Acs Geza, Zhang Paul J, Rebbeck Timothy R, Acs Peter, Verma Ajay
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Cancer. 2002 Sep 1;95(5):969-81. doi: 10.1002/cncr.10787.
Erythropoietin (Epo), induced by hypoxia, controls the survival, proliferation, and differentiation of Epo receptor (EpoR)-bearing erythroid progenitors and plays a role in the protection of neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, resistance to therapy, and selection for cells with diminished apoptotic potential. The authors recently demonstrated the basal and hypoxia-stimulated expression of Epo and EpoR in human breast carcinoma cell lines and in breast carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of mammary neoplasms.
The authors characterized the expression of Epo and EpoR by immunohistochemistry in 184 invasive mammary carcinomas and 158 in situ mammary carcinomas and benign mammary epithelium. They analyzed the correlation of Epo and EpoR immunostaining with clinicopathologic tumor features and the patients' smoking history.
Benign mammary epithelial cells showed weak-to-moderate expression of Epo and EpoR. EpoR immunostaining was increased in carcinomas compared with benign epithelium both in nonsmokers and smokers, and Epo immunostaining was increased in carcinomas compared with benign epithelium in nonsmokers but not in smokers. Prominent Epo staining was seen in tumor cells adjacent to necrotic areas and at the infiltrating edge of tumors. EpoR staining, but not Epo staining, was significantly greater in tumors that showed high histologic grade, tumor necrosis, lymphovascular invasion, lymph node metastases, and loss of hormone receptor expression.
The current findings suggest that increased EpoR expression may play an important role in breast carcinogenesis. The induction of autocrine or paracrine Epo signaling may represent a novel mechanism by which hypoxia can promote breast carcinoma.
由缺氧诱导产生的促红细胞生成素（Epo）可控制表达促红细胞生成素受体（EpoR）的红系祖细胞的存活、增殖和分化，并在保护神经元免受缺氧损伤方面发挥作用。恶性疾病中的缺氧与侵袭、转移、治疗抵抗以及凋亡潜能降低的细胞选择有关。作者最近证明了促红细胞生成素和促红细胞生成素受体在人乳腺癌细胞系和乳腺癌中的基础表达及缺氧刺激表达，提示自分泌促红细胞生成素信号在乳腺肿瘤的缺氧适应中发挥作用。
作者通过免疫组织化学方法对184例浸润性乳腺癌、158例原位乳腺癌和良性乳腺上皮中促红细胞生成素和促红细胞生成素受体的表达进行了特征性分析。他们分析了促红细胞生成素和促红细胞生成素受体免疫染色与临床病理肿瘤特征及患者吸烟史之间的相关性。
良性乳腺上皮细胞显示促红细胞生成素和促红细胞生成素受体呈弱至中度表达。在非吸烟者和吸烟者中，与良性上皮相比，癌组织中的促红细胞生成素受体免疫染色均增加；在非吸烟者中，与良性上皮相比，癌组织中的促红细胞生成素免疫染色增加，但在吸烟者中未增加。在坏死区域附近的肿瘤细胞以及肿瘤的浸润边缘可见明显的促红细胞生成素染色。在组织学分级高、有肿瘤坏死、有淋巴管浸润、有淋巴结转移以及激素受体表达缺失的肿瘤中，促红细胞生成素受体染色而非促红细胞生成素染色显著更强。
目前的研究结果表明，促红细胞生成素受体表达增加可能在乳腺癌发生中起重要作用。自分泌或旁分泌促红细胞生成素信号的诱导可能代表缺氧促进乳腺癌的一种新机制。
