Tumoral Neuroligin 1 Promotes Cancer–Nerve Interactions and Synergizes with the Glial Cell Line-Derived Neurotrophic Factor

Many nervous proteins are expressed in cancer cells. In this report, we asked whether the synaptic protein neuroligin 1 (NLGN1) was expressed by prostatic and pancreatic carcinomas; in addition, given the tendency of these tumors to interact with nerves, we asked whether NLGN1 played a role in this process. Through immunohistochemistry on human tissue microarrays, we showed that NLGN1 is expressed by prostatic and pancreatic cancer tissues in discrete stages and tumor districts. Next, we performed in vitro and in vivo assays, demonstrating that NLGN1 promotes cancer cell invasion and migration along nerves. Because of the established role of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) in tumor–nerve interactions, we assessed a potential NLGN1–GDNF cooperation. We found that blocking GDNF activity with a specific antibody completely inhibited NLGN1-induced in vitro cancer cell invasion of nerves. Finally, we demonstrated that, in the presence of NLGN1, GDNF markedly activates cofilin, a cytoskeletal regulatory protein, altering filopodia dynamics. In conclusion, our data further prove the existence of a molecular and functional cross-talk between the nervous system and cancer cells. NLGN1 was shown here to function along one of the most represented neurotrophic factors in the nerve microenvironment, possibly opening new therapeutic avenues.

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5′-Inositol phosphatase SHIP2 recruits Mena to stabilize invadopodia for cancer cell invasion

The Journal of Cell Biology ◽

10.1083/jcb.201501003 ◽

2016 ◽

Vol 214 (6) ◽

pp. 719-734 ◽

Cited By ~ 19

Author(s):

Charles V. Rajadurai ◽

Serhiy Havrylov ◽

Paula P. Coelho ◽

Colin D.H. Ratcliffe ◽

Kossay Zaoui ◽

...

Keyword(s):

Cancer Cells ◽

Cell Invasion ◽

Regulatory Protein ◽

Cancer Cell Invasion ◽

Inositol Phosphatase ◽

Membrane Protrusions ◽

Ecm Degradation

Invadopodia are specialized membrane protrusions that support degradation of extracellular matrix (ECM) by cancer cells, allowing invasion and metastatic spread. Although early stages of invadopodia assembly have been elucidated, little is known about maturation of invadopodia into structures competent for ECM proteolysis. The localized conversion of phosphatidylinositol(3,4,5)-triphosphate and accumulation of phosphatidylinositol(3,4)-bisphosphate at invadopodia is a key determinant for invadopodia maturation. Here we investigate the role of the 5′-inositol phosphatase, SHIP2, and reveal an unexpected scaffold function of SHIP2 as a prerequisite for invadopodia-mediated ECM degradation. Through biochemical and structure-function analyses, we identify specific interactions between SHIP2 and Mena, an Ena/VASP-family actin regulatory protein. We demonstrate that SHIP2 recruits Mena, but not VASP, to invadopodia and that disruption of SHIP2–Mena interaction in cancer cells leads to attenuated capacity for ECM degradation and invasion in vitro, as well as reduced metastasis in vivo. Together, these findings identify SHIP2 as a key modulator of carcinoma invasiveness and a target for metastatic disease.

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The antihyperlipidemic drug Potassium Piperate impairs migration and tumorgenesis of breast cancer cells via upregulation of miR-31

10.21203/rs.3.rs-290044/v1 ◽

2021 ◽

Author(s):

Junping Lu ◽

Xiaoxia Tian ◽

Mailisu Mailisu ◽

Morigen Morigen ◽

Lifei Fan

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Invasion ◽

Combination Treatment ◽

Breast Cancer Cells ◽

Target Genes ◽

Cancer Cell Invasion

Abstract Background Breast cancer is a leading malignant tumor which causes deaths among women, and metastasis is the primary cause for mortality in breast cancer. Due to the involvement of many regulatory molecules and signaling pathways, the occurrence and development process of metastasis needs to be further studied. MicroRNAs (miRNAs) are ubiquitously expressed small non-coding RNAs that have been shown to play an important role in the diagnosis and treatment of many diseases, as well as constituting an attractive candidate to control metastasis. In this study, we tried to uncover the mechanism of GBK in impairing breast cancer cell invasion and metastasis.Methods We treated cancer cells with GBK or not, found its target miRNA by analyzed miRNA transcriptional changes and the miRNA target genes by performed with the QT-PCR and Western Blot. The proliferation of breast cancer cells in vitro and in vivo under combination treatment with GBK and DDP was measured by CCK-8 kit and the nude mice tumor formation experiment.Results We found tumor suppressor miR-31 was a main target of GBK. GBK treatment affected the epigenetic modification at CpG sites by downregulating DNA methyltransferases, thus the methylation levels at CpG of lncRNA LOC554202 decreased significantly, and in turn upregulating of both miR-31 and its host gene LOC554202 in breast cancer cells. We also observed significant inhibition of miR-31 target genes under GBK stimulation, including RhoA, WAVE3 and SATB2, which all closely related to cancer cell invasion, migration and proliferation. Furthermore, we revealed that combination treatment with GBK and DDP had synergistic and dose reduction potential in inhibiting the proliferation of breast cancer cells in vitro and in vivo, especially in TNBC.Conclusion This study further analyzes the target and underlying mechanism of GBK in inhibiting breast cancer migration and invasion, and provides theoretical support for the development of GBK as an auxiliary drug for clinical treatment.

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A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666180917100640 ◽

2018 ◽

Vol 18 (17) ◽

pp. 1483-1493

Author(s):

Ricardo Imbroisi Filho ◽

Daniel T.G. Gonzaga ◽

Thainá M. Demaria ◽

João G.B. Leandro ◽

Dora C.S. Costa ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Line ◽

Cancer Cell ◽

Cancer Cell Line ◽

Hepatic Function ◽

Anticancer Properties ◽

Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

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α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3

The Journal of Cell Biology ◽

10.1083/jcb.201502040 ◽

2015 ◽

Vol 210 (6) ◽

pp. 1013-1031 ◽

Cited By ~ 72

Author(s):

Nikki R. Paul ◽

Jennifer L. Allen ◽

Anna Chapman ◽

Maria Morlan-Mairal ◽

Egor Zindy ◽

...

Keyword(s):

Cancer Cells ◽

Cell Invasion ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Cancer Cell Invasion ◽

Coupling Protein ◽

Α5β1 Integrin ◽

In Cells

Invasive migration in 3D extracellular matrix (ECM) is crucial to cancer metastasis, yet little is known of the molecular mechanisms that drive reorganization of the cytoskeleton as cancer cells disseminate in vivo. 2D Rac-driven lamellipodial migration is well understood, but how these features apply to 3D migration is not clear. We find that lamellipodia-like protrusions and retrograde actin flow are indeed observed in cells moving in 3D ECM. However, Rab-coupling protein (RCP)-driven endocytic recycling of α5β1 integrin enhances invasive migration of cancer cells into fibronectin-rich 3D ECM, driven by RhoA and filopodial spike-based protrusions, not lamellipodia. Furthermore, we show that actin spike protrusions are Arp2/3-independent. Dynamic actin spike assembly in cells invading in vitro and in vivo is regulated by Formin homology-2 domain containing 3 (FHOD3), which is activated by RhoA/ROCK, establishing a novel mechanism through which the RCP–α5β1 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo.

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Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/β-catenin pathway

Biochemical Journal ◽

10.1042/bcj20170348 ◽

2017 ◽

Vol 474 (22) ◽

pp. 3733-3746 ◽

Cited By ~ 11

Author(s):

Fatima Lahdaoui ◽

Mathieu Messager ◽

Audrey Vincent ◽

Flora Hec ◽

Anne Gandon ◽

...

Keyword(s):

Cancer Cells ◽

Cell Line ◽

Cancer Cell ◽

Gastrointestinal Cancer ◽

Tumour Growth ◽

Cancer Cell Line ◽

Migration And Invasion ◽

Down Regulation

Secreted mucins are large O-glycosylated proteins that participate in the protection/defence of underlying mucosae in normal adults. Alteration of their expression is a hallmark of numerous epithelial cancers and has often been correlated to bad prognosis of the tumour. The secreted mucin MUC5B is overexpressed in certain subtypes of gastric and intestinal cancers, but the consequences of this altered expression on the cancer cell behaviour are not known. To investigate the role of MUC5B in carcinogenesis, its expression was knocked-down in the human gastric cancer cell line KATO-III and in the colonic cancer cell line LS174T by using transient and stable approaches. Consequences of MUC5B knocking-down on cancer cells were studied with respect to in vitro proliferation, migration and invasion, and in vivo on tumour growth using a mouse subcutaneous xenograft model. Western blotting, luciferase assay and qRT–PCR were used to identify proteins and signalling pathways involved. In vitro MUC5B down-regulation leads to a decrease in proliferation, migration and invasion properties in both cell lines. Molecular mechanisms involved the alteration of β-catenin expression, localization and activity and decreased expression of several of its target genes. In vivo xenografts of MUC5B-deficient cells induced a decrease in tumour growth when compared with MUC5B-expressing Mock cells. Altogether, the present study shows that down-regulation of MUC5B profoundly alters proliferation, migration and invasion of human gastrointestinal cancer cells and that these alterations may be, in part, mediated by the Wnt/β-catenin pathway emphasizing the potential of MUC5B as an actor of gastrointestinal carcinogenesis.

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3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo

British Journal of Cancer ◽

10.1038/sj.bjc.6600856 ◽

2003 ◽

Vol 88 (7) ◽

pp. 1111-1118 ◽

Cited By ~ 74

Author(s):

I Kempen ◽

D Papapostolou ◽

N Thierry ◽

L Pochet ◽

S Counerotte ◽

...

Keyword(s):

Cancer Cell ◽

Cell Invasion ◽

Tumour Growth ◽

Cancer Cell Invasion

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A Novel Activating Mutation in the RET Tyrosine Kinase Domain Mediates Neoplastic Transformation

Molecular Endocrinology ◽

10.1210/me.2004-0447 ◽

2006 ◽

Vol 20 (7) ◽

pp. 1633-1643 ◽

Cited By ~ 10

Author(s):

Aaron Cranston ◽

Cristiana Carniti ◽

Sam Martin ◽

Piera Mondellini ◽

Yvette Hooks ◽

...

Keyword(s):

Tyrosine Kinase ◽

Cell Line ◽

Glial Cell ◽

Neurotrophic Factor ◽

Functional Characterization ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Exogenous Substrate

Abstract We report the finding of a novel missense mutation at codon 833 in the tyrosine kinase of the RET proto-oncogene in a patient with a carcinoma of the thyroid. In vitro experiments demonstrate that the R833C mutation induces transformed foci only when present in the long 3′ splice isoform and, in keeping with a model in which the receptor has to dimerize to be completely activated, glial cell line-derived neurotrophic factor stimulation leads the RETR833C receptor to a higher level of activation. Tyrosine kinase assays show that the RETR833C long isoform has weak intrinsic kinase activity and phosphorylation of an exogenous substrate is not elevated even in the presence of glial cell line-derived neurotrophic factor. Furthermore, the R833C mutation is capable of sustaining the transformed phenotype in vivo but does not confer upon the transformed cells the ability to degrade the basement membrane in a manner analogous to metastasis. Our functional characterization of the R833C substitution suggests that, like the V804M and S891A mutations, this tyrosine kinase mutation confers a weak activating potential upon RET. This is the first report demonstrating that the introduction of an intracellular cysteine can activate RET. However, this does not occur via dimerization in a manner analogous to the extracellular cysteine mutants.

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Erratum: OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo

Molecular Cancer ◽

10.1186/s12943-015-0341-1 ◽

2015 ◽

Vol 14 (1) ◽

Cited By ~ 3

Author(s):

Diego Iglesias-Gato ◽

Yin-Choy Chuan ◽

Ning Jiang ◽

Charlotte Svensson ◽

Jing Bao ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cell ◽

Cell Invasion ◽

Prostate Cancer Cell ◽

Cancer Cell Invasion

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Cancer-Associated Fibroblasts Differentiated by Exosomes Isolated from Cancer Cells Promote Cancer Cell Invasion

International Journal of Molecular Sciences ◽

10.3390/ijms21218153 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8153

Author(s):

Kimin Kim ◽

Yeh Joo Sohn ◽

Ruri Lee ◽

Hye Ju Yoo ◽

Ji Yoon Kang ◽

...

Keyword(s):

Endothelial Cells ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Invasion ◽

Cell Types ◽

Cancer Drug ◽

Cancer Microenvironment ◽

Cancer Associated Fibroblasts ◽

Cancer Cell Invasion

Cancer-associated fibroblasts (CAFs) in the cancer microenvironment play an essential role in metastasis. Differentiation of endothelial cells into CAFs is induced by cancer cell-derived exosomes secreted from cancer cells that transfer molecular signals to surrounding cells. Differentiated CAFs facilitate migration of cancer cells to different regions through promoting extracellular matrix (ECM) modifications. However, in vitro models in which endothelial cells exposed to cancer cell-derived exosomes secreted from various cancer cell types differentiate into CAFs or a microenvironmentally controlled model for investigating cancer cell invasion by CAFs have not yet been studied. In this study, we propose a three-dimensional in vitro cancer cell invasion model for real-time monitoring of the process of forming a cancer invasion site through CAFs induced by exosomes isolated from three types of cancer cell lines. The invasiveness of cancer cells with CAFs induced by cancer cell-derived exosomes (eCAFs) was significantly higher than that of CAFs induced by cancer cells (cCAFs) through physiological and genetic manner. In addition, different genetic tendencies of the invasion process were observed in the process of invading cancer cells according to CAFs. Our 3D microfluidic platform helps to identify specific interactions among multiple factors within the cancer microenvironment and provides a model for cancer drug development.

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