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Intercellular communication is a key biological mechanism that is fundamental to maintain tissue homeostasis. Extracellular vesicles (EVs) have emerged as critical regulators of cell-cell communication in both physiological and pathological conditions, due to their ability to shuttle a variety of cell constituents, such as DNA, RNA, lipids, active metabolites, cytosolic, and cell surface proteins. In particular, endothelial cells (ECs) are prominently regulated by EVs released by neighboring cell types. The discovery that cancer cell-derived EVs can control the functions of ECs has prompted the investigation of their roles in tumor angiogenesis and cancer progression. In particular, here, we discuss evidence that supports the roles of exosomes in EC regulation within the tumor microenvironment and in vascular dysfunction leading to atherosclerosis. Moreover, we survey the molecular mechanisms and exosomal cargoes that have been implicated in explanations of these regulatory effects.

The endothelium is the innermost layer of all blood and lymphatic vessels composed of a monolayer of specialized endothelial cells (ECs). It is regarded as a dynamic and multifunctional endocrine organ that takes part in essential processes, such as the control of blood fluidity, the modulation of vascular tone, the regulation of immune response and leukocyte trafficking into perivascular tissues, and angiogenesis. The inability of ECs to perform their normal biological functions, known as endothelial dysfunction, is multi-factorial; for instance, it implicates the failure of ECs to support the normal antithrombotic and anti-inflammatory status, resulting in the onset of unfavorable cardiovascular conditions such as atherosclerosis, coronary artery disease, hypertension, heart problems, and other vascular pathologies. Notably, it is emerging that the ability of ECs to adapt their metabolic status to persistent changes of the tissue microenvironment could be vital for the maintenance of vascular functions and to prevent adverse vascular events. The main purpose of the present article is to shed light on the unique metabolic plasticity of ECs as a prospective therapeutic target; this may lead to the development of novel strategies for cardiovascular diseases and cancer.

Head and neck squamous cell carcinoma (HNSCC) includes a group of aggressive malignancies characterized by the overexpression of the epidermal growth factor receptor (EGFR) in 90% of cases. Neuropilin-1 (NRP-1) acts as an EGFR co-receptor, enhancing, upon ligand stimulation, EGFR signaling in several cellular models. However, NRP-1 remains poorly characterized in HNSCC. By utilizing in vitro cellular models of HNSCC, we report that NRP-1 is involved in the regulation of EGFR signaling. In fact, NRP-1 can lead to cisplatin-induced EGFR phosphorylation, an escape mechanism activated by cancer cells upon cytotoxic stress. Furthermore, we evaluated Neuropilin-1 staining in tissue samples of an HNSCC case series ( n = 218), unraveling a prognostic value for the Neuropilin-1 tissue expression. These data suggest a potential role for NRP-1 in HNSCC cancer progression, expanding the repertoire of signaling in which NRP-1 is involved and eliciting the need for further investigations on NRP-1 as a suitable target for HNSCC novel therapeutic approaches.

Neuropilin-1 (NRP-1) is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF) family members that can be expressed on cancer cells and tumor-infiltrating myeloid, endothelial and lymphoid cells. It has been linked to a tumor-promoting environment upon interaction with semaphorin 3A (Sema3A). Nanobodies (Nbs) targeting NRP-1 were generated for their potential to hamper the NRP-1/Sema3A interaction and their impact on colorectal carcinoma (CRC) development was evaluated in vivo through the generation of anti-NRP-1-producing CRC cells. We observed that tumor growth was significantly delayed and survival prolonged when the anti-NRP-1 Nbs were produced in vivo. We further analyzed the tumor microenvironment and observed that the pro-inflammatory MHC-II high /trophic MHC-II low macrophage ratio was increased in tumors that produce anti-NRP-1 Nbs. This finding was corroborated by an increase in the expression of genes associated with MHC-II high macrophages and a decrease in the expression of MHC-II low macrophage-associated genes in the macrophage pool sorted from anti-NRP-1 Nb-producing tumors. Moreover, we observed a significantly higher percentage of tumor-associated antigen-specific CD8 + T cells in tumors producing anti-NRP-1 Nbs. These data demonstrate that an intratumoral expression of NRP-1/Sema3A blocking biologicals increases anti-tumor immunity.

Melanoma cells addicted to mutated BRAF oncogene activity can be targeted by specific kinase inhibitors until they develop resistance to therapy. We observed that the expression of Galectin-1 (Gal-1), a soluble ligand of Neuropilin-1 (NRP1), is upregulated in melanoma tumor samples and melanoma cells resistant to BRAF-targeted therapy. We then demonstrated that Gal-1 is a novel driver of resistance to BRAF inhibitors in melanoma and that its activity is linked to the concomitant upregulation of the NRP1 receptor observed in drug-resistant cells. Mechanistically, Gal-1 sustains increased expression of NRP1 and EGFR in drug-resistant melanoma cells. Moreover, consistent with its role as a NRP1 ligand, Gal-1 negatively controls p27 levels, a mechanism previously found to enable EGFR upregulation in cancer cells. Finally, the combined treatment with a Gal-1 inhibitor and a NRP1 blocking drug enabled resistant melanoma cell resensitization to BRAF-targeted therapy. In summary, we found that the activation of Galectin-1/NRP1 autocrine signaling is a new mechanism conferring independence from BRAF kinase activity to oncogene-addicted melanoma cells.