronan (ΗΑ), a major extracellular matrix (ECM) glycosaminoglycan, have been correlated with poor clinical outcome in several malignancies, including breast cancer. The high and low molecular weight HΑ forms exert diverse biological functions. Depending on their molecular size, ΗΑ forms either promote or attenuate signaling cascades that regulate cancer progression. In order to evaluate the effects of different ΗΑ forms on breast cancer cells' behavior, ΗΑ fragments of defined molecular size were synthesized. Breast cancer cells of different estrogen receptor (ER) status - the low metastatic, ERα-positive MCF-7 epithelial cells and the highly aggressive, ERß-positive MDA-MB-231 mesenchymal cells - were evaluated following treatment with HA fragments. Scanning electron microscopy revealed that HA fragments critically affect the morphology of breast cancer cells in a molecular-size dependent mode. Moreover, the ΗΑ fragments affect cell functional properties, the expression of major ECM mediators and epithelial-to-mesenchymal transition (ΕΜΤ) markers. Notably, treatment with 200â¯kDa ΗΑ increased the expression levels of the epithelial marker Ε-cadherin and reduced the expression levels of HA synthase 2 and mesenchymal markers, like fibronectin and snail2/slug. These novel data suggest that the effects of HA in breast cancer cells depend on the molecular size and the ER status. An in-depth understanding on the mechanistic basis of these effects may contribute on the development of novel therapeutic strategies for the pharmacological targeting of aggressive breast cancer.
BTH, bovine testes hyaluronidase; Breast cancer; CD44; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; ER, estrogen receptor; Epithelial-to-mesenchymal transition; Estrogen receptors; HA, hyaluronan or hyaluronic acid; HAS, hyaluronan synthase; HMW HA, high molecular weight hyaluronan; HYAL, hyaluronidase; Hyaluronan; LMW HA, low molecular weight hyaluronan; MET, mesenchymal-to-epithelial transition; MMPs, matrix metalloproteinases; SDC, syndecan; SEM, scanning electron microscopy; Scanning electron microscopy; TIMPs, tissue inhibitors of metalloproteinases; o-HA, hyaluronan oligomers; s-HA, sulfated hyaluronan; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator
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MEDLINE
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Ano de publicação:
2019
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Article