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Molecular Targets in Human Neuroendocrine Tumors

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Neuroendocrine Tumors: Review of Pathology, Molecular and Therapeutic Advances

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Abstract

During last few decades, the incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased significantly. In terms of prevalence, GEP-NETs are the second commonest gastrointestinal malignancy after colorectal cancer. Pathologically, these neoplasms range from slowly growing, indolent tumors to more aggressive malignancies. Clinical presentation is quite diverse and contributes to delayed diagnosis. Therefore, 60–80 % cases present with metastatic disease and have unfavorable clinical outcome. Molecular and biologic basis of development, growth, progression, and sensitivity or resistance to emerging therapies is not well understood. Hence, there is an urgent need to characterize these tumors in terms of expression of various molecular targets in the primary vs. metastatic NET tissues, so most promising therapeutically relevant molecular targets can be identified and validated. Similarly, rigorous molecular target expression data sets are required to define rational therapeutic strategies in individual patients. Molecular targets with greatest therapeutic relevance are peptide receptors and receptor tyrosine kinases involved in pathologic angiogenesis in tumor tissues and in tumor growth and progression, along with intracellular targets, like the mammalian target of rapamycin (mTOR). With the implementation of more personalized diagnostic and therapeutic approaches, it is becoming more and more important for diagnostic pathologists to develop and advance expertise in systematic and reproducible evaluation of these molecular targets in human tissues.

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Abbreviations

Akt Protein kinase B

AKT2 kt/mTOR pathway gene

ALDH+ Aldehyde dehydrogenase positive

ATM Protein kinase

BON Pancreatic neuroendocrine tumors cell line

c-Kit Stem cell growth factor receptor

CK19 Cytokeratin 19

CM Pancreatic neuroendocrine tumors cell line

CSC Cancer stem cells

EGF Epidermal growth factor

EGFR Epidermal growth factor receptor

ErbB-1 Epidermal growth factor receptor

ERK Extracellular-regulated kinase

ERK1 Extracellular-regulated kinase 1

ERK2 Extracellular-regulated kinase 2

FGFR3 Fibroblast growth factor receptor 3

FLT1 EGFR gene

FRAP1-mTOR Akt/mTOR pathway gene

GEP-NET Gastroenteropancreatic neuroendocrine tumor

GI Gastrointestinal

HER Human epidermal growth factor receptor

HER2 Human epidermal growth factor receptor 2

HER3 Human epidermal growth factor receptor 3

IHC Immunohistochemistry/immunohistochemical

KIT c-Kit encoding gene

MAPK Mitogen-activated protein kinase

MMP Matrix metalloproteinases

mTOR Mammalian target of rapamycin

mTOR Mammalian target of rapamycin

NET Neuroendocrine tumor

NF1 Neurofibromatosis type 1

PDGFR-alpha Platelet-derived growth factor receptor-alpha

PDPK1 Akt/mTOR pathway gene

P-EGFR Phosphorylated EGFR

PIK3CA Akt/mTOR pathway gene

PI3K Phosphoinositide-3-kinase

PKB Protein kinase B

PMET Phosphorylated MET

PNET Primitive neuroendocrine tumor

PTEN Phosphatase and tensin homolog

QGP-1 Pancreatic neuroendocrine tumors cell line

qPCR Quantitative polymerase chain reaction

Rin-14B Pancreatic delta cell line

RPS6K1 Akt/mTOR pathway gene

RTK Receptor tyrosine kinase

SCF Stem cell factor

SFK Sarcoma family of kinases

siRNA Small interfering RNA

Src Sarcoma

SSA Somatostatin analog

SSTR Somatostatin receptors

SSTR2 Somatostatin receptor 2

SSTR5 Somatostatin receptor 5

STK11 Akt/mTOR pathway gene

TGFα Transforming growth factor-alpha

TSC1 Tuberous sclerosis complex 1 gene

TSC2 Tuberous sclerosis complex 2 gene

VEGFR1 VEGF receptor

VIP Vasoactive intestinal peptide

Author information

Authors and Affiliations

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

    Ujalla Sheikh & Domenico Coppola MD

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

    Jalil Muhammad

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

    Aejaz Nasir MD, MPhil, FCAP

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  1. Ujalla Sheikh
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  2. Jalil Muhammad
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  3. Domenico Coppola MD
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  4. Aejaz Nasir MD, MPhil, FCAP
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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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Sheikh, U., Muhammad, J., Coppola, D., Nasir, A. (2016). Molecular Targets in Human 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_26

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