Neuropilin‐1 expression by tumor cells promotes tumor angiogenesis and progression

Miao, Hua‐Quan; Lee, Percy; Lin, Hank; Söker, Shay; Klagsbrun, Michael

doi:10.1096/fj.00-0250com

Cited by 279 publications

(268 citation statements)

References 48 publications

Supporting

Mentioning

250

Contrasting

Unclassified

Order By: Relevance

“…Whether the protumorigenic effect of combined HH‐IL6 signaling is directly mediated by the HH‐IL6 targets EDN2, PLAT and NRP1 requires further functional studies. In this context, it is noteworthy that PLAT and NRP1 play a well‐documented role in angiogenesis, in line with previous reports about a putative angiogenic function of IL6 in BCC 45, 46, 47. However, as we did not detect a decrease in CD31 + endothelial cells in Il6ra‐deficient mouse BCC (data not shown), it appears rather unlikely that HH‐IL6 signal integration drives BCC growth by supporting tumor angiogenesis.…”

Section: Discussionsupporting

confidence: 90%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin‐6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis‐regulatory sequences by co‐binding of GLI and STAT3 to common HH‐IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI‐driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH‐IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

show abstract

Section: Discussionsupporting

confidence: 90%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…In a prostate cancer model, transfection of NRP-1 increased VEGF 165 binding, basal cell motility, and tumour size in vivo (Miao et al, 2000), suggesting that the receptor functions in a VEGF-dependent fashion to enhance tumorigenicity. However, the survival effects demonstrated in our study occurred in two cell lines that do not express VEGFR-2, although they do express VEGFR-1.…”

Section: Discussionmentioning

confidence: 96%

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

et al. 2005

View full text Add to dashboard Cite

Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by 430% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing 450% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy.

show abstract

“…In addition to its role as a Sema3A receptor, neuropilin-1 is a co-receptor for a specific isoform of VEGF165 and guides endothelial cell migration during vascular morphogenesis (Soker et al, 1998;Lee et al, 2002). The role of neuropilin-1 in tumors has been mostly studied in the context of its interaction with VEGF165 and related to tumor angiogenesis and tumor cell survival (Miao et al, 2000;Bachelder et al, 2001). A recent study suggested that neuropilin-1 contributes to tumor progression by potentiating the activity of hepatocyte growth factor as well (Hu et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

et al. 2009

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is the most malignant glioma type with diffuse borders due to extensive tumor cell infiltration. Therefore, understanding the mechanism of GBM cell dispersal is critical for developing effective therapies to limit infiltration. We identified neuropilin-1 as a mediator of cancer cell invasion by a functional proteomic screen and showed its role in GBM cells. Neuropilin-1 is a receptor for semaphorin3A (Sema3A), a secreted chemorepellent that facilitates axon guidance during neural development. Although neuropilin-1 expression in GBMs was previously shown, its role as a Sema3A receptor remained elusive. Using fluorophore-assisted light inactivation and RNA interference , we showed that neuropilin-1 is required for GBM cell migration. We also showed that GBM cells secrete Sema3A endogenously, and RNA interferencemediated downregulation of Sema3A inhibits migration and alters cell morphology that is dependent on Rac1 activity. Sema3A depletion also reduces dispersal, which is recovered by supplying Sema3A exogenously. Extracellular application of Sema3A decreases cell-substrate adhesion in a neuropilin-1-dependent manner. Using immunohistochemistry, we showed that Sema3A is overexpressed in a subset of human GBMs compared with the non-neoplastic brain. Together, these findings implicate Sema3A as an autocrine signal for neuropilin-1 to promote GBM dispersal by modulating substrate adhesion and suggest that targeting Sema3A-neuropilin-1 signaling may limit GBM infiltration.

show abstract

Neuropilin‐1 expression by tumor cells promotes tumor angiogenesis and progression

Cited by 279 publications

References 48 publications

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

Contact Info

Product

Resources

About