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. 2015 Sep 29;6(29):27566-79.
doi: 10.18632/oncotarget.4491.

Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy

Daniel Kaemmerer  1 , Tina Träger  1   2 , Maike Hoffmeister  3 , Bence Sipos  3 , Merten Hommann  1 , Jörg Sänger  4 , Stefan Schulz  2 , Amelie Lupp  2
Affiliations

Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy

Daniel Kaemmerer et al. Oncotarget. .

Abstract

Introduction: Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC).

Methods: SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 (n = 31), G2 (n = 47), and low (G3a; Ki-67: 21-49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data.

Results: Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors.

Conclusion: We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies.

Keywords: CXCR4; chemokine receptor; neuroendocrine carcinoma; neuroendocrine tumor; somatostatin receptor.

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Conflict of interest statement

CONFLICTS OF INTEREST

Kaemmerer D. received support for travelling to meetings by the companies IPSEN and PFIZER. All other authors declare no conflict of interests.

Figures

Figure 1
Figure 1. Overview over the SSTR-subtype distribution (median values) within the different tumor groups (G1–G3)
Figure 2
Figure 2. Liver metastasis of a neuroendocrine tumor (G1, Ki-67 <2%); immunohistochemistry, counterstaining with hematoxylin; original magnification: x400
Figure 3
Figure 3. Liver metastasis of a neuroendocrine tumor (G2, Ki-67: 4%); immunohistochemistry, counterstaining with hematoxylin; original magnification: x400
Figure 4
Figure 4. Neuroendocrine carcinoma of the colon ascendens (G3, Ki-67: 80%); immunohistochemistry, counterstaining with hematoxylin; original magnification: x400
Figure 5
Figure 5. Percentage of positive cases with a strong SSTR subtype and CXCR4 expression (IRS > 8 points) within the different tumor groups (G1 – G3)
Figure 6
Figure 6
A. Overall survival of patients with a negative CXCR4 expression (IRS ≤ 2, n = 23) and of patients with a positive CXCR4 expression (IRS > 2, n = 37) B. Overall survival of patients with a negative SSTR2A expression (n = 6) and of patients with a positive SSTR2A expression (n = 54).
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