Neuropilin-1 modulates TGFβ signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy

Kwiatkowski, Sam C.; Guerrero, Paola A.; Hirota, Shinya; Chen, Zhihua; Morales, John E.; Aghi, Manish K.; McCarty, Joseph H.

doi:10.1371/journal.pone.0185065

Cited by 37 publications

(42 citation statements)

References 52 publications

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“…In tumor cells, NRP1 expression is upregulated along with GBM tumor progression. Additionally, NRP1 can bind with TGFβRII to activate Smad3 signaling to drive GBM development and the TGF-β/Smad3 signaling is NRP1-dependent during the process (16). In the central nervous system, NRP1 can balance integrin β8-activated TGF-β signaling to control sprouting angiogenesis (42).…”

Section: Discussionmentioning

confidence: 99%

“…3C). Previous studies have reported that NRP1, as a co-receptor of TGF-β1, can modulate the TGF-β signaling pathway in various cell types (16,21). In addition, from the public database LinkedOmics (http://www.linkedomics.…”

Section: High Expression Of Nrp1 Promotes Nsclc Metastasis In Vivo Anmentioning

confidence: 99%

“…Recently, one study demonstrated that neuropilin-1 (NRP1) acts as a TGF-β1 co-receptor and activates latent TGF-β1 in breast cancer (15). Consistently, Kwiatkowski et al reported that NRP1 acts as a co-receptor with TGFβRII to enhance TGF-β1 receptor signaling via Smad3 in glioblastoma (16). Thus, the association between NRP1 and TGF-β signaling pathways in NSCLC remains to be verified.…”

Section: Introductionmentioning

confidence: 97%

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Neuropilin 1 modulates TGF‑β1‑induced epithelial‑mesenchymal transition in non‑small cell lung cancer

Ding

et al. 2019

Int J Oncol

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Previously, the authors reported that neuropilin-1 (NRP1) was significantly increased and acted as a vital promoter in the metastasis of non-small cell lung cancer (NSCLC). However, the regulatory mechanism of NRP1 in NSCLC cell migration and invasion remained unclear. The present study aimed to explore the regulatory mechanism of NRP1 in the transforming growth factor-β (TGF-β) 1-induced migration and invasion of NSCLC cells. The expression level of NRP1 was determined by RT-qPCR analysis in human tissue samples with or without lymph node metastasis. Transwell assay and wound healing assay were conducted to determine the cell migration. Lentivirus-mediated stable knockdown and overexpression of NRP1 cell lines were constructed. Exogenous TGF-β1 stimulation, SIS3 treatment, western blot analysis and in vivo metastatic model were utilized to clarify the underlying regulatory mechanisms. The results demonstrated that the expression of NRP1 was increased in metastatic NSCLC tissues. NRP1 promoted NSCLC metastasis in vitro and in vivo. The Transwell assays, wound healing assays and western blot analysis revealed that the knockdown of NRP1 significantly inhibited TGF-β1-mediated EMT and migratory and invasive capabilities of NSCLC. Furthermore, the overexpression of NRP1 weakened the inhibitory effect of SIS3 on the NSCLC migration and invasion. Co-IP assay revealed that NRP1 interacted with TGFβRII to induce EMT. On the whole, the findings of this study demonstrated that NRP1 was overexpressed in metastatic NSCLC tissues. NRP1 could contributes to TGF-β1-induced EMT and metastasis in NSCLC by binding with TGFβRII.

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Section: Discussionmentioning

confidence: 99%

Section: High Expression Of Nrp1 Promotes Nsclc Metastasis In Vivo Anmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Neuropilin 1 modulates TGF‑β1‑induced epithelial‑mesenchymal transition in non‑small cell lung cancer

Ding

et al. 2019

Int J Oncol

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“…Several previous studies have shown the contribution of different molecules in conferring drug resistance. The transmembrane receptor, neuropilin‐1 (NRP‐1) mediates angiogenesis through VEGF‐A and enhances TGF‐β1 signalling via Smad and hence promotes resistance to anti‐angiogenic agents (Kwiatkowski et al, ). Previously, we reported a significant increase in NRP‐1 levels in the basal subtype of breast cancer, compared with other subtypes (Naik et al, ).…”

Section: Introductionmentioning

confidence: 99%

Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP‐1 and HER2 expression and converted MCF7 breast cancer subtype

Al-Zeheimi

Adham

2020

British J Pharmacology

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Background and Purpose: Patients with locally advanced breast cancer usually receive third-generation neoadjuvant chemotherapy (NAC). Although NAC treatment improved the overall survival, patients' response varies, some acquire resistance and others exhibit a conversion in their breast cancer molecular subtype. We aimed to identify the molecular changes involved in NAC resistance attempting to find new therapeutic targets in different breast cancer subtypes. Experimental Approach: We modelled NAC treatments used in clinical practice and generated resistant cell lines in vitro. The resistant cells were generated by consecutive treatment with four cycles of doxorubicin (adriamycin)/cyclophosphamide (4xAC) followed by an additional four cycles of paclitaxel (4xAC + 4xPAC). Key Results: Our data revealed distinct mechanisms of resistance depending on breast cancer subtype and drugs used. MDA-MB-231 cells resistant to 4xAC + 4xPAC activated neuropilin-1/TNC/integrin β3/FAK/NF-κB p65 axis and displayed a decrease in breast cancer resistance protein (BCRP/ABCB2). However, MCF7 cells resistant to 4xAC treatments induced HER2 expression, which converted MCF7 subtype from luminal A to luminal B HER2 type, up-regulated neuropilin-1, oestrogen receptor-α, and EGFR, and activated PI3K/Akt/NF-κB p65 axis. However, MCF7 cells resistant to 4xAC + 4xPAC exhibited down-regulation of the survival axis and up-regulated BCRP/ABCG2. Co-immunoprecipitation demonstrated a novel interaction between HER2 and neuropilin-1 driving the resistance features.Conclusions and Implications: The concurrent increase in neuropilin-1 and HER2 upon resistance and the inverse relationship between neuropilin-1 and BCRP/ABCG2 suggest that, in addition to HER2, neuropilin-1 status should be assessed in patients undergoing NAC, and as a potential drug target for refractory breast cancer.

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“…Kwiatkowski and his colleagues showed that NRP1 acts as a co-receptor with TGFβR2 to enhance TGF-β1 receptor signaling via Smad3 in Glioblastoma [16]. Thus, the relationship between NRP1 and TGF-β signaling pathways in NSCLC requires to be verified.…”

Section: Introductionmentioning

confidence: 99%

Neuropilin 1 modulates TGF-β1-induced epithelial–mesenchymal transition in non-small cell lung cancer

Ding

et al. 2019

Preprint

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Background: TGF-β1 signaling is a potent inducer of epithelial-mesenchymal transition (EMT) in various cancers. Our previous study has indicated that NRP1 was significantly up-regulated and acted as a vital promoter in the metastasis of non-small cell lung cancer (NSCLC). However, the function of NRP1 in regulation of TGF-β1-induced EMT and NSCLC cell migration and invasion remained unclear. Methods: The differential expression level of NRP1 was determined by RT-PCR analysis in human tissue samples with or without lymph node metastasis. Transwell assay and wound healing assay were conducted to determine cell ability of migration. Lentivirus-mediated stable knockdown and overexpression of NRP1 cell lines were constructed. Exogenous TGF-β1 stimulation, SIS3 treatment, western blot analysis and in vivo metastatic model were utilized to clarify the underlying regulatory mechanism. Results: Increased expression of NRP1 was found in metastatic NSCLC tissues and can promote NSCLC metastasis in vivo. Transwell assays, wound healing assay and western blot analysis showed that knockdown of NRP1 significantly inhibited TGF-β1-mediated EMT and migratory and invasive capabilities of A549 and H226 cells. Furthermore, overexpression of NRP1 could weak the decreased migratory and invasive capabilities with SIS3 treatment. Co-IP data showed that NRP1 can interact with TGFβRⅡ to induce EMT. Conclusion: This is the first time to report that NRP1 can modulate TGF-β1-induced EMT and cell migration and invasion in NSCLC.

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Neuropilin-1 modulates TGFβ signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy

Cited by 37 publications

References 52 publications

Neuropilin 1 modulates TGF‑β1‑induced epithelial‑mesenchymal transition in non‑small cell lung cancer

Neuropilin 1 modulates TGF‑β1‑induced epithelial‑mesenchymal transition in non‑small cell lung cancer

Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP‐1 and HER2 expression and converted MCF7 breast cancer subtype

Neuropilin 1 modulates TGF-β1-induced epithelial–mesenchymal transition in non-small cell lung cancer

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