scholarly journals Mesenchymal Transition of High-Grade Breast Carcinomas Depends on Extracellular Matrix Control of Myeloid Suppressor Cell Activity

Cell Reports ◽  
2016 ◽  
Vol 17 (1) ◽  
pp. 233-248 ◽  
Author(s):  
Sabina Sangaletti ◽  
Claudio Tripodo ◽  
Alessandra Santangelo ◽  
Nadia Castioni ◽  
Paola Portararo ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Activity ◽  
Suppressor Cell ◽  
High Grade ◽  
Breast Carcinomas ◽  
Mesenchymal Transition ◽  
Myeloid Suppressor Cell ◽  
Matrix Control

Extracellular matrix control of smooth muscle cell activity

1993 ◽  
pp. 364-370
Author(s):  
M. Thie ◽  
B. Harrach ◽  
B. Redecker ◽  
J. Rauterberg ◽  
H. Robenek
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Cell Activity ◽  
Matrix Control

scholarly journals GM-CSF Nitration Is a New Driver of Myeloid Suppressor Cell Activity in Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Bianca Calì ◽  
Andrielly H. R. Agnellini ◽  
Chiara Cioccarelli ◽  
Ricardo Sanchez-Rodriguez ◽  
Andrea Predonzani ◽  
...  
Keyword(s):  
Nitrosative Stress ◽  
Immune Cell ◽  
Cell Activity ◽  
Suppressor Cell ◽  
Tryptophan Residue ◽  
Gm Csf ◽  
Myeloid Suppressor Cell ◽  
Cell Functions ◽  
Macrophage Colony ◽  
Colorectal Cancer Patients

Reactive oxygen species, including RNS, contribute to the control of multiple immune cell functions within the tumor microenvironment (TME). Tumor-infiltrating myeloid cells (TIMs) represent the archetype of tolerogenic cells that actively contribute to dismantle effective immunity against cancer. TIMs inhibit T cell functions and promote tumor progression by several mechanisms including the amplification of the oxidative/nitrosative stress within the TME. In tumors, TIM expansion and differentiation is regulated by the granulocyte-macrophage colony-stimulating factor (GM-CSF), which is produced by cancer and immune cells. Nevertheless, the role of GM-CSF in tumors has not yet been fully elucidated. In this study, we show that GM-CSF activity is significantly affected by RNS-triggered post-translational modifications. The nitration of a single tryptophan residue in the sequence of GM-CSF nourishes the expansion of highly immunosuppressive myeloid subsets in tumor-bearing hosts. Importantly, tumors from colorectal cancer patients express higher levels of nitrated tryptophan compared to non-neoplastic tissues. Collectively, our data identify a novel and selective target that can be exploited to remodel the TME and foster protective immunity against cancer.

scholarly journals Actin-associated protein palladin promotes tumor cell invasion by linking extracellular matrix degradation to cell cytoskeleton

2014 ◽  
Vol 25 (17) ◽  
pp. 2556-2570 ◽  
Author(s):  
Pernilla von Nandelstadh ◽  
Erika Gucciardo ◽  
Jouko Lohi ◽  
Rui Li ◽  
Nami Sugiyama ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tumor Cell ◽  
Protein Interaction ◽  
Cell Invasion ◽  
Dominant Negative ◽  
Tumor Cell Invasion ◽  
Matrix Degradation ◽  
Breast Carcinomas ◽  
Mesenchymal Transition ◽  
Extracellular Matrix Degradation

Basal-like breast carcinomas, characterized by unfavorable prognosis and frequent metastases, are associated with epithelial-to-mesenchymal transition. During this process, cancer cells undergo cytoskeletal reorganization and up-regulate membrane-type 1 matrix metalloproteinase (MT1-MMP; MMP14), which functions in actin-based pseudopods to drive invasion by extracellular matrix degradation. However, the mechanisms that couple matrix proteolysis to the actin cytoskeleton in cell invasion have remained unclear. On the basis of a yeast two-hybrid screen for the MT1-MMP cytoplasmic tail-binding proteins, we identify here a novel Src-regulated protein interaction between the dynamic cytoskeletal scaffold protein palladin and MT1-MMP. These proteins were coexpressed in invasive human basal-like breast carcinomas and corresponding cell lines, where they were associated in the same matrix contacting and degrading membrane complexes. The silencing and overexpression of the 90-kDa palladin isoform revealed the functional importance of the interaction with MT1-MMP in pericellular matrix degradation and mesenchymal tumor cell invasion, whereas in MT1-MMP–negative cells, palladin overexpression was insufficient for invasion. Moreover, this invasion was inhibited in a dominant-negative manner by an immunoglobulin domain–containing palladin fragment lacking the dynamic scaffold and Src-binding domains. These results identify a novel protein interaction that links matrix degradation to cytoskeletal dynamics and migration signaling in mesenchymal cell invasion.

scholarly journals Modulating Tumor Cell Functions by Tunable Nanopatterned Ligand Presentation

Nanomaterials ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 212
Author(s):  
Katharina Amschler ◽  
Michael P. Schön
Keyword(s):  
Extracellular Matrix ◽  
Tumor Cell ◽  
Cell Fate ◽  
Epithelial Mesenchymal Transition ◽  
Model Systems ◽  
Cellular Functions ◽  
Biophysical Parameters ◽  
Ligand Density ◽  
Mesenchymal Transition ◽  
Cell Functions

Cancer comprises a large group of complex diseases which arise from the misrouted interplay of mutated cells with other cells and the extracellular matrix. The extracellular matrix is a highly dynamic structure providing biochemical and biophysical cues that regulate tumor cell behavior. While the relevance of biochemical signals has been appreciated, the complex input of biophysical properties like the variation of ligand density and distribution is a relatively new field in cancer research. Nanotechnology has become a very promising tool to mimic the physiological dimension of biophysical signals and their positive (i.e., growth-promoting) and negative (i.e., anti-tumoral or cytotoxic) effects on cellular functions. Here, we review tumor-associated cellular functions such as proliferation, epithelial-mesenchymal transition (EMT), invasion, and phenotype switch that are regulated by biophysical parameters such as ligand density or substrate elasticity. We also address the question of how such factors exert inhibitory or even toxic effects upon tumor cells. We describe three principles of nanostructured model systems based on block copolymer nanolithography, electron beam lithography, and DNA origami that have contributed to our understanding of how biophysical signals direct cancer cell fate.

scholarly journals Abnormal promoter DNA hypermethylation of the integrin, nidogen, and dystroglycan genes in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Vladimir V. Strelnikov ◽  
Ekaterina B. Kuznetsova ◽  
Alexander S. Tanas ◽  
Viktoria V. Rudenko ◽  
Alexey I. Kalinkin ◽  
...  
Keyword(s):  
Cpg Island ◽  
Strong Association ◽  
Cell Activity ◽  
Promoter Hypermethylation ◽  
Normal Breast ◽  
Breast Carcinomas ◽  
Her2 Positive ◽  
A Genome ◽  
Extracellular Matrix Components ◽  
Integrin Α4

AbstractCell transmembrane receptors and extracellular matrix components play a pivotal role in regulating cell activity and providing for the concerted integration of cells in the tissue structures. We have assessed DNA methylation in the promoter regions of eight integrin genes, two nidogen genes, and the dystroglycan gene in normal breast tissues and breast carcinomas (BC). The protein products of these genes interact with the basement membrane proteins LAMA1, LAMA2, and LAMB1; abnormal hypermethylation of the LAMA1, LAMA2, and LAMB1 promoters in BC has been described in our previous publications. In the present study, the frequencies of abnormal promoter hypermethylation in BC were 13% for ITGA1, 31% for ITGA4, 4% for ITGA7, 39% for ITGA9, 38% for NID1, and 41% for NID2. ITGA2, ITGA3, ITGA6, ITGB1, and DAG1 promoters were nonmethylated in normal and BC samples. ITGA4, ITGA9, and NID1 promoter hypermethylation was associated with the HER2 positive tumors, and promoter hypermethylation of ITGA1, ITGA9, NID1 and NID2 was associated with a genome-wide CpG island hypermethylated BC subtype. Given that ITGA4 is not expressed in normal breast, one might suggest that its abnormal promoter hypermethylation in cancer is non-functional and is thus merely a passenger epimutation. Yet, this assumption is not supported by our finding that it is not associated with a hypermethylated BC subtype. ITGA4 acquires expression in a subset of breast carcinomas, and methylation of its promoter may be preventive against expression in some tumors. Strong association of abnormal ITGA4 hypermethylation with the HER2 positive tumors (p = 0.0025) suggests that simultaneous presence of both HER2 and integrin α4 receptors is not beneficial for tumor cells. This may imply HER2 and integrin α4 signaling pathways interactions that are yet to be discovered.

scholarly journals Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma?

2021 ◽  
Author(s):  
Nicole Bechmann ◽  
Graeme Eisenhofer
Keyword(s):  
Extracellular Matrix ◽  
Signaling Pathways ◽  
Metastatic Disease ◽  
Therapeutic Intervention ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Germline Mutations ◽  
Driver Mutations ◽  
Mesenchymal Transition ◽  
Therapeutic Relevance

AbstractGermline or somatic driver mutations linked to specific phenotypic features are identified in approximately 70% of all catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). Mutations leading to stabilization of hypoxia-inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are associated with a higher risk of metastatic disease. Patients with metastatic PPGLs have a variable prognosis and treatment options are limited. In most patients with PPGLs, germline mutations lead to the stabilization of HIF2α. Mutations in HIF2α itself are associated with adrenal pheochromocytomas and/or extra-adrenal paragangliomas and about 30% of these patients develop metastatic disease; nevertheless, the frequency of these specific mutations is low (1.6–6.2%). Generally, mutations that lead to stabilization of HIF2α result in distinct catecholamine phenotype through blockade of glucocorticoid-mediated induction of phenylethanolamine N-methyltransferase, leading to the formation of tumors that lack epinephrine. HIF2α, among other factors, also contributes importantly to the initiation of a motile and invasive phenotype. Specifically, the expression of HIF2α supports a neuroendocrine-to-mesenchymal transition and the associated invasion-metastasis cascade, which includes the formation of pseudopodia to facilitate penetration into adjacent vasculature. The HIF2α-mediated expression of adhesion and extracellular matrix genes also promotes the establishment of PPGL cells in distant tissues. The involvement of HIF2α in tumorigenesis and in multiple steps of invasion-metastasis cascade underscores the therapeutic relevance of targeting HIF2α signaling pathways in PPGLs. However, due to emerging resistance to current HIF2α inhibitors that target HIF2α binding to specific partners, alternative HIF2α signaling pathways and downstream actions should also be considered for therapeutic intervention.

scholarly journals THE EXTRACELLULAR MATRIX CONTROL OF ACUTE PHASE RESPONSE IN RAT HEPATOCYTE CULTURES

Shock ◽  
1995 ◽  
Vol 4 (Supplement) ◽  
pp. 52
Author(s):  
E. Adoeva ◽  
T. Stepanova ◽  
I. Diakonov ◽  
A. Polevschlkov
Keyword(s):  
Extracellular Matrix ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Phase Response ◽  
Rat Hepatocyte ◽  
Hepatocyte Cultures ◽  
Matrix Control

scholarly journals Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1090
Author(s):  
Hassan Sadozai ◽  
Animesh Acharjee ◽  
Thomas Gruber ◽  
Beat Gloor ◽  
Eva Karamitopoulou
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Disease Progression ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Budding ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Mesenchymal Transition

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

scholarly journals O39: THE HISTOPATHOLOGICAL AND MOLECULAR FEATURES OF BREAST CARCINOMA WITH HIGH-GRADE TUMOUR BUDDING

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
A Lloyd ◽  
E Ryan ◽  
M Boland ◽  
S Medani ◽  
Abd Elwahab ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Lymph Node Involvement ◽  
Low Grade ◽  
High Grade ◽  
Prognostic Variables ◽  
Mesenchymal Transition ◽  
Molecular Features ◽  
Newcastle Ottawa Scale ◽  
Tumour Budding

Abstract Background Tumour budding (TB) is an adverse histological feature in many cancers. It is thought to represent epithelial-to-mesenchymal transition, a key step in the metastatic process. The role of TB in breast carcinoma (BC) remains unclear. Aim To investigate the relationship between TB and other histological and molecular features of BC. Method A systematic search was performed to identify studies that compared features of BC based on the presence or absence of high-grade TB. Dichotomous variables were pooled as odds ratios (OR) using the Cochran–Mantel–Haenszel method. Quality assessment of the included studies was performed using the Newcastle-Ottawa scale (NOS). Result Seven studies with a total of 1040 patients (high grade TB n=519, 49.9%; low grade TB n=521, 50.1%) were included. A moderate- to high-risk of bias was noted. The median NOS was 7 (range 6-8). High-grade TB was significantly associated with lymph node involvement (OR 2.28, 95% c.i. 1.74 to 2.98, P<0.001) and lymphovascular invasion (OR 3.08, 95% c.i. 2.13 to 4.47, P<0.001). Regarding molecular subtypes, there was an increased likelihood of high-grade TB in oestrogen- (OR 1.66, 95% c.i. 1.21 to 2.29, P=0.002) and progesterone-receptor positive (OR 1.68, 95% c.i. 1.10 to 2.59, P=0.02) tumours. In contrast triple negative breast cancer had a reduced incidence of high-grade TB (OR 0.46, 95% c.i. 0.30 to 0.72, P=0.0006). Conclusion High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC. Take-home message High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC.

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