Sun Yan-Xi, Wang Jingcheng, Shelburne Charles E, Lopatin Dennis E, Chinnaiyan Arul M, Rubin Mark A, Pienta Kenneth J, Taichman Russell S
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan 48109-1078, USA.
J Cell Biochem. 2003 Jun 1;89(3):462-73. doi: 10.1002/jcb.10522.
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.
人类前列腺癌（PCa）转移至骨骼的能力存在很大差异。鉴定与侵袭性表型相关的分子将有助于定义前列腺癌亚群，并最终带来更好的治疗策略。现在已知趋化因子基质细胞衍生因子-1（SDF-1或CXCL12）及其受体CXCR4可调节包括乳腺癌、胰腺癌、胶质母细胞瘤等在内的越来越多正常和恶性细胞类型的迁移和存活。本研究通过使用从600多名患者队列中获得的临床样本构建的高密度组织微阵列，确定CXCR4和CXCL12在人类中的表达，扩展了我们之前的研究。这些数据表明，CXCR4蛋白表达在局限性癌和转移性癌中显著升高。在RNA水平上，人类前列腺癌肿瘤也表达CXCR4和信息，但总体而言，它们没有显著差异，表明受体的转录后调节在调节蛋白表达中起主要作用。对CXCL12信息也有类似观察结果，但在这种情况下，与正常组织相比，转移性病变表达的CXCL12信息更多。前列腺癌细胞系也表达CXCL12 mRNA，并响应CXCL12调节mRNA表达并分泌生物活性蛋白。此外，针对CXCL12的中和抗体降低了归巢至骨的LNCaP C4-2B和PC3转移性肿瘤细胞的增殖。这些研究提供了有关肿瘤如何“归巢”至骨的分子基础以及可能解释其在选定终末器官中生长的机制的重要新信息。
