Lumican, a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM), displays anti-tumor properties through its direct interaction with MMP-14. Lumican-derived peptides, such as lumcorin (17 amino acids) or L9M (10 amino acids), are able to inhibit the proteolytic activity of MMP-14 and melanoma progression. This work aimed to visualize the interactions of lumican-derived peptides and MMP-14. Molecular modeling was used to characterize the interactions between lumican-derived peptides, such as lumcorin, L9M, and cyclic L9M (L9Mc, 12 amino acids), and MMP-14. The interaction of L9Mc with MMP-14 was preferential with the MT-Loop domain while lumcorin interacted more with the catalytic site. Key residues in the MMP-14 amino acid sequence were highlighted for the interaction between the inhibitory SLRP-derived peptides and MMP-14. In order to validate the in silico data, MMP-14 activity and migration assays were performed using murine B16F1 and human HT-144 melanoma cells. In contrast to the HT-144 melanoma cell line, L9Mc significantly inhibited the migration of B16F1 cells and the activity of MMP-14 but with less efficacy than lumican and lumcorin. L9Mc significantly inhibited the proliferation of B16F1 but not of HT-144 cells in vitro and primary melanoma tumor growth in vivo. Thus, the site of interaction between the domains of MMP-14 and lumcorin or L9Mc were different, which might explain the differences in the inhibitory effect of MMP-14 activity. Altogether, the biological assays validated the prediction of the in silico study. Possible and feasible improvements include molecular dynamics results.

Ovarian cancer remains one of the most fatal cancers due to a lack of robust screening methods of detection at early stages. Extracellular matrix (ECM) mediates interactions between cancer cells and their microenvironment via specific molecules. Lumican, a small leucine-rich proteoglycan (SLRP), maintains ECM integrity and inhibits both melanoma primary tumor development, as well as metastatic spread. The aim of this study was to analyze the effect of lumican on tumor growth of murine ovarian epithelial cancer. C57BL/6 wild type mice (n = 12) and lumican-deficient mice (n = 10) were subcutaneously injected with murine ovarian epithelial carcinoma ID8 cells, and then sacrificed after 18 days. Analysis of tumor volumes demonstrated an inhibitory effect of endogenous lumican on ovarian tumor growth. The ovarian primary tumors were subjected to histological and immunohistochemical staining using anti-lumican, anti-αv integrin, anti-CD31 and anti-cyclin D1 antibodies, and then further examined by label-free infrared spectral imaging (IRSI), second harmonic generation (SHG) and Picrosirius red staining. The IR tissue images allowed for the identification of different ECM tissue regions of the skin and the ovarian tumor. Moreover, IRSI showed a good correlation with αv integrin immunostaining and collagen organization within the tumor. Our results demonstrate that lumican inhibits ovarian cancer growth mainly by altering collagen fibrilogenesis.

Small leucine-rich proteoglycans (SLRPs) are major regulators of extracellular matrix assembly and cell signaling. Lumican, a member of the SLRPs family, and its derived peptides were shown to possess antitumor activity by interacting directly with the catalytic domain of MMP-14 leading to the inhibition of its activity. The aim of the present report was to characterize by in silico three-dimensional (3D) modeling the structure and the dynamics of four SLRPs including their core protein and their specific polysaccharide chains to assess their capacity to bind to MMP-14 and to regulate its activity. Molecular docking experiments were performed to identify the specific amino acids of MMP-14 interacting with each of the four SLRPs. The inhibition of each SLRP (100 nM) on MMP-14 activity was measured and the constants of inhibition ( K_i) were evaluated. The impact of the number of glycan chains, structures, and dynamics of lumican on the interaction with MMP-14 was assessed by molecular dynamics simulations. Molecular docking analysis showed that all SLRPs bind to MMP-14 through their concave face, but in different regions of the catalytic domain of MMP-14. Each SLRPs inhibited significantly the MMP-14 activity. Finally, molecular dynamics showed the role of glycan chains in interaction with MMP-14 and shielding effect of SLRPs. Altogether, the results demonstrated that each SLRP exhibited inhibition of MMP-14 activity. However, the differential targeting of MMP-14 by the SLRPs was shown to be related not only to the core protein conformation but also to the glycan chain structures and dynamics.

Background: Given the high prevalence of anxiety in palliative care and its frequent underestimation by healthcare professionals, it is important to use simplified tools to facilitate the evaluation of anxiety. The State-Trait Anxiety Inventory–State scale is a reference 20-item questionnaire that has been validated in this population, but is too long for some patients. The visual analog scale (VAS) and the numeric rating scale (NRS) are two short instruments that have been validated to assess pain, but not anxiety in palliative care. Aim: This study sought to investigate the correlation between anxiety VAS and NRS and State-Trait Anxiety Inventory-State scale for assessing anxiety in palliative care patients. Methods: A single-center cross-sectional observational study was conducted over 2 years. All palliative care patients followed by the palliative care team of a French university hospital were eligible. Each patient completed the State-Trait Anxiety Inventory-State scale and rated their perceived anxiety using the NRS and VAS. Pearson’s correlation test between the scales and receiver operating characteristic (ROC) curve analysis were performed to determine diagnostic cut-offs. Results: A total of 186 patients were included (89.8% with cancer), 20.4% of whom had severe or very severe anxiety. The NRS/ State-Trait Anxiety Inventory–State scale and VAS/ State-Trait Anxiety Inventory–State scale correlations were 0.62 and 0.70, respectively. The NRS and VAS showed good discrimination, with an area under the ROC curve of 0.81 and 0.88, respectively. Cut-offs of 5 (NRS) and 49 millimeters (VAS) yielded sensitivities of 89.5% and 89.2%, respectively, for the detection of severe or very severe anxiety, with specificities of 60.1% and 70.3%, respectively. Conclusion: Cut-offs of 5 for the NRS and 49 millimeters for the VAS showed excellent sensitivity for detecting anxiety in palliative care.

LRP1 is a multifunctional endocytosis receptor involved in the regulation of cancer cell aggressiveness, fibroblast phenotype and angiogenesis. In breast cancer microenvironment, cancer-associated fibroblasts (CAFs) play a crucial role in matrix remodeling and tumor niche composition. LRP1 expression was described in fibroblasts and CAFs but remains poorly understood regarding its impact on endothelial cell behavior and angiocrine signaling. We analyzed the angio-modulatory effect of LRP1 expression in murine embryonic fibroblasts (MEFs) and breast cancer-educated CAF₂ cells. We employed conditioned media and fibroblast-derived matrices to model fibroblastic cells angiogenic effects on human umbilical vein endothelial cells (HUVEC). Neither the extracellular matrix assembled by MEFs knock-out for LRP1 (PEA-13) nor their secretome modify the migration of HUVEC as compared to wild-type. Conversely, LRP1-deficient CAF₂ secretome and matrices stimulate endothelial cell migration. Using spheroids, we demonstrate that PEA-13 secretome does not affect HUVEC angio-invasion. By contrast, CAF₂ secretome invalidated for LRP1 stimulates endothelial sprouting as compared to controls. In addition, it specifically stabilized peripheral VE-cadherin-mediated endothelial cell junctions. A global proteomic analysis revealed that LRP1 expression in CAFs orchestrates a specific mobilization of secreted matricial components, surface receptors and membrane-associated proteins at the endothelial cell surface, thereby illustrating the deep influence exerted by LRP1 in angiogenic signals emitted by activated fibroblasts.