Met Kinetic Signature Derived from the Response to HGF/SF in a Cellular Model Predicts Breast Cancer Patient Survival

Stein, Gideon Y.; Yosef, Nir; Reichman, Hadar; Horev, Judith; Laser-Azogui, Adi; Berens, Angelique; Resau, James H.; Ruppin, Eytan; Sharan, Roded; Tsarfaty, Ilan

doi:10.1371/journal.pone.0045969

Cited by 6 publications

(5 citation statements)

References 70 publications

(61 reference statements)

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“…Our results suggest that brain metastatic cells are capable of triggering a phenotypic switch from normal astrocytes to TAAs through IL1β-mediated NF-κB pathway. It is probable that astrocytes exert its anti-tumoral activity at an early stage of metastatic growth as described previously (16). However, at the later stage, they may be transformed to TAAs thorough reciprocal interaction with tumor cells, and this reprogramed TAA gains the ability to support the metastatic growth as we found in this study.…”

Section: Discussionmentioning

confidence: 53%

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Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer

et al. 2016

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Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remains poorly understood. Here we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL-8 and CXCL1. Additionally, stimulation of IL1β secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle which generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood-brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention.

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Section: Discussionmentioning

confidence: 53%

“…(15) We also expanded the TKR signature genes that were not available from the previous two data sets and these include FGF (GSE17916), TrkA (GSE18409), Axl (GSE30543), EphB2 (GSE66361), Ret (GSE41405) and c-Met (E-MTAB-762) pathways (16). The complete list of signatures is shown in Table S1.…”

Section: Methodsmentioning

confidence: 99%

Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer

et al. 2016

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“…Upregulation of mesenchymal biomarkers and Met activation have both been associated separately with prognosis in several tumor types (6,(31)(32)(33) and coexistence of both markers with stemness (34). One could hypothesize that the presence of a subset of cells with these markers in SCLC at diagnosis could predict the enrichment of this chemoresistant population at progression after chemotherapy and, therefore, explain the poor prognosis of these patients in our study.…”

Section: Discussionmentioning

confidence: 54%

Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Cañadas

Rojo

Taus

et al. 2014

Clinical Cancer Research

117

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Purpose: Met receptor phosphorylation is associated with poor prognosis in human small cell lung cancer (SCLC). The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/ Met-mediated epithelial-to-mesenchymal transition (EMT) in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models.Experimental Design: SCLC models of HGF-induced EMT were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice) for chemosensitivity and response to Met inhibition with PF-2341066 (crizotinib). Human SCLC samples at diagnosis (N ¼ 87) and relapse (N ¼ 5) were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and these were correlated with patient outcome.Results: We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype, and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival, and were upregulated in chemorefractory disease.Conclusion: These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease. Clin Cancer Res; 20(4); 938-50. Ó2013 AACR.

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“…One study reveals that a specific c-Met tyrosine kinase activation pathway correlates with high risk patients who will go on to develop an aggressive form of the disease; this also suggests that the determination of this c-Met activation signature pathway may be used as a clinical tool to identify and predict patient response for future personalised anti-Met therapies [ 48 ]. The use of such clinical tools will play a key role in the management of breast cancer and may be used in the process of stratifying patients accordingly.…”

Section: Discussionmentioning

confidence: 99%

Boswellia frereana suppresses HGF-mediated breast cancer cell invasion and migration through inhibition of c-Met signalling

Parr¹,

Alayoud²

2018

J Transl Med

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BackgroundHepatocyte growth factor (HGF) plays a pivotal role in breast cancer cell motility, invasion and angiogenesis. These pro-metastatic events are triggered through HGF coupling and activation of the c-Met receptor. Reports have demonstrated that HGF/c-Met signalling plays an important part in breast cancer progression and that their expression is linked to poor patient outcome. In the present study, we investigated the anti-metastatic potential of an extract from traditional Somalian frankincense, Boswellia frereana, on human breast cancer cells. In addition, we also examined the effect of this Boswellia frereana extract (BFE) upon HGF-mediated stimulation of the c-Met receptor.MethodsTwo triple negative human breast cancer cell lines, BT549 and MDA-MB-231, were utilised in the study to examine the effect of BFE on tumour cell proliferation, migration, matrix-adhesion, angiogenesis and invasion. Cell migration was investigated using a Cell IQ time-lapsed motion analysis system; while tumour cell–matrix adhesion, angiogenesis and invasion were assessed through Matrigel-based in vitro assays. Breast cancer cell growth and spheroid formation was examined through proliferation assay and 3D non-scaffold cell culture techniques. Western Blotting was employed to determine the phosphorylation status of the c-Met receptor tyrosine kinase following BFE treatment and subsequent HGF stimulation.ResultsFollowing HGF treatment, the breast cancer cells displayed a significant increase in migration, matrix adhesion, vessel/tubule formation, invasion and c-Met activation. HGF did not appear to have any bearing on the proliferation rate or spheroid formation of these breast cancer cells. The addition of the BFE extract quenched the HGF-enhanced migratory, angiogenic and invasive potential of these cells. Further study revealed that BFE inhibited c-Met receptor tyrosine kinase phosphorylation within these breast cancer cells.ConclusionsOur findings reveal that BFE was able to significantly suppress the influence of HGF in breast cancer cell motility and invasion in vitro, through the ability of BFE to reduce HGF/c-Met signalling events. Therefore, these results indicate that BFE could play a novel role in the treatment of breast cancer.

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Met Kinetic Signature Derived from the Response to HGF/SF in a Cellular Model Predicts Breast Cancer Patient Survival

Cited by 6 publications

References 70 publications

Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer

Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer

Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Boswellia frereana suppresses HGF-mediated breast cancer cell invasion and migration through inhibition of c-Met signalling

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