scholarly journals Modeling the Role of Hypoxia in Glioblastoma Growth and Recurrence Patterns

2019 ◽  
Author(s):  
Lee Curtin ◽  
Andrea Hawkins-Daarud ◽  
Alyx B. Porter ◽  
Markus R. Owen ◽  
Kristoffer G. van der Zee ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cellular Proliferation ◽  
Distant Recurrence ◽  
Typical Feature ◽  
Hypoxic Cell ◽  
Tumor Cell Migration ◽  
Hypoxic Conditions ◽  
Recurrence Patterns ◽  
Distal Recurrence

AbstractA typical feature of glioblastoma (GBM) growth is local recurrence after surgery. However, some GBMs recur distally. It has been noted that GBM patients with perioperative ischemia are more likely to have distal recurrence and that GBM cells migrate faster under hypoxic conditions. We apply the Proliferation Invasion Hypoxia Necrosis Angiogenesis (PIHNA) model to examine the effect of faster hypoxic cell migration on simulated GBM growth. Results suggest that a highly migratory hypoxic cell population drives the growth of the whole tumor and leads to distant recurrence, as do higher normoxic tumor cell migration and low cellular proliferation rates.

scholarly journals Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II

2016 ◽  
Vol 39 (2) ◽  
pp. 802-813 ◽  
Author(s):  
Bhuvana A. Setty ◽  
Yi Jin ◽  
Peter J. Houghton ◽  
Nicholas D. Yeager ◽  
Thomas G. Gross ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Osteosarcoma Cell ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Osteosarcoma Cells ◽  
Protein Levels ◽  
Hypoxic Conditions ◽  
Human Osteosarcoma Cell ◽  
Arginase Ii

Background/Aims: Despite significant advancements in the diagnosis and treatment of osteosarcoma, the overall survival has remained relatively unchanged for over two decades. Hypoxic conditions have been demonstrated in solid tumors and are associated with increased cell proliferation and angiogenesis. L-arginine metabolism by arginase produces L-ornithine, the precursor for polyamine and proline synthesis required for cellular proliferation. We hypothesized that hypoxia would increase cellular proliferation via arginase induction in human osteosarcoma cell lines. Methods: We utilized a variety of approaches to examine the role of arginase II in hypoxic (1% O2, 5% CO2) cellular proliferation. Results: Arginase II mRNA and protein levels were significantly increased in osteosarcoma cells exposed to hypoxia for 48 hours. There were twice as many viable cells following 48 hours of hypoxia than following 48 hours of normoxia (21% O2, 5% CO2). The addition of difluoromethylornithine (DFMO), a putative arginase inhibitor, prevented hypoxia-induced proliferation. Transfection of small interfering RNAs (siRNA) targeting arginase II resulted in knockdown of arginase II protein levels and prevented hypoxia-induced cellular proliferation. Conclusions: These data support our hypothesis that hypoxia increases proliferation of osteosarcoma cells in an arginase II-dependent manner. We speculate that arginase II may represent a therapeutic target in osteosarcoma.

E2F5 promotes prostate cancer cell migration and invasion through regulation of TFPI2, MMP-2 and MMP-9

2020 ◽  
Author(s):  
Deepmala Karmakar ◽  
Jyotirindra Maity ◽  
Payel Mondal ◽  
Puskar Shyam Chowdhury ◽  
Nilabja Sikdar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Migration ◽  
Cellular Proliferation ◽  
Therapeutic Potential ◽  
Quantitative Polymerase Chain Reaction ◽  
Site Directed Mutagenesis ◽  
Migration And Invasion ◽  
Dual Function ◽  
Pc3 Cells

Abstract Previously, our laboratory demonstrated that a deregulated E2F5/p38/SMAD3 axis was associated with uncontrolled cellular proliferation in prostate cancer (PCa). Here, we investigate the role of E2F5 in PCa in further details. RNAi-mediated E2F5 knockdown and pathway-focused gene expression profiling in PC3 cells identified TFPI2 as a downstream target of E2F5. Manipulation of E2F5 expression was also found to alter MMP-2 and MMP-9 levels as detected by Proteome Profiler array, western blot and reverse transcription coupled quantitative polymerase chain reaction Site-directed mutagenesis, dual-luciferase assays and chromatin immunoprecipitation with anti-E2F5-IgG coupled with qPCR confirmed recruitment of E2F5 on TFPI2, MMP-2 and MMP-9 promoters. RNAi-mediated knockdown of E2F5 expression in PC3 caused a significant alteration of cell migration while that of TFFI2 resulted in a modest change. Abrogation of E2F5 and TFPI2 expression was associated with significant changes in the gelatinolytic activity of active forms of MMP-2 and MMP-9. Moreover, E2F5, MMP-2 and MMP-9 levels were elevated in biopsies of PCa patients relative to that of benign hyperplasia, while TFPI2 expression was reduced. MMP-9 was coimmunoprecipitated with anti-TFPI2-IgG in PCa tissue samples suggesting a direct interaction between the proteins. Finally, artemisinin treatment in PC3 cells repressed E2F5 along with MMP-2/MMP-9 while triggering TFPI2 expression which alleviated PC3 aggressiveness possibly through inhibition of MMP activities. Together, our study reinstates an oncogenic role of E2F5 which operates as a dual-function transcription factor for its targets TFPI2, MMP-2 and MMP-9 and promotes cellular invasiveness. This study also indicates a therapeutic potential of artemisinin, a natural compound which acts by correcting dysfunctional E2F5/TFPI2/MMP axis in PCa.

The Cytoplasmic Domain of Tissue Factor Inhibits Migration and Enhances Adhesion of Human Breast Cancer Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1939-1939
Author(s):  
Xiaofeng Jiang ◽  
Tracee S. Panetti ◽  
Michael E. Bromberg
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Cell ◽  
Cell Line ◽  
Human Breast Cancer ◽  
Cytoplasmic Domain ◽  
Human Breast ◽  
Tumor Cell Migration ◽  
Mcf 7

Abstract Tissue factor (TF) is a 47 kDa transmembrane glycoprotein that when complexed with its cofactor, factor VIIa (FVIIa), initiates blood coagulation. Apart from hemostasis, TF has been shown to have roles in cellular signaling, development, inflammation, metastasis and angiogenesis. We showed previously that both the cytoplasmic and extracellular domains of TF are required for the full metastatic effect of TF. Recently, we showed that TF-FVIIa-FXa complex induces cellular signaling in human breast cancer cells and is associated with enhanced cell migration and prevention of apoptosis. However, the role of the cytoplasmic domain of TF in tumor cell function is not fully known. In the present study, the role of the cytoplasmic domain of TF in cell migration and adhesion was investigated using the Adr-MCF-7 cell line, a multidrug resistant subline of the human breast cancer cell line, MCF-7. The Adr-MCF-7 cell line has high endogenous expression of TF and expression of PAR1 and PAR2. Adr-MCF-7 cells were retrovirally transfected with either a cDNA construct encoding a FLAG epitope tag fused to the transmembrane and cytoplasmic domains of TF (known as FLAG-TFCD) or vector (LXSN) alone as a control, and stable, polyclonal cell lines selected using G418. Expression of the FLAG-TFCD construct was verified by RT-PCR, Western blot analysis and flow cytometry. To test the effect of overexpression of the FLAG-TFCD construct on cell motility a modified Boyden chamber chemotaxis assay was used. The control LXSN cell line had a nearly 9 fold increase in cell migration [33.5± 3.2 cells/hpf (mean± SEM)]using the combination of rFVIIa (10 nM) and FX (150 nM) as the chemoattractant compared with 0.1% bovine serum albumin (BSA) [3.9± 1.2 cells/hpf]. In contrast, the FLAG-TFCD cell line had no increase in migration of using the combination of rFVIIa and FX [6.6± 0.57 cells/hpf] compared with BSA [5.4± 0.67 cells/hpf]. We then examined the ability of the transfected cell lines to adhere to type IV collagen. The number of adherent cells for the transfected cell line, FLAG-TFCD, was nearly 3 fold higher than that for the LXSN line using a colorimetric MTS assay (0.295± 0.041 vs 0.119± 0.011). Moreover, treatment of the FLAG-TFCD cells with the combination of rFVIIa and FX increased the adhesion by nearly 2 fold compared with untreated FLAG-TFCD cells (0.561±0.055 vs 0.296±0.044). In summary, overexpression of TF cytoplasmic domain leads to inhibition of tumor cell migration and enhancement of cell adhesion and potentially acts as a dominant negative in these cellular processes. These data suggest that a function of the cytoplasmic domain of TF in metastasis is to regulate tumor cell migration and adhesion.

scholarly journals The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

2020 ◽  
Vol 21 (3) ◽  
pp. 765 ◽  
Author(s):  
Antonio Villalobo ◽  
Martin W. Berchtold
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Small Gtpases ◽  
Vast Number ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Iq Motif ◽  
Metastasis Development ◽  
Cell Invasiveness

Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

Tenascin mediates human glioma cell migration and modulates cell migration on fibronectin

1996 ◽  
Vol 109 (3) ◽  
pp. 643-652 ◽  
Author(s):  
E.I. Deryugina ◽  
M.A. Bourdon
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Cell Morphology ◽  
Radial Distance ◽  
Tumor Cell Migration ◽  
Migration Rates ◽  
Cell Responses ◽  
Coated Surfaces ◽  
Blocking Antibodies

The role of tenascin in mediating tumor cell migration was studied using two cell migration models. In migration/invasion Transwell assays U251.3 glioma cells rapidly migrated through the 8 mu m pore size membranes onto tenascin- and fibronectin-coated surfaces. In this assay the number of cells migrating onto tenascin was 52.2 +/- 9.6% greater than on fibronectin within 4 hours. To assess cell migration rates and cell morphology, U251.3 migration was examined in a two-dimension spheroid outgrowth assay. The radial distance migrated by U251.3 cells from tumor spheroids was found to be 53.8 +/- 4.9% greater on tenascin than on fibronectin. Cells migrating on tenascin display a very motile appearance, while cells migrating on fibronectin spread and maintain close intercellular contacts. Cell migration in the presence of integrin blocking antibodies demonstrated that migration on tenascin and fibronectin is mediated by distinct integrins, alpha2beta1 and alphavbeta5/alphavbeta3, respectively. Since tenascin is coexpressed in malignant tumor matrices with fibronectin, we assessed the effects of tenascin on U251.3 cell migration mediated by fibronectin. Tenascin was found to provide a positive effect on fibronectin-mediated migration by altering cell morphology and enhancing cell motility. These effects of tenascin on fibronectin-mediated cell migration were inhibited by blocking beta1 and alpha2beta1 integrins. The results suggest that tenascin may play a significant role in promoting tumor cell migration and invasiveness by modulating cell responses to normal matrix components.

scholarly journals MEKK1 Regulates Chemokine Expression in Mammary Fibroblasts: Implications for the Breast Tumor Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Saverio Gentile ◽  
Najmeh Eskandari ◽  
Michael A. Rieger ◽  
Bruce D. Cuevas
Keyword(s):  
Gene Expression ◽  
Cell Migration ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Breast Tumor ◽  
Cell Function ◽  
Breast Tumor Cell ◽  
Tumor Cell Migration ◽  
Stroma Cell

Breast tumors contain both transformed epithelial cells and non-transformed stroma cells producing secreted factors that can promote metastasis. Previously, we demonstrated that the kinase MEKK1 regulates cell migration and gene expression, and that transgene-induced breast tumor metastasis is markedly inhibited in MEKK1-deficient mice. In this report, we examined the role of MEKK1 in stroma cell gene expression and the consequent effect on breast tumor cell function. Using a heterotypic cell system to quantify the effect of stroma cells on breast tumor cell function, we discovered that MEKK1−/− fibroblasts are significantly less effective at inducing tumor cell invasion than MEKK1+/+ fibroblasts. Expression array analysis revealed that both baseline and tumor cell-induced expression of the chemokines CCL3, CCL4, and CCL5 were markedly reduced in MEKK1−/− mammary fibroblasts. By focusing on the role of MEKK1 in CCL5 regulation, we discovered that MEKK1 kinase activity promotes CCL5 expression, and inactive mutant MEKK1 strongly inhibits CCL5 transcription. CCL5 and the other MEKK1-dependent chemokines are ligands for the GPCR CCR5, and we show that the CCR5 antagonist Maraviroc strongly inhibits fibroblast-induced tumor cell migration. Finally, we report that fibroblast growth factor 5 (FGF-5) is secreted by MDA-MB 231 cells, that FGF-5 activates MEKK1 effectors ERK1/2 and NFκB in fibroblasts, and that chemical inhibition of NFκB inhibits CCL5 expression. Our results suggest that MEKK1 contributes to the formation of a breast tumor microenvironment that supports metastasis by promoting expression of stroma cell chemokine genes in response to tumor cell-induced paracrine signaling.

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