Iduronate-2-Sulfatase-Regulated Dermatan Sulfate Levels Potentiate the Invasion of Breast Cancer Epithelia through Collagen Matrix

Abstract

Cancer epithelia show elevation in levels of sulfated proteoglycans including dermatan sulfates (DS). The effect of increased DS on cancer cell behavior is still unclear. We hypothesized that decreased expression of the enzyme Iduronate-2-sulfatase (IDS) can lead to increased DS levels, which would enhance the invasion of cancer cells. Breast cancer sections shows depleted IDS levels in tumor epithelia, when compared with adjacent untransformed breast tissues. IDS signals showed a progressive decrease in the non-transformed HMLE, transformed but non-invasive MCF-7 and transformed and invasive MDA-MB-231 cells, respectively, when cultured on Type 1 collagen scaffolds. DS levels measured by ELISA increased in an inverse-association with IDS levels. Knockdown of IDS in MCF-7 epithelia also increased the levels of DS. MCF-7 cells with depleted IDS expression, when imaged using two photon-excited fluorescence and second harmonic generation microscopy, exhibited a mesenchymal morphology with multiple cytoplasmic projections compared with epithelioid control cells, interacted with their surrounding matrix, and showed increased invasion through Type 1 collagen matrices. Both these traits were phenocopied when control MCF-7 cells were cultivated on Type 1 collagen gels polymerized in the presence of DS. In monolayer cultures, DS had no effect on MCF-7 migration. In the context of our demonstration that DS enhances the elastic modulus of Type 1 collagen gels, we propose that a decrease of IDS expression leads to accumulation within cancer epithelia of DS: the latter remodels the collagen around cancer cells leading to changes in cell shape and invasiveness through fibrillar matrix milieu.