Abstract
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.
Highlights
Pancreatic neuroendocrine tumors represent a group of rare neoplasms that originate from pancreatic endocrine cells [1]
We propose that during adult angiogenesis, arteriolar endothelial cells (ECs) can signal recruitment and appropriate differentiation of arteriolar smooth muscle cell (SMC), leading to the development of arterioles, under ischemic and oncological conditions
De novo arteriogenesis may be the case in highly angiogenic Pancreatic neuroendocrine tumors (pNETs), in which the antiangiogenic drug sunitinib is partially effective as a targeted therapy against tumor vessels [104]
Summary
Pancreatic neuroendocrine tumors (pNETs) represent a group of rare neoplasms that originate from pancreatic endocrine cells [1]. These vessels develop into neoangiogenesis by three distinct but parallel interrelated processes: angiogenesis, arteriogenesis, and venogenesis [20,27,28], as well as vasculogenesis by the formation of capillaries via endothelial progenitor cells or cancer stem cells [29,30] (Figure 1) These different angiogenic processes may be determined by heterogeneous groups of vascular ECs that constitute the linings of the entire vascular system within TMEs. ECs that are. Though the vessels in grade 3, NETs display the highest EC angiogenic activity, and they have regained pericyte coverage [101] These studies suggest an increase in the formation of matured blood vessels and possibly the development into arterioles within the TME of pNETs. The development of arteriogenesis is supported by studies showing the high levels of pro-arteriogenic factors VEGF, VEGF receptors, and FGF-2 in NETs, but not in normal islet cells. De novo arteriogenesis may be the case in highly angiogenic pNETs, in which the antiangiogenic drug sunitinib is partially effective as a targeted therapy against tumor vessels [104]
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