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Somatostatin Receptor Subtypes in Human Thymoma and Inhibition of Cell Proliferation by Octreotide in Vitro

Departments of Internal Medicine III (D.F., M.P.v.H., P.M.v.K., D.M.M., E.G.R.L.-K., S.W.J.L., L.J.H.), Immunology (M.P.v.H.), and Nuclear Medicine (D.J.K.), Erasmus University, 3015 AD Rotterdam, The Netherlands; Department of Integrative Biology and Pharmacology, University of Texas (A.S.), Houston, Texas 77225; and Department of Molecular and Clinical Endocrinology and Oncology, Federico II University (D.F., A.C.), 80131 Naples, Italy

Address all correspondence and requests for reprints to: Dr. Leo J. Hofland, Department of Internal Medicine III, Room Bd 277, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: hofland{at}inw3.azr.nl

Somatostatin (SS) and SS receptor (SSR) subtypes, code-named sst_1–5, are heterogeneously expressed in the normal human thymus. This suggests their involvement in controlling the immune and/or neuroendocrine functions in this organ. Moreover, recently a high in vivo uptake of [¹¹¹In-DTPA-D-Phe¹]octreotide has been reported in patients bearing thymoma. The present study characterizes in vivo and in vitro, functional SS-binding sites in a human thymoma.

A high uptake of [¹¹¹In-DTPA-D-Phe¹]octreotide was observed in the chest of a patient with myasthenia gravis due to a cortical thymoma. Specific binding of [¹²⁵I-Tyr¹¹]SS-14 was found on a membrane preparation of the surgically removed thymoma. Scatchard analysis showed high affinity binding sites (K_d, 47.5 ± 2.5 pmol/L) with low maximum binding capacity (23.5 ± 2.5 fmol/mg membrane protein). RT-PCR analysis showed the presence of sst₁, sst_2A, and a predominant sst₃ messenger RNA (mRNA) expression in the tumor tissue. Primary cultured tumor cells expressed sst₃ mRNA only. In contrast to the normal thymus, SS mRNA was not expressed. By immunohistochemistry, the tumor cells highly expressed sst₃ receptors, weakly expressed sst₁ receptors, and showed no immunostaining for sst_2A receptors. sst_2A immunoreactivity was found in the stromal compartment of the tumor, particularly on the endothelium of small intratumoral blood vessels. In primary cultured tumor cells, both SS and octreotide (10 nmol/L) significantly inhibited [³H]thymidine incorporation by 40.6% and 43.2%, respectively.

The following conclusions were reached. 1) As this tumor displayed a high immunoreactivity for sst₃ and the cultured tumor cells expressed the sst₃ mRNA only, this SSR may be the subtype involved in the inhibition of epithelial tumor cell proliferation by octreotide in vitro. 2) A loss of endogenous SS production in this thymoma might be implicated in the uncontrolled cell growth. 3) In this case, the sst₃ may play a role in determining the uptake of [¹¹¹In-DTPA-D-Phe¹]octreotide by in vivo SS receptor scintigraphy.

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