Accumulating data suggest that metastatic dissemination often occurs early during tumour formation, but the mechanisms of early metastatic spread have not yet been addressed. Here, by studying ...metastasis in a HER2-driven mouse breast cancer model, we show that progesterone-induced signalling triggers migration of cancer cells from early lesions shortly after HER2 activation, but promotes proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by increased HER2 expression and tumour-cell density involving microRNA-mediated progesterone receptor downregulation, and was reversible. Cells from early, low-density lesions displayed more stemness features, migrated more and founded more metastases than cells from dense, advanced tumours. Notably, we found that at least 80% of metastases were derived from early disseminated cancer cells. Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination.
Although apoptosis and necrosis have distinct features, the identification and discrimination of apoptotic and necrotic cell death in vitro is challenging. Immunocytological and biochemical assays ...represent the current gold standard for monitoring cell death pathways; however, these standard assays are invasive, render large numbers of cells and impede continuous monitoring experiments. In this study, both room temperature (RT)-induced apoptosis and heat-triggered necrosis were analyzed in individual Saos-2 and SW-1353 cells by utilizing Raman microspectroscopy. A targeted analysis of defined cell death modalities, including early and late apoptosis as well as necrosis, was facilitated based on the combination of Raman spectroscopy with fluorescence microscopy. Spectral shifts were identified in the two cell lines that reflect biochemical changes specific for either RT-induced apoptosis or heat-mediated necrosis. A supervised classification model specified apoptotic and necrotic cell death based on single cell Raman spectra. To conclude, Raman spectroscopy allows a non-invasive, continuous monitoring of cell death, which may help shedding new light on complex pathophysiological or drug-induced cell death processes.
The immunopeptidomic landscape of ovarian carcinomas Schuster, Heiko; Peper, Janet K.; Bösmüller, Hans-Christian ...
Proceedings of the National Academy of Sciences - PNAS,
11/2017, Letnik:
114, Številka:
46
Journal Article
Recenzirano
Odprti dostop
Immunotherapies, particularly checkpoint inhibitors, have set off a revolution in cancer therapy by releasing the power of the immune system. However, only little is known about the antigens that are ...essentially presented on cancer cells, capable of exposing them to immune cells. Large-scale HLA ligandome analysis has enabled us to exhaustively characterize the immunopeptidomic landscape of epithelial ovarian cancers (EOCs). Additional comparative profiling with the immunopeptidome of a variety of benign sources has unveiled a multitude of ovarian cancer antigens (MUC16, MSLN, LGALS1, IDO1, KLK10) to be presented by HLA class I and class II molecules exclusively on ovarian cancer cells. Most strikingly, ligands derived from mucin 16 and mesothelin, a molecular axis of prognostic importance in EOC, are prominent in a majority of patients. Differential gene-expression analysis has allowed us to confirm the relevance of these targets for EOC and further provided important insights into the relationship between gene transcript levels and HLA ligand presentation.
Purpose
Cervical cancer screening by visual inspection with acetic acid (VIA) during colposcopy can be challenging and is highly dependent on the clinical experience of the examiner. Health-care ...systems lack qualified physicians able to perform the examination in both industrialized and low- and middle-income countries. Previous work has shown the general potential of hyperspectral imaging (HSI) to discriminate CIN from normal tissue, but clinical translation has been limited due to the lack of medically approved HSI systems.
Methods
In this study, we evaluate the feasibility of a commercially available HSI system for CIN detection in a prospective monocentric clinical trial.
Results
By obtaining spectral fingerprints of 41 patients with CIN 1–3 we show that HSI-based differentiation between CIN and normal tissue is possible with high statistical significance. Major spectral differences were seen in the 555–585 wavelength area.
Conclusion
HSI advances tissue differentiation by associating each pixel with high-dimensional spectra and thereby obtains morphological and biochemical information of the observed tissue. Currently available and medically approved HSI systems may represent a contact- and marker-free examiner-independent method for the diagnosis of CIN.
Uterus transplantation (UTx) is currently the only available treatment for absolute uterine factor infertility. The International Society of Uterus Transplantation (ISUTx) was formally founded in ...2017 and joined the Transplantation Society as a formal section in 2021. The Third International Congress of the ISUTx was held in Tübingen, Germany, in October 2021, as a hybrid meeting, attended virtually by about 450 delegates and in person by 35 delegates. This report summarizes the Tübingen meeting and complementary topics of relevance presented at the Second ISUTx state-of-the-art webinar meeting, held in Prague, in October 2020. Main topics covered included surgical considerations, including dissection of veins in living donors and the pros and cons of minimally invasive surgery; managing immune risks; UTx during the COVID-19 pandemic; lessons learnt in the areas of imaging and cytomegalovirus infection; long-term psychological outcomes; opportunities to increase organ availability; and new horizons in UTx, including potential reuse of transplants and the utilization of robotic approaches. Implementation of an International UTx Registry was discussed and considered crucial to assure quality, safety, and further progress in UTx. Attempts made thus far have been promising.
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The development of new therapeutic approaches to treat type 1 diabetes mellitus (T1D) relies on the precise understanding and deciphering of insulin-secreting β-cell biology, as well ...as the mechanisms responsible for their autoimmune destruction. β-cell or islet transplantation is viewed as a potential long-term therapy for the millions of patients with diabetes. To advance the field of insulin-secreting cell transplantation, two main research areas are currently investigated by the scientific community: (1) the identification of the developmental pathways that drive the differentiation of stem cells into insulin-producing cells, providing an inexhaustible source of cells; and (2) transplantation strategies and engineered transplants to provide protection and enhance the functionality of transplanted cells. In this review, we discuss the biology of pancreatic β-cells, pathology of T1D and current state of β-cell differentiation. We give a comprehensive view and discuss the different possibilities to engineer enhanced insulin-secreting cell/islet transplantation from a translational perspective.
The newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and ...others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort.
ProMisE (POLE; MMR-D; p53 wt/NSMP; p53 abn) classification results from a cohort of 452 EC were available for analysis. L1CAM expression was studied by immunohistochemistry on whole slides. Correlations between clinicopathological data and survival were calculated.
Expression of L1CAM was most frequent in p53 abnormal tumours (80%). L1CAM status was predictive of worse outcome among tumours with no specific molecular profile (p53 wt/NSMP) (p < 0.0001). Among p53 wt/NSMP EC, L1CAM remained a significant prognosticator for disease-specific survival after multivariate analysis (p = 0.035).
L1CAM status was able to significantly stratify risk among tumours of the large p53 wt/NSMP ProMisE subgroup of EC. Furthermore, our study confirms a highly significant correlation between mutation-type p53 immunostaining and abnormal L1CAM expression in EC.