Department of Chemistry, University of J.J. Strossmayer of Osijek, Cara Hadrijana 8/A, HR-31000 Osijek, Croatia; Division of Hematology and Oncology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.
Division of Hematology and Oncology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA; The Warren Alpert Medical School of Brown University, 222 Richmond Street, Providence, RI 02903, USA.
Exp Mol Pathol. 2018 Aug;105(1):89-97. doi: 10.1016/j.yexmp.2018.05.014. Epub 2018 May 29.
The critical molecular and cellular mechanisms involved in the development and progression of prostate cancer remain elusive. In this report, we demonstrate that normal rat prostate epithelial cells (PEC) undergo spontaneous transformation at high passage (p > 85) evidenced by the acquisition of anchorage independent growth when plated on soft agar and tumorigenicity when injected into immunodeficient mice. In addition, we also report the discovery of a minor subpopulation of spontaneously transformed PEC derived from high passage PEC with the ability to migrate through a layer of 1% agar and form expanding colonies on the underlying plastic substratum. Comparison of these soft agar invasive (SAI) cells with low (p < 35), mid (p36-84) and high passage (p > 85) PEC identified marked differences in cell morphology, proliferation and motility. The SAI subpopulation was more tumorigenic than the high passage anchorage independent cultures from which they were isolated, as manifested by a decreased latency period and an increase in the size of tumors arising in immunodeficient mice. In contrast, low and mid passage cells were unable to grow on soft agar and failed to form tumors when injected into immunodeficient mice. Screening with antibody-based signaling arrays identified several differences in the altered expression levels of signaling proteins between SAI-derived cells and low or high passage PEC, including the up-regulation of EGFR and MAPK-related signaling pathways in SAI-selected cells. In summary, these studies suggest that the SAI assay selects for a novel, highly tumorigenic subpopulation of transformed cells that may represent an early step in the progression of slow growing prostatic carcinomas into more rapidly growing and aggressive tumors.
前列腺癌发生和发展所涉及的关键分子和细胞机制仍然难以捉摸。在本报告中，我们证明正常大鼠前列腺上皮细胞（PEC）在高传代（p > 85）时会自发转化，表现在软琼脂上培养时获得锚定非依赖性生长，以及注射入免疫缺陷小鼠时形成肿瘤。此外，我们还报告了从高传代 PEC 中分离出具有穿过 1%琼脂层并在下面塑料基底上形成扩展菌落能力的自发转化 PEC 的小亚群的发现。将这些软琼脂侵袭性（SAI）细胞与低（p < 35）、中（p36-84）和高传代（p > 85）PEC 进行比较，发现细胞形态、增殖和运动能力存在明显差异。SAI 亚群比它们分离自的高传代锚定非依赖性培养物具有更高的致瘤性，表现为潜伏期缩短和免疫缺陷小鼠中肿瘤形成的增加。相比之下，低传代和中传代细胞无法在软琼脂上生长，并且当注射到免疫缺陷小鼠中时无法形成肿瘤。基于抗体的信号转导阵列筛选发现，SAI 衍生细胞与低或高传代 PEC 之间信号蛋白表达水平的改变存在几种差异，包括 SAI 选择细胞中 EGFR 和 MAPK 相关信号通路的上调。总之，这些研究表明，SAI 测定法选择了一种新型的、高致瘤性转化细胞亚群，这可能代表缓慢生长的前列腺癌向更快速生长和侵袭性肿瘤进展的早期步骤。
