Shim Hyunsuk, Lau Stephen K, Devi Sarojini, Yoon Younghyoun, Cho Heidi T, Liang Zhongxing
Department of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
Biochem Biophys Res Commun. 2006 Jul 21;346(1):252-8. doi: 10.1016/j.bbrc.2006.05.110. Epub 2006 May 26.
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)-1alpha 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 non-neoplastic 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-1alpha. 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-1alpha 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-1alpha 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.
基质细胞衍生因子-1（SDF-1）是CXC趋化因子受体4（CXCR4）的独特配体，其在乳腺癌转移中起关键作用。在转移的常见靶器官如淋巴结、肺、肝和骨中高水平的SDF-1吸引CXCR4阳性肿瘤细胞。SDF-1与CXCR4之间的相互作用导致特定信号通路的激活，从而实现归巢和转移进展。然而，关于转移器官部位CXCR4表达的调控尚未有充分记录。我们通过免疫组织化学染色检测乳腺癌组织中CXCR4和缺氧诱导因子（HIF）-1α的表达，并使用实时RT-PCR分析原发性肿瘤和淋巴结中的SDF-1。与淋巴结中相应的转移瘤相比，原发性浸润性癌对CXCR4的染色更强，尤其是在细胞膜上。与非肿瘤性乳腺组织相比，原发性肿瘤和淋巴结转移灶中CXCR4表达水平均较高。因此，我们推测淋巴结中的肿瘤环境可能导致转移瘤细胞中CXCR4水平降低，原因如下：（1）SDF-1水平高；（2）HIF-1α水平低。我们的体外数据表明，高水平的SDF-1可通过溶酶体途径诱导CXCR4的内化和降解。此外，淋巴结转移灶中较低水平的HIF-1α可能由缺氧程度较低的环境诱导，进一步降低了CXCR4水平。这些结果表明，配体依赖性降解和较低的HIF-1α水平可能是与原发性肿瘤相比淋巴结中CXCR4水平降低的潜在原因。我们的研究表明，肿瘤细胞中的CXCR4水平受其微环境调控。这些发现可能增强我们对乳腺癌生物学行为的理解能力。
