Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy

Roy, Sohini; Bag, Arup K.; Singh, Rakesh K.; Talmadge, James E.; Batra, Surinder K.; Datta, Kaustubh

doi:10.3389/fimmu.2017.01228

Cited by 176 publications

(215 citation statements)

References 281 publications

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“…NRP1 is expressed in a wide range of non‐tumor cells that may be present in a tumor, including endothelial cells, fibroblasts, and bone marrow‐derived macrophages and immune cells ; moreover, tumor cells may also express NRP1 . The potential prognostic effect of NRP1 expression in cancer has, however, remained unclear.…”

Section: Discussionmentioning

confidence: 99%

VEGF receptor‐2/neuropilin 1 trans‐complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival

Morin

Sjöberg

Tjomsland

et al. 2018

The Journal of Pathology

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Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro‐angiogenic vascular endothelial growth factor (VEGF) receptor‐2 (VEGFR2) is modulated by VEGFA‐dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans‐complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans‐complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans‐complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans‐complex formation is an independent predictor of PDAC patient survival. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

VEGF receptor‐2/neuropilin 1 trans‐complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival

Morin

Sjöberg

Tjomsland

et al. 2018

The Journal of Pathology

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“…Since SEMA3s compete with VEGF for NRP binding, treatment with SEMA3s may enhance anti-tumor activity by impairing Treg infiltration induced by VEGF. However, the functions of NRP2 in immune systems are poorly understood ( Roy et al, 2017 ; Schellenburg et al, 2017 ). Further studies are needed to identify the effect of SEMA3F as an immune modulator.…”

Section: Introductionmentioning

confidence: 99%

Semaphorin 3F and Netrin-1: The Novel Function as a Regulator of Tumor Microenvironment

et al. 2018

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Axon guidance molecules play an important role in regulating proper neuronal networking during neuronal development. They also have non-neuronal properties, which include angiogenesis, inflammation, and tumor development. Semaphorin 3F (SEMA3F), a member of the class 3 semaphorins, was initially identified as an axon guidance factor, that repels axons and collapses growth cones. However, SEMA3F has similar effects on endothelial cells (ECs) and tumor cells. In this review, we discuss the novel molecular mechanisms underlying SEMA3F activity in vascular and tumor biology. Recent evidence suggests that SEMA3F functions as a PI3K-Akt-mTOR inhibitor in mammalian cells, including T cells, ECs, and tumor cells. Therefore, SEMA3F may have broad therapeutic implications. We also discuss the key role of axon guidance molecules as regulators of the tumor microenvironment. Netrin-1, a chemoattractant factor in the neuronal system, promotes tumor progression by enhancing angiogenesis and metastasis. Moreover, our recent studies demonstrate that netrin-1/neogenin interactions augment CD4+ T cell chemokinesis and elicit pro-inflammatory responses, suggesting that netrin-1 plays a key role in modulating the function of a tumor and its surrounding cells in the tumor microenvironment. Overall, this review focuses on SEMA3F and netrin-1 signaling mechanisms to understand the diverse biological functions of axon guidance molecules.

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“…Recent studies have shown that aberrant expression of axonal guidance cue molecules such as semaphorins in cancer, and their dysregulated signaling plays a significant role in cancer angiogenesis and metastasis [ 4 – 9 ]. Several studies have demonstrated the expression and role of subclass-5 member Semaphorin-5A (SEMA5A) in various malignancies including glioma, lung, prostate, pancreas, melanoma and gastric [ 10 – 23 ]. SEMA5A has not been associated with a univocal role in cancer [ 17 ], as it acts as a tumor promoter in cancers like gastric [ 14 – 16 ], prostate [ 20 ] and, ovary [ 23 ] while it acts as a tumor suppressor in glioma [ 11 , 12 ] and lung cancer [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Pathological and functional significance of Semaphorin-5A in pancreatic cancer progression and metastasis

Saxena

Hayashi

et al. 2017

Oncotarget

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Semaphorin-5A (SEMA5A) has differential cell surface expression between normal and cancer cells and represents an attractive target for therapeutic intervention in pancreatic cancer (PC). In this study, we delineated the pathological expression and significance of SEMA5A during PC progression and metastasis. We utilized human tissue microarrays and different PC mouse models (Pdx1-cre; LSL- Kras(G12D), Pdx1-Cre; LSL-Kras(G12D); LSL-p53(R172H) and RIP1-Tag2) to analyze SEMA5A expression during PC progression. Using human patients and different mouse models, we demonstrated that SEMA5A expression was highest in liver metastases, followed by primary pancreatic tumors, and the lowest expression was found in the normal pancreas. SEMA5A expression was localized on tumor cells with no staining in the surrounding stroma. To understand the functional significance of SEMA5A, we treated PC cell lines with recombinant SEMA5A. We observed an increase in migration, chemotaxis, and scattering of PC cells. To delineate the signaling axis of SEMA5A, we generated SEMA5A receptor-Plexin-B3 knockdown in T3M-4 and CD18/HPAF PC cell lines and observed that the effect of SEMA5A treatment was absent in the Plexin-B3 knockdown counterparts of T3M-4 and CD18/HPAF cells. SEMA5A treatment leads to phosphorylation of cMET in Plexin-B3 dependent manner. Our data demonstrate that there is an increase in SEMA5A expression during PC progression and the elevation of this expression takes place at metastatic sites especially the liver in both exocrine and endocrine tumors. SEMA5A can elicit a migratory response in cells by activating cMET through the Plexin-B3 receptor. In conclusion, SEMA5A signaling represents a potential molecule for targeting metastasis in pancreatic cancer.

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Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy

Cited by 176 publications

References 281 publications

VEGF receptor‐2/neuropilin 1 trans‐complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival

VEGF receptor‐2/neuropilin 1 trans‐complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival

Semaphorin 3F and Netrin-1: The Novel Function as a Regulator of Tumor Microenvironment

Pathological and functional significance of Semaphorin-5A in pancreatic cancer progression and metastasis

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