Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors
Abstract
1. Introduction
2. Heterogeneity of Vascular Endothelial Cells
3. De Novo Arteriogenesis, an Emerging Concept of Formation of New Vascular Networks
4. Tumor Arteriogenesis: Potential Target in pNETs
5. Antiangiogenic Therapy in pNETs: Challenges and Prospective
5.1. Notch Pathway: The Potential Target in pNETs
5.2. Control of pNET Progression by Targeting Vascular Niche and CSC Plasticity
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Name | Mechanisms & Functions | Reference(s) |
---|---|---|
CVM-1118 | Phase II clinical trial for patients with advanced NETs, including pNETs; de novo development of vascular networks via vascular mimicry, which is associated with a malignant phenotype and a poor clinical outcome. Vascular mimicry was presented in pNET animal models. | https://clinicaltrials.gov/ct2/show/NCT03600233; Chu et al., Am J Pathol 2013; Wagenblast, et al., Nature 2015; Hendrix, et al., Pharmacol Ther 2016 [211,212,213] |
Cabozantinib | Phase III clinical trial of in patients with advanced neuroendocrine tumors after progression on everolimus (CABINET) A VEGFR, c-MET and AXL inhibitor; attenuate sunitinib therapy-mediated pro-metastasis in xenograft mouse tumor models of renal cell carcinoma. | https://clinicaltrials.gov/ct2/show/NCT03375320; Zhou et al., Oncogene, 2015 [214] |
Lenvatinib | A multi-kinase inhibitor with a preferential antiangiogenic activity. | Capdevila, et al. J Clin Oncol, 2019; Capozzi, et al., Cancer Manag Res 2019 [215,216] |
TH-302 (evofosfamide) | A hypoxia-activated prodrug, which is metabolized to its active form, bromo-isophosphoramide mustard (Br-IPM), under hypoxic conditions. Used in combination with sunitinib. | Grande, et al., abstract. J Clin Oncol, 2019 [217] |
Doublecortin-like kinase 1 (DCLK1) | A potential marker for pNET CSCs; induce epithelial-mesenchymal transition (EMT). | Ikezono, et al., Mol Cancer Res, 2017 [218] |
MEDI3617 | A monoclonal antibody targeting angiopoietin-2; in combination with VEGF-targeted therapies. | Rigamonti, et al., Cell Rep 2014; Biel, et al., Cancer Letters, 2016 [219,220] |
Sema3A (Semaphorin 3A) | Overcome cancer hypoxia and metastatic dissemination induced by sunitinib treatment in mice. In combination with sunitinib, Sema3A synergistically enhanced RIP-Tag2 mouse survival. | Maione, F, et al., J Clin Invest, 2012 [221] |
Brivanib | A dual FGF/VEGF inhibitor; vascular inhibition and tumor stability. | Allen, et al., Clin Cancer Res, 2011 [222] |
PlGF signaling inhibitor? | High PIGF expression in pNET patients with poor outcome; overcome resistance to antiangiogenic factors. | Fischer et al., Cell, 2007; Hilfenhaus, et al., Endocr Relat Cancer, 2013 [223,224] |
EZH2 inhibitor? | Sensitize tumor to sunitinib in cell lines and PDX models. | Marconcini, et al., 2016 [225] |
Autotaxin (ATX) inhibitors? LPA receptor-specific antagonists? | High ATX expression in pNET tissues, which was associated with higher tumor grade, TNM staging and lymph node metastasis; ATX drives LPA expression, which is also linked to tumor angiogenesis and arteriolar differentiation and malignancy of tumor cells. | Liu et al., Cancer Cell, 2009; Chen, et al., Front Biosci (Landmark Ed) 2013; Ren, et al., Arterioscler Thromb Vasc Biol, 2016; Liu et al., Cancer Lett 2016; Dong et al., Oncotarget, 2017 [20]; Yang et al., Endocr. Connect, 2018 [21,226,227,228,229] |
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Ren, B.; Rose, J.B.; Liu, Y.; Jaskular-Sztul, R.; Contreras, C.; Beck, A.; Chen, H. Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors. J. Clin. Med. 2019, 8, 1980. https://doi.org/10.3390/jcm8111980
Ren B, Rose JB, Liu Y, Jaskular-Sztul R, Contreras C, Beck A, Chen H. Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors. Journal of Clinical Medicine. 2019; 8(11):1980. https://doi.org/10.3390/jcm8111980
Chicago/Turabian StyleRen, Bin, J. Bart Rose, Yehe Liu, Renata Jaskular-Sztul, Carlo Contreras, Adam Beck, and Herbert Chen. 2019. "Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors" Journal of Clinical Medicine 8, no. 11: 1980. https://doi.org/10.3390/jcm8111980
APA StyleRen, B., Rose, J. B., Liu, Y., Jaskular-Sztul, R., Contreras, C., Beck, A., & Chen, H. (2019). Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors. Journal of Clinical Medicine, 8(11), 1980. https://doi.org/10.3390/jcm8111980