Assoun Erika N, Meyer April N, Jiang Maggie Y, Baird Stephen M, Haas Martin, Donoghue Daniel J
Division of Biological Sciences, University of California San Diego, La Jolla, San Diego, CA 92093, USA.
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, San Diego, CA 92093, USA.
Oncotarget. 2020 Mar 24;11(12):1075-1084. doi: 10.18632/oncotarget.27524.
Prostate cancer affects hundreds of thousands of men and families throughout the world. Although chemotherapy, radiation, surgery, and androgen deprivation therapy are applied, these therapies do not cure metastatic prostate cancer. Patients treated by androgen deprivation often develop castration resistant prostate cancer which is incurable. Novel approaches of treatment are clearly necessary. We have previously shown that prostate cancer originates as a stem cell disease. A prostate cancer patient sample, #87, obtained from prostatectomy surgery, was collected and frozen as single cell suspension. Cancer stem cell cultures were grown, single cell-cloned, and shown to be tumorigenic in SCID mice. However, outside its natural niche, the cultured prostate cancer stem cells lost their tumor-inducing capability and stem cell marker expression after approximately 8 transfers at a 1:3 split ratio. Tumor-inducing activity could be restored by inducing the cells to pluripotency using the method of Yamanaka. Cultures of human prostate-derived normal epithelial cells acquired from commercial sources were similarly induced to pluripotency and these did not acquire a tumor phenotype . To characterize the iPS87 cell line, cells were stained with antibodies to various markers of stem cells including: ALDH7A1, LGR5, Oct4, Nanog, Sox2, Androgen Receptor, and Retinoid X Receptor. These markers were found to be expressed by iPS87 cells, and the high tumorigenicity in SCID mice of iPS87 was confirmed by histopathology. This research thus characterizes the iPS87 cell line as a cancer-inducing, stem cell-like cell line, which can be used in the development of novel treatments for prostate cancer.
前列腺癌影响着全球成千上万的男性及其家庭。尽管应用了化疗、放疗、手术和雄激素剥夺疗法,但这些疗法并不能治愈转移性前列腺癌。接受雄激素剥夺治疗的患者常常会发展为去势抵抗性前列腺癌,而这种癌症是无法治愈的。显然需要新的治疗方法。我们之前已经表明,前列腺癌起源于一种干细胞疾病。从前列腺切除术手术中获取的前列腺癌患者样本#87,被收集并冻存为单细胞悬液。培养癌干细胞,进行单细胞克隆,并证明其在SCID小鼠中具有致瘤性。然而,在其天然生态位之外,培养的前列腺癌干细胞在以1:3的比例传代约8次后,失去了肿瘤诱导能力和干细胞标志物表达。通过使用山中伸弥的方法将细胞诱导为多能性,可以恢复肿瘤诱导活性。从商业来源获取的人前列腺来源的正常上皮细胞培养物也同样被诱导为多能性,并且这些细胞没有获得肿瘤表型。为了表征iPS87细胞系,用针对各种干细胞标志物的抗体对细胞进行染色,这些标志物包括:醛脱氢酶7A1(ALDH7A1)、富含亮氨酸重复序列的G蛋白偶联受体5(LGR5)、八聚体结合转录因子4(Oct4)、Nanog、性别决定区Y框蛋白2(Sox2)、雄激素受体和视黄酸X受体。发现这些标志物在iPS87细胞中表达,并且通过组织病理学证实了iPS87在SCID小鼠中的高致瘤性。因此,这项研究将iPS87细胞系表征为一种具有癌症诱导能力的、类似干细胞的细胞系,可用于开发前列腺癌的新疗法。