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Pathologic Angiogenesis in Neuroendocrine Tumors

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Neuroendocrine Tumors: Review of Pathology, Molecular and Therapeutic Advances

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Abstract

In recent years, a number of therapeutic agents have been tested in clinical trials and approved for neuroendocrine tumors (NETs), including an antiangiogenic agent (sunitinib) and an mTOR inhibitor (everolimus). Despite this clinical success, we still do not have biomarkers that can predict efficacy and provide clinically relevant information on potential resistance mechanisms against various antiangiogenic therapies (AA-Rxs). In order to address this important clinical challenge, there is an urgent need for pathologists to implement robust biomarker strategies to evaluate the expression of various members of the VEGF/VEGF receptor pathway and other relevant targets/biomarkers in human NET tissues. This will provide valuable biologic insights into pathologic angiogenesis, antiangiogenesis, and various resistance mechanisms in human NETs. Furthermore, selection of NET patients based on relevant biomarker or target expression in a given NET subtype will enable the current and emerging antiangiogenic therapies to be tailored to the right NET patients and will help achieve highest levels of clinical efficacy for these agents. An emerging approach to overcome resistance against AA-Rxs is concurrent targeting of VEGF and transcription factors or of multiple angiogenic pathways, such as VEGF and FGF.

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Abbreviations

PNET Pancreatic neuroendocrine tumor

mTOR Mammalian target of rapamycin

VEGF Vascular endothelial cell growth factor

VEGFR Vascular endothelial growth factor receptor

VEGFR1 Vascular endothelial growth factor receptor 1

VEGFR2 Vascular endothelial growth factor receptor 2

VEGFR3 Vascular endothelial growth factor receptor 3

VEGFA Vascular endothelial growth factor -A

VEGFB Vascular endothelial growth factor -B

VEGFC Vascular endothelial growth factor -C

VEGFD Vascular endothelial growth factor -D

AA-Rx Antiangiogenesis therapy

RTK Receptor tyrosine kinase

KDR Kinase insert domain receptor (VEGFR2)

PIGF Placental growth factor

NET Neuroendocrine tumor

RIP1-Tag2 Rat insulin promoter T antigen transgene

PET Pancreatic endocrine tumor

NEC Neuroendocrine carcinoma

MVD Microvascular density

HIF-1α Hypoxia-inducible factors-1α

Ang-2 Angiopoietin-2

Tie-2 Transmembrane vascular endothelial tyrosine kinase

GEP-NET Gastro-entero-pancreatic neuroendocrine tumor

IHC Immunohistochemistry

RT-PCR Reverse transcriptase polymerase chain reaction

PDGFR Platelet-derived growth factor receptor

PDGFR-beta Platelet-derived growth factor receptor-beta

c-KIT Tyrosine protein kinase

EGFR Epidermal growth factor receptor

TKI Tyrosine kinase inhibitor

RET Rearranged during transfection (receptor)

PDGFR-alpha Platelet-derived growth factor receptor-alpha

FGFR1 Fibroblast growth factor receptor 1

PFS Progression-free survival

NET Neuroendocrine tumor

AA Antiangiogenesis

FGF Fibroblast growth factor

BMDC Bone marrow-derived cell

c-Met The mesenchymal epithelial transition

HIF Hypoxia-inducible factor

RAF Rapidly accelerated fibrosarcoma (protein kinase family)

Author information

Authors and Affiliations

  1. Diagnostic and Experimental Pathology (Tailored Therapeutics), Lilly Research Laboratories, Room 2391, Building 98C/2C, Eli Lilly and Co., 893 South Delaware St., Indianapolis, IN, USA

    Aejaz Nasir MD, MPhil, FCAP

  2. Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Ujalla Sheikh & Domenico Coppola MD

  3. Department of Neuroscience, George Mason University, Fairfax, VA, USA

    Jalil Muhammad

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  1. Aejaz Nasir MD, MPhil, FCAP
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  2. Ujalla Sheikh
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  3. Jalil Muhammad
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  4. Domenico Coppola MD
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Corresponding author

Correspondence to Aejaz Nasir MD, MPhil, FCAP .

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Editors and Affiliations

  1. Diagnostic & Experimental Pathology Lilly Res Laboratories, Eli Lilly & Co., Indianapolis, Indiana, USA

    Aejaz Nasir

  2. H. Lee Moffitt Cancer Ctr & Res, University of South Florida, Tampa, Florida, USA

    Domenico Coppola

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Nasir, A., Sheikh, U., Muhammad, J., Coppola, D. (2016). Pathologic Angiogenesis in Neuroendocrine Tumors. In: Nasir, A., Coppola, D. (eds) Neuroendocrine Tumors: Review of Pathology, Molecular and Therapeutic Advances. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3426-3_25

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  • DOI: https://doi.org/10.1007/978-1-4939-3426-3_25

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