Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo
Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo
复制标题
DOI：
10.1002/jcb.10522
复制
发表时间：
2003-06-01
影响因子：
4
通讯作者：
Taichman, RS
中科院分区：
文献类型：
--
作者：
Sun, YX;Wang, JC;Taichman, RS
人类前列腺癌（PCa）在向骨骼转移的能力方面表现出很大差异。识别与侵袭性表型相关的分子将有助于确定前列腺癌的亚型，并最终带来更好的治疗策略。趋化因子基质衍生因子 - 1（SDF - 1或CXCL12）及其受体CXCR4目前已知可调节越来越多的正常和恶性细胞类型的迁移和存活，包括乳腺癌、胰腺癌、胶质母细胞瘤等。本研究通过使用由600多名患者的临床样本构建的高密度组织微阵列确定CXCR4和CXCL12在人体中的表达，扩展了我们之前的研究。这些数据表明，CXCR4蛋白在局限性和转移性癌症中的表达显著升高。在RNA水平上，人类前列腺癌肿瘤也表达CXCR4和相关信息，但总体而言，差异不显著，这表明受体的转录后调控在调节蛋白表达中起主要作用。对于CXCL12信息也有类似的观察结果，但在这种情况下，与正常组织相比，转移性病变表达更多的CXCL12信息。前列腺癌细胞系也表达CXCL12 mRNA，并响应CXCL12调节mRNA表达且分泌具有生物活性的蛋白质。此外，针对CXCL12的中和抗体降低了亲骨性LNCaP C4 - 2B和PC3转移性肿瘤细胞的增殖。这些研究为肿瘤如何“归巢”到骨骼的分子基础以及可能解释其在特定靶器官中生长的机制提供了重要的新信息。
Human prostate cancers (PCa) express great variability in their ability to metastasize to bone. The identification of molecules associated with aggressive phenotypes will help to define PCa subsets and will ultimately lead to better treatment strategies. The chemokine stromal-derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 are now known to modulate the migration and survival of an increasing array of normal and malignant cell types including breast, pancreatic cancers, glioblastomas, and others. The present investigation extends our previous investigations by determining the expression of CXCR4 and CXCL12 in humans using high-density tissue microarrays constructed from clinical samples obtained from a cohort of over 600 patients. These data demonstrate that CXCR4 protein expression is significantly elevated in localized and metastastic cancers. At the RNA level, human PCa tumors also express CXCR4 and message, but overall, they were not significantly different suggesting post-transcriptional regulation of the receptor plays a major role in regulating protein expression. Similar observations were made for CXCL12 message, but in this case more CXCL12 message was expressed by metastastic lesions as compared to normal tissues. PCa cell lines also express CXCL12 mRNA, and regulate mRNA expression in response to CXCL12 and secrete biologically active protein. Furthermore, neutralizing antibody to CXCL12 decreased the proliferation of bone homing LNCaP C4-2B and PC3 metastastic tumor cells. These investigations provide important new information pertaining to the molecular basis of how tumors may 'home' to bone, and the mechanisms that may account for their growth in selected end organs.