Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors

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.

LPA/PKD-1 signaling promotes development of arteriolar niche that supports self-renewal of breast cancer stem cells and stemness

“…Therefore, our study uncovers a previously underappreciated vascular type within the tumor microenvironment to promote BC progression likely via perfusion of nutrients and oxygen. This finding is supported by a recent seminal study (85) and other previous studies (22).…”

“…They can accumulate in the perivascular regions in tumor microenvironment (32,81) . The interactions between CSCs and their heterogeneous vasculature (21,22) may determine CSC development and fate. Additionally, circulating tumor cells contain a distinct subset of circulating CSCs that bear metastasis-initiating capabilities (44), and more CSCs exist in arterial blood than in venous blood (82).…”

“…Unfortunately, current anti-angiogenic therapies are ineffective under experimental conditions (14)(15)(16) and show limited efficacy in the clinic (17)(18)(19). The resistance to anti-angiogenic therapy may result from resistance to an established mature vasculature (16,20), indicating that the current strategies targeting the vascular niche should consider heterogeneity in tumor vasculature (20)(21)(22).…”

“…Aberrant tumor vascularity has repeatedly been shown to be important for satisfying voracious demands for nutrients by rapidly growing tumors, permitting metastasis, and serving as abnormal CSC niches (23,24). Arterial networks may exist in solid tumors (21,22,25) to provide oxygen and nutrients for tumor progression (19,22,26,27). Furthermore, studies have shown that liver and lung metastases are arterialized (28,29).…”

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

“…However, more studies are necessary in order to assess the potential applicability of nanomaterials-based strategies for clinical studies. Considering the heterogeneity of the tumor vasculature [156,157], one promising direction of nanotechnology-based anti-angiogenic strategy for cancer treatment is represented by the specific targeting of small arteries and veins within the tumor microenvironment for inducing necrosis.…”