Targeting Neuropilin-1 Interactions is a Promising Anti-Tumor Strategy
Neuropilins (NRPs), specifically NRP1 and NRP2, are multifunctional receptor proteins that play crucial roles in various physiological and pathological processes, including nerve development, angiogenesis, and tumor progression. Initially identified as neuronal proteins, NRPs have since been found to be expressed on the surface of endothelial and immune cells, making them key players in cancer biology. This article provides a comprehensive overview of the role of NRP1 in tumorigenesis, progression, and treatment, highlighting its potential as a therapeutic target in cancer therapy.
Structure, Expression, and Function of NRP1
NRP1 was first discovered in 1987 as an antigen of a monoclonal antibody bound to neuronal cell surface proteins in the Xenopus nervous system. The NRP1 gene, located on human chromosome 10q12, spans 112 kb and contains 17 exons and 16 introns. The NRP1 protein consists of an intracellular domain, a transmembrane domain, and an extracellular domain. The extracellular domain is divided into five subdomains (a1, a2, b1, b2, and c), each associated with different molecular and cellular interactions.
NRP1 is expressed in various cell types, including neurons, endothelial cells, immune cells, osteoblasts, and hepatic stellate cells. It is also highly expressed in many tumor cells, such as those in leukemia, melanoma, glioma, lung cancer, and gastric cancer. The expression of NRP1 in these cells is often associated with poor prognosis, making it a critical factor in cancer progression.
NRP1 functions as a co-receptor for multiple ligands, including class 3 semaphorins (Sema3A) and vascular endothelial growth factor (VEGF). It forms complexes with VEGF and its receptor (VEGFR) to promote angiogenesis, a process essential for tumor growth and metastasis. Additionally, NRP1 interacts with other growth factors, such as transforming growth factor-beta (TGF-β) and hepatocyte growth factor (HGF), to influence cell migration, survival, and proliferation.
NRP1 in Tumor Angiogenesis
Angiogenesis, the formation of new blood vessels from pre-existing ones, is a hallmark of cancer. NRP1 plays a pivotal role in this process by forming complexes with VEGF and VEGFR2. The interaction between NRP1 and VEGF enhances the activation of VEGFR2, leading to increased angiogenesis. This is particularly evident in tumors, where the overexpression of NRP1 correlates with increased vascularization and tumor growth.
In addition to VEGF, NRP1 interacts with other pro-angiogenic factors, such as fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF). These interactions further contribute to the recruitment of perivascular cells and the stabilization of newly formed blood vessels. Genetic studies have shown that NRP1 deficiency leads to defects in vascular morphogenesis, underscoring its importance in angiogenesis.
NRP1 in Tumor Proliferation and Migration
Beyond its role in angiogenesis, NRP1 is also involved in tumor cell proliferation and migration. The binding of VEGF to NRP1 activates the RhoA signaling pathway, which promotes the degradation of the cell cycle inhibitor p27kip1, leading to increased cell proliferation. This mechanism has been observed in various cancers, including skin cancer, prostate cancer, and glioblastoma.
NRP1 also interacts with PDGF and its receptor (PDGFR) to stimulate tumor growth. The phosphorylation of PDGFR by NRP1 enhances cell migration and invasion, contributing to tumor metastasis. Furthermore, NRP1 promotes endothelial cell migration through the NRP1-ABL1 pathway, which has been implicated in non-small cell lung cancer and breast cancer.
NRP1 in Tumor Immunity
NRP1 is widely expressed in immune cells, including dendritic cells (DCs) and regulatory T cells (Tregs). In the tumor microenvironment (TME), NRP1+ Tregs play a significant role in suppressing anti-tumor immunity. These Tregs inhibit the activity of CD4+ and CD8+ T cells, leading to immune escape and tumor progression.
The interaction between NRP1 and Semaphorin-4a (Sema4a) on Tregs enhances their function and survival, further suppressing the immune response. In mouse models, the knockout of NRP1 in Tregs has been shown to reduce tumor growth, highlighting the importance of NRP1 in immune regulation.
NRP1 is also involved in the function of tumor-associated macrophages (TAMs). TAMs are macrophages that infiltrate the tumor stroma and promote tumor progression by enhancing angiogenesis and immunosuppression. The deletion of NRP1 in macrophages reduces their pro-angiogenic and immunosuppressive functions, leading to decreased tumor growth and metastasis.
NRP1 in Cancer Stem Cells
Recent studies have demonstrated a link between NRP1 expression and tumor-initiating cells (TICs), also known as cancer stem cells. TICs are responsible for the initiation and maintenance of tumors and are characterized by their ability to self-renew and differentiate. NRP1 has been shown to maintain the tumor-initiating phenotype in gliomas and skin cancer cells, suggesting that it plays a role in cancer stem cell biology.
In lung cancer, cells expressing NRP1 exhibit characteristics similar to TICs, including high clonal ability and tumor-initiating properties. This indicates that NRP1 may serve as a biomarker for TICs and a potential target for cancer therapy.
Therapeutic Strategies Targeting NRP1
Given its central role in tumor angiogenesis, proliferation, migration, and immune regulation, NRP1 has emerged as a promising therapeutic target in cancer therapy. Several strategies have been developed to inhibit NRP1 function, including blocking its interaction with VEGF, reducing its expression, and targeting NRP1+ Tregs.
Blocking NRP1 Pathway Interactions
One of the most well-characterized inhibitors of NRP1 is EG00229, which specifically inhibits the interaction between NRP1 and VEGF. This inhibitor has shown significant tumor-suppressive effects in gliomas and squamous cell carcinomas. Another approach involves the use of nanobodies, such as HS45, which have high affinity for human NRP1 and can block its function.
Inhibiting NRP1 in Tregs
Targeting NRP1 in Tregs has been shown to enhance anti-tumor immunity. The NRP1 antagonist Fc(AAG)-TPP11 selectively inhibits the function and survival of NRP1+ Tregs, leading to increased anti-tumor activity in the TME. This approach has been validated in mouse models, where it resulted in reduced tumor growth without apparent toxicity.
Reducing NRP1 Expression
MicroRNAs (miRNAs) have been explored as a means to reduce NRP1 expression. miRNAs such as miR-130a, miR-130b, miR-9-5p, and miR-628 have been shown to target NRP1 and inhibit its expression in various cancers, including gastric cancer, osteosarcoma, and acute lymphoblastic leukemia. These miRNAs not only reduce tumor proliferation and invasion but also increase the sensitivity of cancer cells to chemotherapy.
Competitive Inhibitors of NRP1 Binding Proteins
Another strategy involves the use of competitive inhibitors that prevent NRP1 from binding to its downstream targets. For example, SEMA3A can partially reverse the binding of VEGF to NRP1, reducing angiogenesis and tumor growth. A SEMA3A point mutant has been developed to competitively bind to PLXNA4, a co-receptor for NRP1, leading to vascular normalization and reduced tumor hypoxia.
Recombinant Soluble NRP1
Recombinant soluble NRP1 (sNRP1) variants have also been explored as therapeutic agents. These variants, such as s12NRP1, s11NRP1, sIIINRP1, and sIVNRP1, act as VEGF165 antagonists and inhibit tumor angiogenesis. In prostate cancer models, overexpression of s12NRP1 has been shown to induce apoptosis and reduce tumor vascularization.
Multi-Drug Combination Therapy
Combination therapy targeting NRP1 has shown promise in enhancing the efficacy of cancer treatment. For example, the tumor homing peptide iRGD, which targets NRP1, has been used to increase the penetration of chemotherapeutic agents into tumors. Combining iRGD with 5-fluorouracil has been shown to improve the prognosis of gastric cancer patients.
Conclusion and Future Directions
NRP1 is a multifaceted protein that plays a critical role in tumor angiogenesis, proliferation, migration, and immune regulation. Its overexpression in various cancers and its involvement in multiple signaling pathways make it an attractive target for cancer therapy. Several therapeutic strategies targeting NRP1 have shown promise in preclinical and clinical studies, including inhibitors of NRP1-VEGF interactions, miRNA-based approaches, and combination therapies.
However, further research is needed to fully understand the molecular mechanisms underlying NRP1’s role in cancer and to develop more effective and targeted therapies. Combining NRP1 inhibitors with other treatment modalities, such as immunotherapy, radiotherapy, and chemotherapy, may provide a more comprehensive approach to cancer treatment. As our understanding of NRP1 continues to grow, it is likely that new and innovative therapeutic strategies will emerge, offering hope for improved outcomes in cancer patients.
doi.org/10.1097/CM9.0000000000001200
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