Arteriogenesis supplies oxygen and nutrients in the tumor microenvironment (TME), which may play an important role in tumor growth and metastasis. Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic malignancy and are frequently metastatic on presentation. Nearly a third of pNETs secrete bioactive substances causing debilitating symptoms. Current treatment options for metastatic pNETs are limited. Importantly, these tumors are highly vascularized and heterogeneous neoplasms, in which the heterogeneity of vascular endothelial cells (ECs) and de novo arteriogenesis may be critical for their progression. Current anti-angiogenetic targeted treatments have not shown substantial clinical benefits, and they are poorly tolerated. This review article describes EC heterogeneity and heterogeneous tumor-associated ECs (TAECs) in the TME and emphasizes the concept of de novo arteriogenesis in the TME. The authors also emphasize the challenges of current antiangiogenic therapy in pNETs and discuss the potential of tumor arteriogenesis as a novel therapeutic target. Finally, the authors prospect the clinical potential of targeting the FoxO1-CD36-Notch pathway that is associated with both pNET progression and arteriogenesis and provide insights into the clinical implications of targeting plasticity of cancer stem cells (CSCs) and vascular niche, particularly the arteriolar niche within the TME in pNETs, which will also provide insights into other types of cancer, including breast cancer, lung cancer, and malignant melanoma.

Neuroendocrine (NE) cancers arise from cells within the neuroendocrine system. Chemotherapies and endoradiotherapy have been developed, but their clinical efficacy is limited. The objective of this study was to develop a dual-targeted extracellular vesicles (EV)-delivered combined therapies to treat NE cancer. Specifically, we produced EV in stirred-tank bioreactors and surface tagged both anti-somatostatin receptor 2 (SSTR 2) monoclonal antibody (mAb) and anti-C-X-C motif chemokine receptor 4 (CXCR4) mAb to generate mAbs-EV. Both live-cell confocal microscopy imaging and In Vivo Imaging System (IVIS) imaging confirmed that mAbs-EV specifically targeted and accumulated in NE cancer cells and NE tumor xenografts. Then the highly potent natural cytotoxic marine compound verrucarin A (Ver-A) with IC₅₀ of 2.2–2.8 nM and microtubule polymerization inhibitor mertansine (DM1) with IC₅₀ of 3.1–4.2 nM were packed into mAbs-EV. The in vivo maximum tolerated dose study performed in non-tumor-bearing mice indicated minimal systemic toxicity of mAbs-EV-Ver-A/DM1. Finally, the in vivo anticancer efficacy study demonstrated that the SSTR2/CXCR4 dual-targeted EV-Ver-A/DM1 is more effective to inhibit NE tumor growth than the single targeting and single drug. The results from this study could expand the application of EV to targeting deliver the combined potent chemotherapies for cancer treatment.

Pulmonary carcinoids are a type of neuroendocrine tumor (NET) accounting for 1–2% of lung cancer cases. Currently, Positron Emission Tomography (PET)/CT based on the radiolabeled sugar analogue [¹⁸F]-FDG is used to diagnose and stage pulmonary carcinoids, but is suboptimal due to low metabolic activity in these tumors. A new technique for pulmonary carcinoid imaging, using PET/CT with radiolabeled somatostatin analogs that specifically target somatostatin receptor subtype 2 (SSTR2), is becoming more standard, as many tumors overexpress SSTR2. However, pulmonary carcinoid patients with diminished SSTR2 expression are not eligible for this imaging or any type of SSTR2-specific treatment. We have found that histone deacetylase (HDAC) inhibitors can upregulate the expression of SSTR2 in pulmonary carcinoid cell lines. In this study, we used a non-cytotoxic dose of HDAC inhibitors to induce pulmonary carcinoid SSTR2 expression in which we confirmed in vitro and in vivo. A non-cytotoxic dose of the HDAC inhibitors: thailandepsin A (TDP-A), romidepsin (FK228), suberoylanilide hydroxamic acid (SAHA), AB3, and valproic acid (VPA) were administered to promote SSTR2 expression in pulmonary carcinoid cell lines and xenografts. This SSTR2 upregulation technique using HDAC inhibitors could enhance radiolabeled somatostatin analog-based imaging and the development of potential targeted treatments for pulmonary carcinoid patients with marginal or diminished SSTR2 expression.