Lee Misu, Lupp Amelie, Mendoza Nigel, Martin Niamh, Beschorner Rudi, Honegger Jürgen, Schlegel Jürgen, Shively Talia, Pulz Elke, Schulz Stefan, Roncaroli Federico, Pellegata Natalia S
Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany
Endocr Relat Cancer. 2015 Feb;22(1):111-9. doi: 10.1530/ERC-14-0472. Epub 2014 Dec 16.
Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not amenable to complete surgical resection. Radiotherapy is the only post-operative option for patients with large invasive or recurrent lesions. No medical treatment is available for these patients. The somatostatin analogs (SSAs) octreotide and lanreotide that preferentially target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted that the expression of specific SSTR subtypes determines the response to SSAs. Given that previous studies on mRNA and protein expression of SSTRs in GPAs have generated conflicting results, we investigated the expression of SSTR2, SSTR3, and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well-characterized cohort of 108 patients with GPAs. A total of 118 samples were examined by immunohistochemistry using validated and specific MABs. Matched primary and recurrent tissues were available for ten patients. The results obtained were validated in an independent cohort of 27 GPAs. We observed that SSTR3 was significantly more abundant than SSTR2 (P<0.0001) in GPAs, while full-length SSTR5 was only expressed in few tumors. Expression of SSTR3 was similar in primary and recurrent adenomas, was high in potentially aggressive lesions, and did not change significantly in adenomas that recurred after irradiation. In conclusion, low levels of expression of SSTR2 may account for the limited response of GPAs to octreotide and lanreotide. Given the potent anti-proliferative, pro-apoptotic, and anti-angiogenic activities of SSTR3, targeting this receptor with a multireceptor ligand SSA such as pasireotide may be indicated for potentially aggressive GPAs.
促性腺激素垂体腺瘤（GPA）通常表现为侵袭性大腺瘤，难以进行完整的手术切除。放疗是患有大型侵袭性或复发性病变患者的唯一术后选择。这些患者尚无可用的药物治疗。优先靶向2型生长抑素受体（SSTR2）的生长抑素类似物（SSA）奥曲肽和兰瑞肽对GPA几乎没有作用。人们普遍认为特定SSTR亚型的表达决定了对SSA的反应。鉴于先前关于GPA中SSTRs mRNA和蛋白表达的研究结果相互矛盾，我们在108例临床和病理特征明确的GPA患者队列中研究了SSTR2、SSTR3和SSTR5（现有SSA的主要靶点）的表达。使用经过验证的特异性单克隆抗体通过免疫组织化学检查了总共118个样本。10例患者有配对的原发组织和复发组织。在27例GPA的独立队列中验证了所得结果。我们观察到，在GPA中SSTR3的表达明显高于SSTR2（P<0.0001），而全长SSTR5仅在少数肿瘤中表达。SSTR3在原发腺瘤和复发腺瘤中的表达相似，在潜在侵袭性病变中表达较高，并且在放疗后复发的腺瘤中没有明显变化。总之，SSTR2低表达水平可能是GPA对奥曲肽和兰瑞肽反应有限的原因。鉴于SSTR3具有强大的抗增殖、促凋亡和抗血管生成活性，对于潜在侵袭性GPA，可能需要使用多受体配体SSA如帕西瑞肽靶向该受体。
