Lower expression of CXCR4 in lymph node metastases than in primary breast cancers:: Potential regulation by ligand-dependent degradation and HIF-1α
Lower expression of CXCR4 in lymph node metastases than in primary breast cancers:: Potential regulation by ligand-dependent degradation and HIF-1α
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DOI：
10.1016/j.bbrc.2006.05.110
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发表时间：
2006-07-21
影响因子：
3.1
通讯作者：
Liang, Zhongxing
中科院分区：
文献类型：
--
作者：
Shim, Hyunsuk;Lau, Stephen K.;Liang, Zhongxing
基质衍生因子-1（SDF-1）是CXC趋化因子受体4（CXCR 4）的独特配体，其在乳腺癌转移中起关键作用。在转移的常见目的器官（如淋巴结、肺、肝和骨）中高水平的SDF-1吸引CXCR4阳性肿瘤细胞。SDF-1和CXCR4之间的相互作用导致特定信号通路的激活，从而允许归巢和转移进展。然而，在转移器官部位的CXCR4表达的调节没有很好的记录。我们通过免疫组化染色检测乳腺肿瘤组织中CXCR 4和缺氧诱导因子（HIF）-1 α的表达，并使用实时RT-PCR分析原发性肿瘤和淋巴结中SDF-1的表达。与淋巴结中相应的转移肿瘤相比，原发性浸润性癌显示出更强的CXCR4染色，特别是在细胞膜上。原发性肿瘤和淋巴结转移灶的CXCR4表达水平均高于非肿瘤性乳腺组织。因此，我们假设淋巴结中的肿瘤环境可能导致转移性肿瘤细胞中CXCR4水平的降低，因为：（1）高SDF-1水平和（2）低HIF-1 α水平。我们的体外数据表明，高水平的SDF-1可以通过溶酶体途径诱导CXCR 4的内化和降解。此外，淋巴结转移中较低水平的HIF-1 α，可能是由低氧环境引起的，进一步降低了CXCR4水平。这些结果表明，与原发性肿瘤相比，配体依赖性降解和较低的HIF-1 α水平可能是淋巴结中CXCR 4水平降低的潜在原因。我们的研究表明，肿瘤细胞中的CXCR4水平受其微环境的调节。这些发现可能会增强我们理解乳腺癌生物学行为的能力。(c)2006年爱思唯尔公司All rights reserved.
Stromal-derived factor-1 (SDF-1) is a unique ligand of the CXC chemokine receptor 4 (CXCR4), which is critically involved in the metastasis of breast cancer. High levels of SDF-1 in the common destination organs of metastasis, such as the lymph nodes, lungs, liver, and bones, attract CXCR4-positive tumor cells. The interaction between SDF-1 and CXCR4 leads to the activation of specific signaling pathways, allowing for homing and metastatic progression. However, regulation of CXCR4 expression at the metastatic organ site is not well-documented. We detected the expression of CXCR4 and hypoxia inducible factor (HIF)-1 alpha in breast tumor tissues by immunohistochemical staining and analyzed SDF-1 in primary tumors and lymph nodes using real-time RT-PCR. Compared to the corresponding metastasized tumors in the lymph nodes, primary invasive carcinomas showed more intense staining for CXCR4, particularly on the cellular membrane. Both primary tumors and lymph node metastases exhibited higher levels of CXCR4 expression compared to nonneoplastic breast tissues. Therefore, we hypothesized that the tumor environment in the lymph nodes may cause the reduction of CXCR4 levels in the metastatic tumor cells because of: (1) high SDF-1 levels and (2) lower levels of HIF-1 alpha. Our in vitro data demonstrated that high levels of SDF-1 can induce the internalization and degradation of CXCR4 through the lysosome pathway. In addition, lower levels of HIF-1 alpha in the lymph node metastases, probably induced by the less hypoxic environment, further lowered CXCR4 levels. These results indicate that ligand-dependent degradation and lower HIF-1 alpha levels may be potential causes of lowered levels of CXCR4 in the lymph nodes compared to the primary tumors. Our study suggests that CXCR4 levels in tumor cells are regulated by its microenvironment. These findings may enhance our ability to understand the biological behavior of breast cancers. (c) 2006 Elsevier Inc. All rights reserved.