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Cystatins are endogenous and reversible inhibitors of cysteine peptidases that are important players in cancer progression. Besides their primary role as regulators of cysteine peptidase activity, cystatins are involved in cancer development and progression through proteolysis-independent mechanisms. Mechanistic studies of cystatin function revealed that they affect all stages of cancer progression including tumor growth, apoptosis, invasion, metastasis and angiogenesis. Recently, the involvement of cystatins in the antitumor immune responses was reported. In this review, we discuss molecular mechanisms and clinical aspects of cystatins in cancer. Altered expression of cystatins in cancer resulting in harmful excessive cysteine peptidase activity has been a subject of several studies in order to find correlations with clinical outcome and therapy response. However, involvement in anti-tumor immune response and signaling cascades leading to cancer progression designates cystatins as possible targets for development of new anti-tumor drugs. Image 1 • Cystatins are inhibitors of cysteine cathepsins. • Cystatins can act also via proteolysis-independent mechanisms. • Cystatins can be used as biomarkers for prediction of clinical outcome and therapy responses of cancer patient. • Mechanistic studies revealed that cystatins affect all stages of cancer progression. • Cystatins interfere with the antitumor immune response. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive primary brain tumor with poor patient survival that is at least partly caused by malignant and therapy-resistant glioma stem-like cells (GSLCs) that are protected in GSLC niches. Previously, we have shown that the chemo-attractant stromal-derived factor-1α (SDF-1α), its C-X-C receptor type 4 (CXCR4) and the cysteine protease cathepsin K (CatK) are localized in GSLC niches in glioblastoma. Here, we investigated whether SDF-1α is a niche factor that through its interactions with CXCR4 and/or its second receptor CXCR7 on GSLCs facilitates their homing to niches. Furthermore, we aimed to prove that SDF-1α cleavage by CatK inactivates SDF-1α and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1α after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1α at 3 sites in the N-terminus, which is the region of SDF-1α that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1α and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1α had chemotactic activity whereas CatK cleavage products of SDF-1α did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1α. This implies that CatK activity facilitates migration of GSLCs out of niches. We propose that activation of CatK may be a promising strategy to prevent homing of GSLCs in niches and thus render these cells sensitive to chemotherapy and radiation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether urinary bisphenol A (BPA) levels in men adversely influence semen quality and embryo development after medically assisted reproduction. Design: Prospective, cohort study. Setting: University-based tertiary care center. Patient(s): A total of 149 couples undergoing their first or second IVF or intracytoplasmic sperm injection (ICSI) procedure. Intervention(s): None. Main Outcome Measure(s): Semen quality and embryo development parameters until the blastocyst stage after the IVF or ICSI procedure. Result(s): Bisphenol A was detected in 98% (n = 146) of the samples with 0.1 ng/mL limit of detection. The geometric mean BPA concentration was 1.55 ng/mL. After the adjustment for potential confounders using linear regression models, an increase of natural logarithm transformed urinary BPA concentration was associated with lower natural logarithm transformed sperm count (β = −0.241, 95% confidence interval [CI] −0.470 to −0.012), natural logarithm transformed sperm concentration (β = −0.219, 95% CI −0.436 to −0.003), and sperm vitality (β = −2.660, 95% CI −4.991 to −0.329). The embryo development parameters from oocyte fertilization to the blastocyst formation stage were not affected by BPA exposure. Conclusion(s): Urinary BPA concentrations in male partners of subfertile couples may influence semen quality parameters, but do not affect embryo development up to the blastocyst stage after medically assisted reproduction. [ABSTRACT FROM AUTHOR]

Epithelial-to-mesenchymal transition (EMT) is an essential molecular and cellular process that is part of normal embryogenesis and wound healing, and also has a ubiquitous role in various types of carcinoma and glioblastoma. EMT is activated and regulated by specific microenvironmental endogenous triggers and a complex network of signalling pathways. These mostly include epigenetic events that affect protein translation-controlling factors and proteases, altogether orchestrated by the switching on and off of oncogenes and tumour-suppressor genes in cancer cells. The hallmark of cancer-linked EMT is that the process is incomplete, as it is opposed by the reverse process of mesenchymal-to-epithelial transition, which results in a hybrid epithelial/mesenchymal phenotype that shows notable cell plasticity. This is a characteristic of cancer stem cells (CSCs), and it is of the utmost importance in their niche microenvironment, where it governs CSC migratory and invasive properties, thereby creating metastatic CSCs. These cells have high resistance to therapeutic treatments, in particular in glioblastoma. • Epithelial-to-mesenchymal transition is an essential molecular and cellular process in carcinogenesis. • CSCs exhibit a high level of plasticity to shift between epithelial and mesenchymal states, resulting in tumour metastasis. • Tumour microenvironment plays an important role in regulation of EMT/MET process of tumour cells. • Epithelial-to-mesenchymal transition has emerged as a therapeutic target in cancer therapy. [ABSTRACT FROM AUTHOR]