Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Int J Cancer. 2010 Jul 15;127(2):321-31. doi: 10.1002/ijc.25043.
Prostate cancer is the most common malignancy in men, and patients with metastatic disease have poor outcome even with the most advanced therapeutic approaches. Most cancer therapies target the bulk tumor cells, but may leave intact a small population of tumor-initiating cells (TICs), which are believed to be responsible for the subsequent relapse and metastasis. Using specific surface markers (CD44, integrin alpha(2)beta(1) and CD133), Hoechst 33342 dye exclusion, and holoclone formation, we isolated TICs from a panel of prostate cancer cell lines (DU145, C4-2 and LNCaP). We have found that prostate TICs have significant telomerase activity which is inhibited by imetelstat sodium (GRN163L), a new telomerase antagonist that is currently in Phase I/II clinical trials for several hematological and solid tumor malignancies. Prostate TICs telomeres were of similar average length to the telomeres of the main population of cells and significant telomere shortening was detected in prostate TICs as a result of imetelstat treatment. These findings suggest that telomerase inhibition therapy may be able to efficiently target the prostate TICs in addition to the bulk tumor cells, providing new opportunities for combination therapies.
前列腺癌是男性最常见的恶性肿瘤，即使采用最先进的治疗方法，转移性疾病患者的预后仍然很差。大多数癌症疗法针对的是大量肿瘤细胞，但可能会使一小部分肿瘤起始细胞（TICs）完好无损，这些细胞被认为是导致随后复发和转移的原因。我们使用特定的表面标记物（CD44、整合素 alpha(2)beta(1)和 CD133）、Hoechst 33342 染料排除和全克隆形成，从一系列前列腺癌细胞系（DU145、C4-2 和 LNCaP）中分离出 TICs。我们发现前列腺 TICs 具有显著的端粒酶活性，这种活性被 imetelstat 钠（GRN163L）抑制，imetelstat 钠是一种新的端粒酶拮抗剂，目前正在进行几项血液学和实体瘤恶性肿瘤的 I/II 期临床试验。前列腺 TICs 的端粒与主要细胞群体的端粒具有相似的平均长度，并且由于 imetelstat 治疗，在前列腺 TICs 中检测到明显的端粒缩短。这些发现表明，端粒酶抑制疗法除了可以针对大量肿瘤细胞外，还可能能够有效地针对前列腺 TICs，为联合治疗提供新的机会。
