Identification of putative stem cell markers, CD133 and CXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens
Identification of putative stem cell markers, CD133 and CXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens
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DOI：
10.1158/0008-5472.can-06-4429
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Rhim, Johng S.
中科院分区：
文献类型：
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作者：
Miki, Jun;Furusato, Bungo;Rhim, Johng S.
了解正常和癌症干细胞可能会为前列腺癌的起源和新的治疗方法提供洞察力。前列腺癌和正常前列腺干细胞最近被鉴定为CD44(+)/α(2)β(高)(1)/CD133(+)表型。基质细胞衍生因子-1(SDF-1)及其受体CXCR4具有多种重要功能，包括干细胞归巢和癌细胞转移。我们在这里展示了人类端粒酶逆转录酶(HTERT)永生化的原代非恶性(RC-165N/hTERT)和恶性(RC-92a/hTERT)肿瘤来源的人前列腺上皮细胞株保持干细胞特性的CD133(+)/CD44(+)/α(2)β(+)(1)/34βE12(+)/CK18(+)/p63(-)/雄激素受体(AR)(-)/PSA(-)表型。HTERT永生化细胞中CD133的表达高于原代前列腺细胞。这些永生化细胞在非贴壁培养系统中表现出“前哨球体”，并保持了较高的CD133表达。这些永生化细胞系的CD133细胞具有较高的增殖能力，并能分化为AR(+)表型。在三维培养中，RC-165N/hTERT细胞的CD133(+)细胞产生分枝状结构，而RC-92a/hTERT细胞的CD133(+)细胞产生大的不规则球体，分枝结构较少。SDF-1诱导共表达CXCR4的RC-92a/hTERT细胞的CD133(+)细胞迁移，但抗CXCR4抗体可抑制CD133(+)细胞的迁移。CXCR4/SDF-I可能支持肿瘤干细胞对肿瘤的趋化作用。此外，临床前列腺癌标本的免疫组织化学染色显示CD133在前列腺癌细胞亚群中有表达，并与AR的缺失相对应。CD133(+)癌细胞中也有CXCR4的表达。这些新颖的体外模型可能为研究正常和肿瘤干细胞在前列腺癌中的生物学特性和功能整合提供有用的工具。
Understanding normal and cancer stem cells may provide insight into the origin of and new therapeutics for prostate cancer. Normal and cancer stem cells in prostate have recently been identified with a CD44(+)/alpha(2)beta(high)(1)/CD133(+) phenotype. Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, have multiple essential functions, including homing of stem cells and metastasis of cancer cells. We show here that human telomerase reverse transcriptase (hTERT)-immortalized primary nonmalignant (RC-165N/hTERT) and malignant (RC-92a/ hTERT) tumor-derived human prostate epithelial cell lines retain stem cell properties with a CD133(+)/CD44(+)/alpha(2)beta(+)(1)/ 34 beta E12(+)/CK18(+)/p63(-)/androgen receptor (AR)(-)/PSA(-) phenotype. Higher CD133 expression was detected in the hTERT-immortalized cells than in primary prostate cells. These immortalized cells exhibited "prostaspheres" in nonadherent culture systems and also maintained higher CD133 expression. The CD133 cells from these immortalized cell lines had high proliferative potential and were able to differentiate into AR(+) phenotype. In three-dimensional culture, the CD133(+) cells from RC-165N/hTERT cells produced branched structures, whereas the CD133(+) cells from RC-92a/hTERT cells produced large irregular spheroids with less branched structures. SDF-1 induced, but anti-CXCR4 antibody inhibited, migration of CD133(+) cells from RC-92a/hTERT cells, which coexpressed CXCR4. CXCR4/SDF-I may sustain tumor chemotaxis in cancer stem cells. Furthermore, immumostaining of clinical prostate specimens showed that CD133 expression was detected in a subpopulation of prostate cancer cells and corresponded to the loss of AR. Expression of CXCR4 was also detected in CD133(+) cancer cells. These novel in vitro models may offer useful tools for the study of the biological features and functional integration of normal and cancer stem cells in prostate.