Breast cancer cells secreted platelet‐derived growth factor‐induced motility of vascular smooth muscle cells is mediated through neuropilin‐1

Banerjee, Snigdha; Sengupta, Krishanu; Dhar, Kakali; Mehta, Smita; D'Amore, Patricia A.; Dhar, Gopal; Banerjee, Sushanta K.

doi:10.1002/mc.20248

Cited by 84 publications

(94 citation statements)

References 58 publications

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“…The phenotype was ascribed largely to EC-specific perturbation of VEGF signaling, since NRP-1 promotes VEGF signal transduction (16,29,41). However, recent studies suggesting that NRP-1 Ab could attenuate pericyte recruitment to tumors provided preliminary evidence that vascular wall cells other than ECs may also be a target for the actions of NRP-1 (18,42). Thus, the present work is timely, since it highlights the sinusoidal HSC as an important target of NRP-1 in liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells

et al. 2010

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PDGF-dependent hepatic stellate cell (HSC) recruitment is an essential step in liver fibrosis and the sinusoidal vascular changes that accompany this process. However, the mechanisms that regulate PDGF signaling remain incompletely defined. Here, we found that in two rat models of liver fibrosis, the axonal guidance molecule neuropilin-1 (NRP-1) was upregulated in activated HSCs, which exhibit the highly motile myofibroblast phenotype. Additionally, NRP-1 colocalized with PDGF-receptor β (PDGFRβ) in HSCs both in the injury models and in human and rat HSC cell lines. In human HSCs, siRNA-mediated knockdown of NRP-1 attenuated PDGF-induced chemotaxis, while NRP-1 overexpression increased cell motility and TGF-β-dependent collagen production. Similarly, mouse HSCs genetically modified to lack NRP-1 displayed reduced motility in response to PDGF treatment. Immunoprecipitation and biochemical binding studies revealed that NRP-1 increased PDGF binding affinity for PDGFRβ-expressing cells and promoted downstream signaling. An NRP-1 neutralizing Ab ameliorated recruitment of HSCs, blocked liver fibrosis in a rat model of liver injury, and also attenuated VEGF responses in cultured liver endothelial cells. In addition, NRP-1 overexpression was observed in human specimens of liver cirrhosis caused by both hepatitis C and steatohepatitis. These studies reveal a role for NRP-1 as a modulator of multiple growth factor targets that regulate liver fibrosis and the vascular changes that accompany it and may have broad implications for liver cirrhosis and myofibroblast biology in a variety of other organ systems and disease conditions.

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Section: Discussionmentioning

confidence: 99%

Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells

et al. 2010

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“…The Western blot analysis was performed according to the previous method (23). Signals were detected with SuperSignal Chemiluminescent Substrate (Pierce) by using ID Image Analysis Software version 3.6 (Eastman Kodak Co.).…”

Section: Methodsmentioning

confidence: 99%

CCN5/WISP-2 Expression in Breast Adenocarcinoma Is Associated with Less Frequent Progression of the Disease and Suppresses the Invasive Phenotypes of Tumor Cells

et al. 2008

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Although previous in vitro studies predicted that CCN5/ WISP-2 may act as an anti-invasive gene in breast cancer, the distribution pattern of CCN5 in breast cancer samples is conflicting. Thus, we systematically investigated the CCN5 expression profile in noninvasive and invasive breast tumor samples and its functional relevance in breast cancer progression. The studies showed that CCN5 expression is biphasic, such that in normal samples CCN5 expression is undetectable, whereas its expression is markedly increased in noninvasive breast lesions, including atypical ductal hyperplasia and ductal carcinoma in situ. Further, CCN5 mRNA and protein levels are significantly reduced as the cancer progresses from a noninvasive to invasive type. Additionally, we showed that CCN5 mRNA and protein level was almost undetectable in poorly differentiated cancers compared with the moderately or well-differentiated samples and its expression inversely correlated with lymph node positivity. The result was further supported by evaluating the RNA expression profile in microdissected sections using real-time PCR analysis. Therefore, our data suggest a protective function of CCN5 in noninvasive breast tumor cells. This hypothesis was further supported by our in vitro studies illuminating that CCN5 is a negative regulator of migration and invasion of breast cancer cells, and these events could be regulated by CCN5 through the modulation of the expression of genes essential for an invasive front. These include Snail-E-cadherin signaling and matrix metalloproteinase (MMP)-9 and MMP-2. Collectively, these studies suggest that the protective effect of CCN5 in breast cancer progression may have important therapeutic implications. [Cancer Res 2008;68(18):7606-12]

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“…Transwell migration assays were performed as described earlier (31). Briefly, MCF-7 cells (20,000 per well) were seeded on 8-Am pore transwell filter insert (Becton Dickinson) coated with fibronectin (10 Ag/mL).…”

Section: Methodsmentioning

confidence: 99%

Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

et al. 2008

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CCN5/WISP-2 is overexpressed in noninvasive breast cancer cells and tissue samples, whereas its expression is minimal or undetected in invasive conditions. CCN5/WISP-2 has been considered as an antiinvasive gene because CCN5/WISP-2 silencing augments the invasive phenotypes in vitro. However, the mechanism of silencing of CCN5 during the progression of the disease has been elusive. Because p53 mutations are associated with breast cancer progression and have been shown to correlate inversely with CCN5/WISP-2 expression in other cancer cell types, the objective of this study was to explore whether p53 mutants suppress CCN5 expression in breast tumor cells resulting in the progression of this disease. We found CCN5 expression is inversely correlated with the mutational activation of p53 in human breast tumor cells. The ectopic expression of p53 mutants in ER-positive noninvasive breast tumor cells silenced the CCN5/WISP-2 expression and enhanced invasive phenotypes, including the induction of morphologic changes from the epithelial-to-mesenchymal type along with the alterations of hallmark proteins of these cell types and an augmentation of the migration of these cells. The suppression of CCN5 by the p53 mutants can be nullified by estrogen signaling in these cells through the transcriptional activation of the CCN5 gene. Moreover, the invasive changes can be imitated by blocking the CCN5/WISP-2 expression through RNA interference or can be reversed by the addition of CCN5/WISP-2 recombinant protein in the culture. Thus, these studies suggest that CCN5 inactivation could be an essential molecular event for p53 mutant-induced invasive phenotypes. [Cancer Res 2008;68(12):4580-7]

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Breast cancer cells secreted platelet‐derived growth factor‐induced motility of vascular smooth muscle cells is mediated through neuropilin‐1

Cited by 84 publications

References 58 publications

Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells

Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells

CCN5/WISP-2 Expression in Breast Adenocarcinoma Is Associated with Less Frequent Progression of the Disease and Suppresses the Invasive Phenotypes of Tumor Cells

Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

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