Somatostatin Receptors in Lung Cancer: From Function to Molecular Imaging and Therapeutics

J. Clay Callison Jr; Ronald C. Walker; Pierre P. Massion

doi:10.6058/jlc.2011.10.2.69

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Jr, Walker, and Massion: Somatostatin Receptors in Lung Cancer: From Function to Molecular Imaging and Therapeutics

Original Article

J Lung Cancer 2011;10(2):69-76.

Published online: 11 January 2011

DOI: https://doi.org/10.6058/jlc.2011.10.2.69

Somatostatin Receptors in Lung Cancer: From Function to Molecular Imaging and Therapeutics

J. Clay Callison Jr, M.D.¹, Ronald C. Walker, M.D.^2,3,4,^2,3,4,^2,3,4, Pierre P. Massion, M.D.^1,2,4,^1,2,4,^1,2,4

¹Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

²Tennessee Valley VA Healthcare System, Vanderbilt University Medical Center, Nashville, Tennessee, USA

³Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA

⁴Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA

Address for correspondence Pierre P. Massion, M.D. Vanderbilt-Ingram Cancer Center, 2220, Pierce Avenue, 640 Preston Research Building, Nashville, TN 37232-6838, USA Tel: 1-615-936-1279 Fax: 1-615-936-3322 E-mail: pierre.massion@vanderbilt.edu

This study was supported by VA Merit Review I01BX007080 to RCW and CA 102353 to PPM.

Revised 4 December 2011 Accepted 5 December 2011

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Lung cancer is a deadly disease that is difficult to diagnose and even more difficult to treat effectively. Many pathways are known to affect tumor growth, and targeting these pathways provides the cornerstone by which cancer is treated. Somatostatin receptors (SSTR) are a family of G protein coupled receptors that signal to alter hormonal secretion, increase apoptosis, and decrease cellular proliferation. These receptors are expressed in many normal and malignant cells, including both small cell and non-small cell lung cancer. Synthetic analogs of SSTRs are commercially available, but their effects in lung cancer are still largely uncertain. Signaling pathway studies have shown that SSTRs signal through phosphotyrosine phosphatases to induce apoptosis as well as to decrease cell proliferation. Radiolabeled SSTR2 analogs are utilized for radiographic imaging of tumors, which, when combined with positron emission tomography-computed tomography (PET-CT) may improve detection of lung cancer. These radiolabeled SSTR2 analogs also hold promise for targeted chemotherapy as well as radiotherapy. In this review, we summarize what is known about SSTRs and focus our discussion on the knowledge as it relates to lung cancer biology, as well as discuss current and future uses of these receptors for imaging and therapy of lung cancer. (J Lung Cancer 2011;10(2):69 ? 76)

Keywords: Somatostatin receptors, Lung neoplasms, Neuroendocrine tumors, Molecular imaging

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Fig. 1.

Somatostatin receptor sig-naling cascade. SSTR activation decreases hormonal secretion in most cells by decreasing cyclic AMP and by altering voltage gat-ed potassium and calcium cha-nnels. In a minority of cells (pan-creatic B-cells), hormonal secretion is increased. SSTR signals through PTPases to alter ERK1/2 phosphorylation to impair p27 ^kip1 degradation which leads to cell growth arrest. SSTR also signals through PTPases to induce apoptosis. Rarely SSTR2 induces proliferation. ERK: extracellular signal- regulated kinase, G_α, G_β, G_γ: G- protein subunit, PLC: phospholi-apse C, cAMP: cyclic adenosine monophosphate, IP3: inositol tri-phosphate, PTPase: phosphotyrosine phosphatase, SRIF: somatostatin, SHP: Src homology phosphatase, PTP-η: phosphotyrosine phosphatase η.

Fig. 2.

Use of a new synthetic somatostatin analog in lung cancer: Axial (A, B) and coronal (C, D) fused PET/CT images in a patient with newly diagnosed, un-treated adenocarcinoma of the right upper lobe (arrows). The tumor is easily seen with both the somatostatin analog (⁶⁸ Ga-DOTATATE; A, C) and with conventional PET imaging (¹⁸ F-FDG: B, D) with com-parable uptake (each had an SUV value of 2.7). The combination of both imaging agents may help reduce false positive exams with ¹8 F-FDG PET/CT imaging alone, decreasing unnecessary biopsies or thoracotomies. Images by the authors.

Table 1.

Somatostatin Receptor Properties

Receptor subtype
Gene	SSTR1	SSTR2	SSTR3	SSTR4	SSTR5
Chromosome	14q13	17q24	22q13.1	1 20p11.2	16p13.3
Molecular weight (kDa)	42.7	41.3	45.9	41.9	39.2
Glycosylation sites	3	4	2	1	3
Proliferation	↓	↑↓	↓	↑↓	↓
Apoptosis		↑	↑
Hormonal secretion		↓			↓

This table is adapted from Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2003;2:999-1017. Reproduced with the permission of Nature.

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