Mammary carcinoma behavior is programmed in the precancer stem cell
Mammary carcinoma behavior is programmed in the precancer stem cell
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DOI：
10.1186/bcr2104
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发表时间：
2008-01-01
影响因子：
7.4
通讯作者：
Borowsky, Alexander D.
中科院分区：
文献类型：
--
作者：
Damonte, Patrizia;Hodgson, J. Graeme;Borowsky, Alexander D.
导管原位癌（DCIS）的“MINO”（乳腺上皮内瘤样增生）小鼠模型由6个具有不同形态表型和行为的系组成，每个系都符合实验定义的“癌前病变”标准。具体来说，这些细胞系在清除的乳腺脂肪垫中生长，并持续发展为能够异位生长的侵袭性表型。每个细胞系向癌的转移具有一致的潜伏期，其中三个细胞系也表现出肺转移的潜力。方法采用细菌人工染色体和寡核苷酸阵列比较基因组杂交、微卫星PCR、端粒酶重复扩增等方法对腺清除原位癌前MINO移植组织进行分析。将MINO细胞分离后进行三维培养，移植到同基因乳腺清除的乳腺脂肪垫中。结果比较基因组杂交表明，癌前和侵袭性肿瘤在遗传上是稳定的，在一些品系中存在低水平的改变，包括整个染色体的增加。虽然偶尔会发现自发的病灶放大和缺失，但没有变化与进展相关。微卫星分析显示，在一条MINO线内，低频的变化主要是永久性的。与正常小鼠乳腺相比，MINO和衍生肿瘤的端粒酶活性均升高。分离癌前病变细胞和单细胞的三维“球形”培养揭示了肌上皮和管腔分化的双电位，以及独特的三维“微球”的形成。这些微球表现出介于来源于正常细胞和癌细胞的球状体之间的特征。移植单细胞衍生的MINOsphere再现了癌前形态的生长和向癌的进展。结论这些数据证实了癌前“干细胞”具有自我更新和多谱系分化的能力，是侵袭性癌症的起源。在该模型的背景下，这些细胞具有程序化的潜伏和转移潜力，似乎不需要连续的遗传“命中”来进行转化。
Introduction The 'MINO' (mammary intraepithelial neoplasia outgrowth) mouse model of ductal carcinoma in situ (DCIS) consists of six lines with distinct morphologic phenotypes and behavior, each meeting experimentally defined criteria for 'precancer'. Specifically, these lines grow orthotopically in cleared mammary fat pads and consistently progress to an invasive phenotype that is capable of ectopic growth. Transition to carcinoma has a consistent latency for each line, and three of the lines also exhibit pulmonary metastatic potential.Methods Gland cleared orthotopic transplanted precancer MINO tissues were analyzed by bacterial artifical chromosome and oligo array comparative genomic hybridization, microsatellite PCR, and telomerase repeat amplification assay. MINO cells were dissociated and cultured in three dimensional culture and transplanted in syngeneic gland cleared mammary fat pads.Results Comparative genomic hybridization shows that the precancer and invasive tumors are genetically stable, with low level changes including whole chromosome gains in some lines. No changes are associated with progression, although spontaneous focal amplifications and deletions were detected occasionally. Microsatellite analysis shows a low frequency of alterations that are predominantly permanent within a MINO line. Telomerase activity is increased in both the MINO and the derived tumors when compared with normal mouse mammary gland. Dissociation of the precancer lesion cells and three dimensional 'spheroid' culture of single cells reveals a bipotential for myoepithelial and luminal differentiation and the formation of unique three-dimensional 'MINOspheres'. These MINOspheres exhibit features that are intermediate between spheroids that are derived from normal and carcinoma cells. Transplantation of a single cell derived MINOsphere recapitulates the outgrowth of the precancer morphology and progression to carcinoma.Conclusion These data establish a precancer 'stem' cell that is capable of self-renewal and multilineage differentiation as the origin of invasive cancer. Within the context of this model, these cells have programmed potential for latency and metastasis that does not appear to require sequential genetic 'hits' for transformation.