Modulation of NCAM/FGFR1 signaling suppresses EMT program in human proximal tubular epithelial cells

Životić, Maja; Tampe, Björn; Müller, Gerhard A.; Müller, Claudia; Lipkovski, Aleksandar; Xu, Xingbo; Nyamsuren, Gunsmaa; Zeisberg, Michael; Marković-Lipkovski, Jasmina

doi:10.1371/journal.pone.0206786

Cited by 13 publications

(11 citation statements)

References 37 publications

(52 reference statements)

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“…A link between NCAM and FGFR signaling was reported and it appears that the tetrameric form of NCAM triggers the activation of FGFR by lateral associations through the membrane. If NCAM ligands are present, spectrin mediates the colocalization of NCAM proteins with other molecules in lipid raft areas, leading to Fyn kinase activation, that in turn activates FAK (159)(160)(161).…”

Section: The Essential Role Of Cd56 In Development Of Cns Leukemiamentioning

confidence: 99%

A narrative review of central nervous system involvement in acute leukemias

Deak¹,

Gorcea-Andronic²,

Sas³

et al. 2021

Ann Transl Med

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Acute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although

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Section: The Essential Role Of Cd56 In Development Of Cns Leukemiamentioning

confidence: 99%

A narrative review of central nervous system involvement in acute leukemias

Deak¹,

Gorcea-Andronic²,

Sas³

et al. 2021

Ann Transl Med

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“…The FGF ligand alone could not promote neurite outgrowth, which was dependent on FGF-integrin-β1 signaling [ 278 ]. Recently, an NCAM-FGFR1 signaling axis was identified downstream of transforming growth factor β (TGFβ), that promotes transforming growth factor β (TGFβ)-driven EMT of human proximal tubular epithelial cells [ 293 ]. NCAM is also associated with negatively regulating tumor progression.…”

Section: Noncanonical Regulators Of Fgfr Signaling In Cancermentioning

confidence: 99%

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Ferguson

Smith

Francavilla

2021

Cells

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Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the importance of such context-dependent signaling in cancer. Aberrant FGFR signaling has been characterized in almost all cancer types, most commonly non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer and gastrointestinal cancer. This occurs primarily through amplification and over-expression of FGFR1 and FGFR2 resulting in ligand-independent activation. Mutations and translocations of FGFR1-4 are also identified in cancer. Canonical FGF-FGFR signaling is tightly regulated by ligand-receptor combinations as well as direct interactions with the FGFR coreceptors heparan sulfate proteoglycans (HSPGs) and Klotho. Noncanonical FGFR signaling partners have been implicated in differential regulation of FGFR signaling. FGFR directly interacts with cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins, contributing to invasive and migratory properties of cancer cells, whereas interactions with other receptor tyrosine kinases (RTKs) regulate angiogenic, resistance to therapy, and metastatic potential of cancer cells. The diversity in FGFR signaling partners supports a role for FGFR signaling in cancer, independent of genetic aberration.

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“…In addition, ITGA5 silencing also induced a larger cell size in both cell types (Figure 2E and F), again implicating cell differentiation towards the myofibroblastic phenotype. Since ITGA5 activation is often associated with increased TGF-β signaling, 19 we explored several known TGF-β targets following the ITGA5 siRNA treatment. Interestingly, all tested targets (e.g.…”

Section: Itga5 Silencing Leads To Fibroblast To Myofibroblast Transitmentioning

confidence: 99%

Integrin alpha-5 silencing leads to myofibroblastic differentiation in IPF-derived human lung fibroblasts

Shochet

Brook

Bardenstein-Wald

et al. 2020

Therapeutic Advances in Chronic Disease

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Background and objective: The term ‘fibroblast’ covers a heterogeneous cell population in idiopathic pulmonary fibrosis (IPF). The fibroblasts are considered as main effector cells, because they promote disease progression by releasing exaggerated amounts of extracellular matrix proteins and modifying cell microenvironment. As IPF-derived human lung fibroblasts (IPF-HLFs) were shown to express higher levels of integrin alpha-5 (ITGA5) than normal derived HLFs (N-HLFs), we explored the importance of ITGA5 to IPF progression. Methods: IPF-HLF and N-HLF primary cultures were established. ITGA5 was silenced by specific small interfering RNA (siRNA)s and its effects on cell phenotype (e.g. cell number, size, cell death, migration) and gene expression (e.g. RNA sequencing, quantitative polymerase chain reaction [qPCR], western blot and immunofluorescence) were tested. Specific integrin expression was evaluated in IPF patient formalin-fixed paraffin embedded sections by immunohistochemistry (IHC). Results: ITGA5-silencing resulted in reduced IPF-HLF proliferation rates and cell migration ( p < 0.05), as well as elevated cell death. transforming growth factor beta (TGF-β) targets (e.g. Fibronectin (FN1), Matrix metalloproteinase 2 (MMP2), TGFB1) were surprisingly elevated following ITGA5 silencing ( p < 0.05). N-HLFs, however, were only slightly affected. Interestingly, ITGA5-silenced cells differentiated into myofibroblasts (e.g. elevated alpha-smooth muscle actin [αSMA], collagen1a, large cell size). RNA-sequencing revealed that following differentiation on 3D-Matrigel for 24 h, ITGA5 levels are reduced while integrin alpha-8 (ITGA8) are elevated in IPF-HLFs. This was confirmed in IPF patients, in which ITGA5 was mainly found in fibroblastic foci, while ITGA8 was mostly observed in old fibrous tissue in the same patient. Conclusions: ITGA5 expression facilitates a more aggressive proliferative phenotype. Downregulation of this integrin results in myofibroblastic differentiation, which is accompanied by elevated ITGA8. Specific targeting could present a therapeutic benefit.

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Modulation of NCAM/FGFR1 signaling suppresses EMT program in human proximal tubular epithelial cells

Cited by 13 publications

References 37 publications

A narrative review of central nervous system involvement in acute leukemias

A narrative review of central nervous system involvement in acute leukemias

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Integrin alpha-5 silencing leads to myofibroblastic differentiation in IPF-derived human lung fibroblasts

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