Comedo-ductal carcinoma in situ A paradoxical role for programmed cell death
Comedo-ductal carcinoma in situ A paradoxical role for programmed cell death
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DOI：
10.4161/cbt.7.11.6781
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发表时间：
2008-11-01
影响因子：
3.6
通讯作者：
Miller, Fred R.
中科院分区：
文献类型：
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作者：
Shekhar, Malathy P. V.;Tait, Larri;Miller, Fred R.
粉刺-DCIS 是浸润前乳腺肿瘤的一种组织学亚型，其特征是显着的细胞凋亡，并且比其他 DCIS 亚型具有更大的恶性潜力。我们研究了粉刺 DCIS 中的细胞凋亡机制及其在粉刺 DCIS 转化为浸润性癌中的作用。对临床粉刺 DCIS 切除和 MCF10DCIS.com 人类乳腺癌模型进行了分析，该模型产生类似于粉刺 DCIS 的病变。通过 TUNEL 鉴定凋亡的管腔细胞和肌上皮细胞，并通过蛋白质印迹、Mitocapture 和免疫组织化学测定评估对切割的 PARP 抗体的反应性和细胞死亡。 MCF10DCIS.com 细胞在体外发生自发凋亡，无论是单层细胞还是多细胞球体；它与线粒体膜通透性增加、Bax/Bcl-2 比率增加有关，并通过 caspase-9 依赖性 p53 独立途径发生。这表明细胞凋亡不依赖于基质，并且细胞被编程为经历细胞凋亡。使用裂解的 PARP 抗体进行的免疫染色显示，在临床粉刺 DCIS 和体内 MCF10DCIS.com 病变中，肌上皮细胞凋亡发生在病变进展为粉刺 DCIS 之前。在临床和 MCF10DCIS.com 病变中转化为粉刺型 DCIS 之前，在实体 DCIS 病变的间质和上皮中观察到 MMP-2、MMP-3、MMP-9 和 MMP-11 的强烈染色。明胶酶谱显示 MCF10DCIS 裂解物和条件培养基中 MMP-2 水平较高。 com 细胞正在发生凋亡。这些数据表明，来自导管外部（微环境）和内部（内部遗传改变）的信号协同作用，触发肌上皮和管腔上皮细胞的凋亡。我们的研究结果表明自发性细胞凋亡与粉刺导管原位癌的病因和进展有关。自发性细胞凋亡可能促进细胞的消除，从而允许对自发性细胞凋亡具有抵抗力的癌细胞扩张和恶性转化。
Comedo-DCIS is a histologic subtype of preinvasive breast neoplasia that is characterized by prominent apoptotic cell death and has greater malignant potential than other DCIS subtypes. We investigated the mechanisms of apoptosis in comedo-DCIS and its role in conversion of comedo-DCIS to invasive cancer. Clinical comedo-DCIS excisions and the MCF10DCIS.com human breast cancer model which produces lesions resembling comedo-DCIS were analyzed. Apoptotic luminal and myoepithelial cells were identified by TUNEL and reactivity to cleaved PARP antibody and cell death assessed by Western blotting, Mitocapture and immunohistochemical assays. MCF10DCIS.com cells undergo spontaneous apoptosis in vitro, both in monolayers and multicellular spheroids; it is associated with increased mitochondrial membrane permeability, increase in Bax/Bcl-2 ratio and occurs via caspase-9-dependent p53-independent pathway. This suggests that apoptosis is stromal-independent and that the cells are programmed to undergo apoptosis. Immunostaining with cleaved PARP antibody showed that myoepithelial apoptosis occurs before lesions progress to comedo-DCIS in both clinical comedo-DCIS and in vivo MCF10DCIS.com lesions. Intense staining for MMP-2, MMP-3, MMP-9 and MMP-11 was observed in the stroma and epithelia of solid DCIS lesions prior to conversion to comedo-DCIS in clinical and MCF10DCIS.com lesions. Gelatin zymography showed higher MMP-2 levels in lysates and conditioned media of MCF10DCIS. com cells undergoing apoptosis. These data suggest that signals arising from the outside (microenvironmental) and inside (internal genetic alterations) of the duct act in concert to trigger apoptosis of myoepithelial and luminal epithelial cells. Our findings implicate spontaneous apoptosis in both the etiology and progression of comedo-DCIS. It is possible that spontaneous apoptosis facilitates elimination of cells thus permitting expansion and malignant transformation of cancer cells that are resistant to spontaneous apoptosis.