TGFß-induced cytoskeletal remodeling mediates elevation of cell stiffness and invasiveness in NSCLC.

Importance of growth factor (GF) signaling in cancer progression is widely acknowledged. Transforming growth factor beta (TGFß) is known to play a key role in epithelial-to-mesenchymal transition (EMT) and metastatic cell transformation that are characterized by alterations in cell mechanical architecture and behavior towards a more robust and motile single cell phenotype. However, mechanisms mediating cancer type specific enhancement of cell mechanical phenotype in response to TGFß remain poorly understood. Here, we combine high-throughput mechanical cell phenotyping, microarray analysis and gene-silencing to dissect cytoskeletal mediators of TGFß-induced changes in mechanical properties of on-small-cell lung carcinoma (NSCLC) cells. Our experimental results show that elevation of rigidity and invasiveness of TGFß-stimulated NSCLC cells correlates with upregulation of several cytoskeletal and motor proteins including vimentin, a canonical marker of EMT, and less-known unconventional myosins. Selective probing of gene-silenced cells lead to identification of unconventional myosin MYH15 as a novel mediator of elevated cell rigidity and invasiveness in TGFß-stimulated NSCLC cells. Our experimental results provide insights into TGFß-induced cytoskeletal remodeling of NSCLC cells and suggest that mediators of elevated cell stiffness and migratory activity such as unconventional cytoskeletal and motor proteins may represent promising pharmaceutical targets for restraining invasive spread of lung cancer.

Expression ratio of the TGFß-inducible gene MYO10 is prognostic for overall survival of squamous cell lung cancer patients and predicts chemotherapy response.

In lung cancer a deregulation of Transforming Growth Factor-ß (TGFß) signaling has been observed. Yet, the impact of TGFß in squamous cell carcinoma of the lung (LUSC) remained to be determined. We combined phenotypic and transcriptome-wide studies and showed that the stimulation of the LUSC cell line SK-MES1 with TGFß results in an increase of migratory invasive properties. The analysis of the dynamics of gene expression by next-generation sequencing revealed that TGFß stimulation orchestrates the upregulation of numerous motility- and actin cytoskeleton-related genes. Among these the non-muscle myosin 10 (MYO10) showed the highest upregulation in a LUSC patient cohort of the Cancer Genome Atlas (TCGA). Knockdown of MYO10 abrogated TGFß-induced collagen gel invasion of SK-MES1 cells. The analysis of MYO10 mRNA expression in paired tissues of 151 LUSC patients with corresponding 80-month clinical follow-up data showed that the mRNA expression ratio of MYO10 in tumor and tumor-free tissue is prognostic for overall survival of LUSC patients and predictive for the response of these patients to adjuvant chemotherapy. Thus, MYO10 represents a new clinical biomarker for this aggressive disease and due to its role in cellular motility and invasion could serve as a potential molecular target for therapeutic interventions in patients with LUSC.

Polymerized degradable hyaluronan--a platform for stent coating with inherent inhibitory effects on neointimal formation in a porcine coronary model.

Biodegradable hyaluronan (hyaluronic acid, HA) made insoluble by self-cross-linking in the presence of N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide (EDC) has been used to cover stents. The maximum polymer-mass on a 16-mm stainless steel stent is approximately 2 mg. During manual crimping and simulated application, the loss of polymerized HA is negligible. The insoluble HA coating has an advantageous inherent antiproliferative effect regarding neointimal formation after local vessel wall injury (overstretch model) and leads to a reduced inflammatory response compared to uncoated stainless-steel stents, used as control, in undiseased pig coronary arteries, over a follow-up period of four weeks. Thus, cross-linked HA stent coating warrants further research as an interactive degradable biomaterial with an inherent inhibitory effect on neointimal formation as a possible biomatrix for local drug delivery to reduce restenosis rate.

Characterization of four cell lines derived from a human malignant fibrous histiocytoma of the maxillary sinus.

We have established four cell lines from a human malignant fibrous histiocytoma. Each cell line had human aneuploid karyotype and DNA aneuploidy. Cells in all lines expressed CD13, CD68 and vimentin but lacked CD11, CD14, CD15, CD16, CD45, HLA class II and other mesenchymal and epithelial markers such as desmin, alpha-smooth muscle, myoglobin, S-100 protein, and cytokeratin. None of the cells expressed surface IgG or C3 receptor, nor did any of them phagocytose latex particles. The cells reacted with an antibody for prolyl-4-hydroxylase, but no collagen (types I, II, III, or IV) was detected in any of the cell lines. The homogenates of all cell lines had cyclic nucleotide phosphodiesterase 3 activity. Two cell lines produced granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1alpha, IL-6 and tumor necrosis factor alpha, another line produced G-CSF, IL-1alpha, IL-6 and platelet-derived growth factor (PDGF)-AB, and the remaining cell line produced only PDGF-AB. None of the cells produced transforming growth factor-alpha. The results indicated that the cell lines were immunophenotypically similar to primitive mesenchymal cells.

Aggressive infantile fibromatosis of the submandibular region.

Aggressive infantile fibromatosis is an unusual, tumor-like, proliferative lesion which grows infiltratively. The clinical and histological features of aggressive infantile fibromatosis in the submandibular region of a 3-year-old girl are reported.