scholarly journals Integrins regulate stemness in solid tumor: an emerging therapeutic target

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jiangling Xiong ◽  
Lianlian Yan ◽  
Cheng Zou ◽  
Kai Wang ◽  
Mengjie Chen ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Intracellular Signaling ◽  
Wide Spectrum ◽  
Cellular Functions ◽  
Epithelial Plasticity ◽  
Oncogenic Pathways ◽  
Extracellular Matrix Components ◽  
Therapeutic Development ◽  
And Migration ◽  
Organotropic Metastasis

AbstractIntegrins are the adhesion molecules and transmembrane receptors that consist of α and β subunits. After binding to extracellular matrix components, integrins trigger intracellular signaling and regulate a wide spectrum of cellular functions, including cell survival, proliferation, differentiation and migration. Since the pattern of integrins expression is a key determinant of cell behavior in response to microenvironmental cues, deregulation of integrins caused by various mechanisms has been causally linked to cancer development and progression in several solid tumor types. In this review, we discuss the integrin signalosome with a highlight of a few key pro-oncogenic pathways elicited by integrins, and uncover the mutational and transcriptomic landscape of integrin-encoding genes across human cancers. In addition, we focus on the integrin-mediated control of cancer stem cell and tumor stemness in general, such as tumor initiation, epithelial plasticity, organotropic metastasis and drug resistance. With insights into how integrins contribute to the stem-like functions, we now gain better understanding of the integrin signalosome, which will greatly assist novel therapeutic development and more precise clinical decisions.

Glioblastoma invasion and NMDA receptors: A novel prospect

2019 ◽  
Vol 106 (3) ◽  
pp. 250-260 ◽  
Author(s):  
DN Nandakumar ◽  
P Ramaswamy ◽  
C Prasad ◽  
D Srinivas ◽  
K Goswami
Keyword(s):  
Glutamate Receptors ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Transcript Level ◽  
Glioblastoma Cells ◽  
Invasion And Migration ◽  
Matrigel Invasion ◽  
Nmdar Activation ◽  
And Migration

Purpose Glioblastoma cells create glutamate-rich tumor microenvironment, which initiates activation of ion channels and modulates downstream intracellular signaling. N-methyl-D-aspartate receptors (NMDARs; a type of glutamate receptors) have a high affinity for glutamate. The role of NMDAR activation on invasion of glioblastoma cells and the crosstalk with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is yet to be explored. Main methods LN18, U251MG, and patient-derived glioblastoma cells were stimulated with NMDA to activate NMDAR glutamate receptors. The role of NMDAR activation on invasion and migration and its crosstalk with AMPAR were evaluated. Invasion and migration of glioblastoma cells were investigated by in vitro trans-well Matrigel invasion and trans-well migration assays, respectively. Expression of NMDARs and AMPARs at transcript level was evaluated by quantitative real-time polymerase chain reaction. Results We determined that NMDA stimulation leads to enhanced invasion in LN18, U251MG, and patient-derived glioblastoma cells, whereas inhibition of NMDAR using MK-801, a non-competitive antagonist of the NMDAR, significantly decreased the invasive capacity. Concordant with these findings, migration was significantly augmented by NMDAR in both cell lines. Furthermore, NMDA stimulation upregulated the expression of GluN2 and GluA1 subunits at the transcript level. Conclusions This study demonstrated the previously unexplored role of NMDAR in invasion of glioblastoma cells. Furthermore, the expression of the GluN2 subunit of NMDAR and the differential overexpression of the GluA1 subunit of AMPAR in both cell lines provide a plausible rationale of crosstalk between these calcium-permeable subunits in the glutamate-rich microenvironment of glioblastoma.

scholarly journals Syndecans and Pancreatic Ductal Adenocarcinoma

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 349
Author(s):  
Nausika Betriu ◽  
Juan Bertran-Mas ◽  
Anna Andreeva ◽  
Carlos E. Semino
Keyword(s):  
Extracellular Matrix ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Physiological Processes ◽  
Extracellular Matrix Components ◽  
Detection And Diagnosis ◽  
And Migration ◽  
Early Detection And Diagnosis

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.

scholarly journals MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer

2021 ◽  
Author(s):  
Andrea Lampis ◽  
Jens C. Hahne ◽  
Pierluigi Gasparini ◽  
Luciano Cascione ◽  
Somaieh Hedayat ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Critical Role ◽  
Tumour Volume ◽  
Cell Permeability ◽  
Oncogenic Pathways ◽  
Morphogenetic Protein ◽  
Cancer Phenotype ◽  
And Migration ◽  
2D And 3D

AbstractJunctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.

scholarly journals The Expression of the Cancer-Associated lncRNA Snhg15 Is Modulated by EphrinA5-Induced Signaling

2021 ◽  
Vol 22 (3) ◽  
pp. 1332
Author(s):  
Daniel Pensold ◽  
Julia Gehrmann ◽  
Georg Pitschelatow ◽  
Asa Walberg ◽  
Kai Braunsteffer ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Intracellular Signaling ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Membrane Receptors ◽  
In Vitro Assays ◽  
Eph Receptor ◽  
Medulloblastoma Cell Line ◽  
And Migration

The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli into our genome through a great gene regulatory spectrum. Applying a combination of functional in vitro assays, RNA sequencing, and qPCR analysis, we found that the proliferation and migration promoting stimulation of mouse cerebellar granule cells (CB) with ephrinA5 diminishes the expression of the cancer-related lncRNA Snhg15. In a human medulloblastoma cell line (DAOY) ephrinA5 stimulation similarly reduced SNHG15 expression. Computational analysis identified triple-helix-mediated DNA-binding sites of Snhg15 in promoters of genes found up-regulated upon ephrinA5 stimulation and known to be involved in tumorigenic processes. Our findings propose a crucial role of Snhg15 downstream of ephrinA5-induced signaling in regulating gene transcription in the nucleus. These findings could be potentially relevant for the regulation of tumorigenic processes in the context of glioma.

scholarly journals Anti-neoplastic Effect of Ginkgolide C through Modulating c-Met Phosphorylation in Hepatocellular Carcinoma Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 8303
Author(s):  
Min Hee Yang ◽  
Seung Ho Baek ◽  
Jae-Young Um ◽  
Kwang Seok Ahn
Keyword(s):  
Hepatocellular Carcinoma ◽  
Invasion And Migration ◽  
Oncogenic Pathways ◽  
Tumor Growth And Metastasis ◽  
And Migration ◽  
Induced Apoptosis ◽  
Interfering Rna ◽  
Hepatocyte Growth ◽  
Hcc Cells ◽  
Met Phosphorylation

Ginkgolide C (GGC) derived from Ginkgo biloba, has been reported to exhibit various biological functions. However, the anti-neoplastic effect of GGC and its mechanisms in liver cancer have not been studied previously. Hepatocyte growth factor (HGF)/c-mesenchymal–epithelial transition receptor (c-Met) pathway can regulate tumor growth and metastasis in hepatocellular carcinoma (HCC) cells. This study aimed to evaluate the anti-neoplastic effect of GGC against HCC cells and we observed that GGC inhibited HGF-induced c-Met and c-Met downstream oncogenic pathways, such as PI3K/Akt/mTOR and MEK/ERK. In addition, GGC also suppressed the proliferation of expression of diverse tumorigenic proteins (Bcl-2, Bcl-xL, Survivin, IAP-1, IAP-2, Cyclin D1, and COX-2) and induced apoptosis. Interestingly, the silencing of c-Met by small interfering RNA (siRNA) mitigated c-Met expression and enhanced GGC-induced apoptosis. Moreover, it was noted that GGC also significantly reduced the invasion and migration of HCC cells. Overall, the data clearly demonstrate that GGC exerts its anti-neoplastic activity through modulating c-Met phosphorylation and may be used as an effective therapy against HCC.

Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4142-4151 ◽  
Author(s):  
Marcin Majka ◽  
Anna Janowska-Wieczorek ◽  
Janina Ratajczak ◽  
M. Anna Kowalska ◽  
Gaston Vilaire ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Phosphatidyl Inositol ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Proliferative Effect ◽  
Normal Human ◽  
And Migration ◽  
Induced Apoptosis

Abstract The role of the chemokine binding stromal-derived factor 1 (SDF-1) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin (TPO) have not been determined. In this study it was found that SDF-1, unlike TPO, does not stimulate αIIbβ3+ cell proliferation or differentiation or have an antiapoptotic effect. However, it does induce chemotaxis, trans-Matrigel migration, and secretion of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) by these cells, and both SDF-1 and TPO increase the adhesion of αIIbβ3+ cells to fibrinogen and vitronectin. Investigating the intracellular signaling pathways induced by SDF-1 and TPO revealed some overlapping patterns of protein phosphorylation/activation (mitogen-activated protein kinase [MAPK] p42/44, MAPK p38, and AKT [protein kinase B]) and some that were distinct for TPO (eg, JAK-STAT) and for SDF-1 (eg, NF-κB). It was also found that though inhibition of phosphatidyl-inositol 3-kinase (PI-3K) by LY294002 in αIIbβ3+ cells induced apoptosis and inhibited chemotaxis adhesion and the secretion of MMP-9 and VEGF, the inhibition of MAPK p42/44 (by the MEK inhibitor U0126) had no effect on the survival, proliferation, and migration of these cells. Hence, it is suggested that the proliferative effect of TPO is more related to activation of the JAK-STAT pathway (unique to TPO), and the PI-3K–AKT axis is differentially involved in TPO- and SDF-1–dependent signaling. Accordingly, PI-3K is involved in TPO-mediated inhibition of apoptosis, TPO- and SDF-1–regulated adhesion to fibrinogen and vitronectin, and SDF-1–mediated migration. This study expands the understanding of the role of SDF-1 and TPO in normal human megakaryopoiesis and indicates the molecular basis of the observed differences in cellular responses.

scholarly journals The Role of the Extracellular Matrix Components in Cutaneous Wound Healing

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Pawel Olczyk ◽  
Łukasz Mencner ◽  
Katarzyna Komosinska-Vassev
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Growth Factors ◽  
Wound Repair ◽  
Structural Integrity ◽  
Healing Process ◽  
Cellular Functions ◽  
Extracellular Matrix Components ◽  
Essential Components ◽  
Matrix Components

Wound healing is the physiologic response to tissue trauma proceeding as a complex pathway of biochemical reactions and cellular events, secreted growth factors, and cytokines. Extracellular matrix constituents are essential components of the wound repair phenomenon. Firstly, they create a provisional matrix, providing a structural integrity of matrix during each stage of healing process. Secondly, matrix molecules regulate cellular functions, mediate the cell-cell and cell-matrix interactions, and serve as a reservoir and modulator of cytokines and growth factors’ action. Currently known mechanisms, by which extracellular matrix components modulate each stage of the process of soft tissue remodeling after injury, have been discussed.

S16020 pyridocarbazole derivatives display high activity to lung cancer cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Gabriela Chabowska ◽  
Helena Moreira ◽  
Beata Tylińska ◽  
Ewa Barg
Keyword(s):  
Cell Viability ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Wide Spectrum ◽  
A549 Cells ◽  
Biological Evaluation ◽  
Dna Intercalation ◽  
P Glycoprotein ◽  
Low Toxicity ◽  
And Migration

Background: Despite the dynamic development of medicine, globally cancer diseases remain the second leading cause of death. Therefore, there is a strong necessity to improve chemotherapy regimens and search for new anticancer agents. Pyridocarbazoles are compounds with confirmed antitumor properties based on multimodal mechanisms, i.a. DNA intercalation and topoisomerase II-DNA complex inhibition. One of them, S16020, displayed a wide spectrum of activity. Objective: The aim of the study was to investigate the antitumor potency of six S16020 derivatives, synthesized according to the SAR (structure-activity relationship) method. Methods: The biological evaluation included influence on cancer cell viability, proliferation, and migration, as well as P-glycoprotein activity. NHDF, A549, MCF-7, LoVo, and LoVo/DX cell lines were used in the study. Results: All derivatives displayed low toxicity to normal (NHDF) cells at 1 and 2 µM (≤ 20% of cell growth inhibition). The highest reduction in cell viability was noted in A549 cells which was accompanied by significant disruption of cells proliferation and motility. Compound 1 exhibited the strongest cytotoxic, antiproliferative, and antimigratory effects, higher than the reference olivacine. A significant reduction in P-glycoprotein activity was found for derivatives 6 and 1. Conclusion: S16020 derivatives could be considered as potential candidates for new anticancer drugs.

scholarly journals The Extracellular Matrix Glycoprotein Tenascin C and Adult Neurogenesis

2021 ◽  
Vol 9 ◽  
Author(s):  
Milena Tucić ◽  
Vera Stamenković ◽  
Pavle Andjus
Keyword(s):  
Extracellular Matrix ◽  
Adult Neurogenesis ◽  
Specific Reference ◽  
Neuron Development ◽  
Regulatory Pathways ◽  
Tenascin C ◽  
Extracellular Matrix Components ◽  
Adult Hippocampus ◽  
And Migration ◽  
Regenerative Therapies

Tenascin C (TnC) is a glycoprotein highly expressed in the extracellular matrix (ECM) during development and in the adult central nervous system (CNS) in regions of active neurogenesis, where neuron development is a tightly regulated process orchestrated by extracellular matrix components. In addition, newborn cells also communicate with glial cells, astrocytes and microglia, indicating the importance of signal integration in adult neurogenesis. Although TnC has been recognized as an important molecule in the regulation of cell proliferation and migration, complete regulatory pathways still need to be elucidated. In this review we discuss the formation of new neurons in the adult hippocampus and the olfactory system with specific reference to TnC and its regulating functions in this process. Better understanding of the ECM signaling in the niche of the CNS will have significant implications for regenerative therapies.

scholarly journals Nonneuronal Cholinergic System in Breast Tumors and Dendritic Cells: Does It Improve or Worsen the Response to Tumor?

2013 ◽  
Vol 2013 ◽  
pp. 1-12
Author(s):  
Marisa Vulcano ◽  
María Gabriela Lombardi ◽  
María Elena Sales
Keyword(s):  
Dendritic Cells ◽  
Cholinergic System ◽  
Parasympathetic Nervous System ◽  
Immune Cell ◽  
Breast Tumors ◽  
Cell Types ◽  
Cellular Functions ◽  
And Migration ◽  
And Function

Besides being the main neurotransmitter in the parasympathetic nervous system, acetylcholine (ACh) can act as a signaling molecule in nonneuronal tissues. For this reason, ACh and the enzymes that synthesize and degrade it (choline acetyltransferase and acetylcholinesterase) as well as muscarinic (mAChRs) and nicotinic receptors conform the non-neuronal cholinergic system (nNCS). It has been reported that nNCS regulates basal cellular functions including survival, proliferation, adhesion, and migration. Moreover, nNCS is broadly expressed in tumors and in different components of the immune system. In this review, we summarize the role of nNCS in tumors and in different immune cell types focusing on the expression and function of mAChRs in breast tumors and dendritic cells (DCs) and discussing the role of DCs in breast cancer.

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