Brunner Markus, Thurnher Dietmar, Pammer Johannes, Geleff Silvana, Heiduschka Gregor, Reinisch Christina M, Petzelbauer Peter, Erovic Boban M
Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
Mod Pathol. 2008 Jul;21(7):876-84. doi: 10.1038/modpathol.2008.63. Epub 2008 Apr 11.
Merkel cell carcinoma is a rare but very aggressive tumor of the skin. With current treatment options, Merkel cell carcinoma is associated with a high incidence of recurrence and metastasis. Targeted anticancer therapies such as receptor tyrosine kinase inhibitors and antisense oligonucleotides have been found to be a promising new type of treatment for various types of cancer. To evaluate whether the use of targeted therapies is a possible treatment option in Merkel cell carcinoma, we determined the expression of the target molecules c-kit, Mcl-1, Bmi-1, vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-receptor 2 (VEGF-R2), platelet-derived growth factor (PDGF)-alpha, PDGF-beta, epidermal growth factor receptor (EGFR) and Her-2/Neu in a tissue microarray of 32 samples of 29 patients with Merkel cell carcinoma. C-kit-positive samples were analyzed for mutations in exons 9 and 11. The tissue microarray was stained immunohistochemically with antibodies directed against the above-mentioned proteins, and an immunoreactivity score was calculated. DNA was extracted from c-kit-positive samples and was analyzed for exon 9 and 11 mutations using direct DNA sequencing. We found that c-kit (7%), Mcl-1 (88%), Bmi-1 (78%), VEGF-A (91%), VEGF-C (75%) VEGF-R2 (88%), PDGF-alpha (72%) and PDGF-beta (13%) were expressed in Merkel cell carcinomas. All samples showed a lack of EGFR and Her-2/Neu expression. Analysis of c-kit revealed no mutations. As VEGF-A, VEGF-C, VEGF-R2, PDGFs and c-kit are targets of new cytostatic agents used in the treatment of other cancers, inhibition by a multitargeted chemotherapy could be a very promising treatment option. High expression of Bmi-1 and Mcl-1 warrants further studies on the use of antisense oligonucleotides in Merkel cell carcinoma.
默克尔细胞癌是一种罕见但极具侵袭性的皮肤肿瘤。就目前的治疗方案而言，默克尔细胞癌的复发和转移发生率很高。诸如受体酪氨酸激酶抑制剂和反义寡核苷酸等靶向抗癌疗法已被发现是针对各类癌症的一种有前景的新型治疗方法。为评估靶向疗法在默克尔细胞癌中是否为一种可行的治疗选择，我们在一个包含29例默克尔细胞癌患者的32个样本的组织微阵列中，测定了靶分子c-kit、Mcl-1、Bmi-1、血管内皮生长因子（VEGF）-A、VEGF-C、VEGF受体2（VEGF-R2）、血小板衍生生长因子（PDGF）-α、PDGF-β、表皮生长因子受体（EGFR）和Her-2/Neu的表达情况。对c-kit阳性样本分析第9和11外显子的突变情况。用针对上述蛋白质的抗体对组织微阵列进行免疫组织化学染色，并计算免疫反应性评分。从c-kit阳性样本中提取DNA，使用直接DNA测序分析第9和11外显子的突变情况。我们发现，c-kit（7%）、Mcl-1（88%）、Bmi-1（78%）、VEGF-A（91%）、VEGF-C（75%）、VEGF-R2（88%）、PDGF-α（72%）和PDGF-β（13%）在默克尔细胞癌中表达。所有样本均未显示EGFR和Her-2/Neu表达。对c-kit的分析未发现突变。由于VEGF-A、VEGF-C、VEGF-R2、PDGFs和c-kit是用于治疗其他癌症的新型细胞抑制剂的靶点，多靶点化疗抑制可能是一种非常有前景的治疗选择。Bmi-1和Mcl-1的高表达值得进一步研究反义寡核苷酸在默克尔细胞癌中的应用。
