Macrophage-Derived Neuropilin-2 Exhibits Novel Tumor-Promoting Functions

Roy, Sohini; Bag, Arup K.; Dutta, Samikshan; Polavaram, Navatha S.; Islam, Ridwan; Schellenburg, Samuel; Banwait, Jasjit K.; Guda, Chittibabu; Ran, Sophia; Hollingsworth, Michael A.; Singh, Rakesh K.; Talmadge, James E.; Muders, Michael H.; Batra, Surinder K.; Datta, Kaustubh

doi:10.1158/0008-5472.can-18-0562

Cited by 63 publications

(90 citation statements)

References 55 publications

(67 reference statements)

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“…This same cluster also had upregulated SIGLEC1 , which can serve as an independent predictor of poor prognosis [( 14 , 43 ), Supp.]. A separate TAM cluster in the same study was enriched in PPARG and NRP2 , indicating distinct functional properties as a potential suppressor of T-cell activity through NRP2 ( 43 , 119 ). Azizi et al ( 43 ) further validated the individuality of the clusters and rejected the null hypothesis of unimodality across components that explain their variation.…”

Section: Tam/mdsc Identification Across Tumor Typesmentioning

confidence: 89%

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

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Tumor-mediated regulation of the host immune system involves an intricate signaling network that results in the tumor's inherent survival benefit. Myeloid cells are central in orchestrating the mechanisms by which tumors escape immune detection and continue their proliferative programming. Myeloid cell activation has historically been classified using a dichotomous system of classical (M1-like) and alternative (M2-like) states, defining general pro- and anti-inflammatory functions, respectively. Explosions in bioinformatics analyses have rapidly expanded the definitions of myeloid cell pro- and anti-inflammatory states with different combinations of tissue- and disease-specific phenotypic and functional markers. These new definitions have allowed researchers to target specific subsets of disease-propagating myeloid cells in order to modify or arrest the natural progression of the associated disease, especially in the context of tumor-immune interactions. Here, we discuss the myeloid cell contribution to solid tumor initiation and maintenance, and strategies to reprogram their phenotypic and functional fate, thereby disabling the network that benefits tumor survival.

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Section: Tam/mdsc Identification Across Tumor Typesmentioning

confidence: 89%

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

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“…NRP2 expression increases during the differentiation of monocytes to macrophages (Schellenburg et al, 2017) next to inflammatory zones to induce phagocytosis. NRP2 sialylation reduces phagocytosis capacity of the macrophages (Stamatos et al, 2014;Roy et al, 2018), thus NRP2+ M2 macrophages promote tumor progression (Niland and Eble, 2019).…”

Section: Macrophagesmentioning

confidence: 99%

Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment

Dumond

Pagès

2020

Front. Cell Dev. Biol.

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Angiogenesis is one of the key mechanisms involved in tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors (VEGFR) represent one of the major signaling pathways which mediates angiogenesis. The VEGF/VEGFR axis was intensively targeted by monoclonal antibodies or by tyrosine kinase inhibitors to destroy the tumor vascular network. By inhibiting oxygen and nutrient supply, this strategy was supposed to cure cancers. However, despite a lengthening of the progression free survival in several types of tumors including colon, lung, breast, kidney, and ovarian cancers, modest improvements in overall survival were reported. Anti-angiogenic therapies targeting VEGF/VEGFR are still used in colon and ovarian cancer and remain reference treatments for renal cell carcinoma. Although the concept of inhibiting angiogenesis remains relevant, new targets need to be discovered to improve the therapeutic index of anti-VEGF/VEGFR. Neuropilin 1 and 2 (NRP1/2), initially described as neuronal receptors, stimulate angiogenesis, lymphangiogenesis and immune tolerance. Moreover, overexpression of NRPs in several tumors is synonymous of patients' shorter survival. This article aims to overview the different roles of NRPs in cells constituting the tumor microenvironment to highlight the therapeutic relevance of their targeting.

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“…This hypothesis is further strengthened by a study that showed NRP2 expression during macrophage differentiation, which is induced by tumor cells and regulates phagocytosis in macrophages. Furthermore, NRP2 promoted efferocytosis of apoptotic tumor cell debris by TAMs and facilitated tumor growth [86]. However, it is not clear whether those miR-protein complexes are non-selectively released after cell necrosis or whether they are exported in a regulated fashion.…”

Section: Rna-binding Protein-mediated Mir Transfermentioning

confidence: 99%

MicroRNA—A Tumor Trojan Horse for Tumor-Associated Macrophages

Syed

Frank

Raue

et al. 2019

Cells

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MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal gene regulation in the tumor microenvironment (TME). In the TME, both tumor and stroma cells cross-communicate via diverse factors including miRs, which are taking central stage as a therapeutic target of anti-tumor therapy. One of the immune escape strategies adopted by tumor cells is to release miRs as a Trojan horse to hijack circulating or tumor-localized monocytes/macrophages to tune them for pro-tumoral functions. On the other hand, macrophage-derived miRs exert anti-tumor functions. The transfer of miRs from host to recipient cells depends on the supramolecular structure and composition of miR carriers, which determine the distinct uptake mechanism by recipient cells. In this review, we provide a recent update on the miR-mediated crosstalk between tumor cells and macrophages and their mode of uptake in the TME.(TNF-α), and provoke the secretion of pro-inflammatory cytokines including interleukin-1 (IL-1), IL-6, IL-12, IL-23, and TNF-α and reactive nitrogen and oxygen intermediates (RNI, ROI) [5]. In contrast, anti-inflammatory stimuli such as IL-4, IL-13, IL-10, and glucocorticoid or immune complexes (IC) plus LPS induce macrophages to an M2 phenotype. This type is characterized by a decreased production of pro-inflammatory cytokines, increased production of anti-inflammatory cytokines (e.g., IL-10), and factors that mediate immunosuppression and tissue remodeling. M2 macrophages have been divided into further subgroups. The M2a type is generated in response to IL-3 and IL-13, while M2b macrophages respond to immune complexes and Toll-like receptor (TLR) activation. M2c macrophages represent deactivated macrophages that suppress pro-inflammatory cytokines, while the M2d type represents a regulatory macrophage [6] that is often grouped with TAMs [5,7,8]. In line with these varied responses, Janus-faced macrophage functions are largely determined by their microenvironment rather than their genetic imprint [9,10]. In tumors and during the resolution of inflammation, hijacked macrophages attain pro-tumor or wound healing phenotypes due to tumor-derived factors [11], which emerge as a target for tumor therapy [12,13]. TAMs expressing classical activation markers produce pro-inflammatory cytokines and reactive oxygen species (ROS) and, thus, are crucial for tumor cell killing [14,15]. The high degree of plasticity demonstrated by macrophages in pathological conditions can be attributed to a) dynamic regulation of gene expression and b) rapid activation of signaling cascades that determine their effector functions. Signaling cascades triggered by local environmental cues and controlling the transcriptional machinery, ultimately determine the effector functions of macrophages in the tumor microenvironment (TME). Hence, understanding and modulating these ...

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Macrophage-Derived Neuropilin-2 Exhibits Novel Tumor-Promoting Functions

Cited by 63 publications

References 55 publications

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment

MicroRNA—A Tumor Trojan Horse for Tumor-Associated Macrophages

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