Morikawa Akemi, Takeuchi Tamotsu, Kito Yusuke, Saigo Chiemi, Sakuratani Takuji, Futamura Manabu, Yoshida Kazuhiro
Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Frontier Science for Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan.
PLoS One. 2015 May 8;10(5):e0125762. doi: 10.1371/journal.pone.0125762. eCollection 2015.
We examined the pathobiological properties of beclin-1, which is a key regulator of autophagosome formation in invasive ductal carcinoma of the breast, with a particular focus on the cancer microenvironment. Immunohistochemistry demonstrated that cancer cells and stromal mesenchymal cells expressed beclin-1 in 68 and 38 of 115 invasive ductal cancers, respectively. Expression of beclin-1 in cancer or stromal cells alone did not correlate with patient prognosis. In contrast, loss of beclin-1 in cancer cells and overexpression in stromal mesenchymal cells was associated with local cancer recurrence, postoperative lymph node metastasis, and a poor disease-free survival rate. A comprehensive gene expression analysis was performed on a co-culture of breast cancer cells and mesenchymal stromal cells, that latter of which either expressed beclin-1 or was depleted of beclin-1 by siRNA. Notably, siRNA-mediated downregulation of beclin-1 in mesenchymal cells co-cultured with breast cancer cells decreased the levels of various pro-inflammatory cytokines, their receptors, and collagen receptors. Quantitative reverse transcription polymerase chain reaction analysis confirmed that reduction of stromal beclin-1 expression decreased the expression of IL-1β and collagen receptor discoidin domain receptor 2 (DDR2). Microenvironmental IL-1β is believed to play an important role in tumor invasion. Recent work has also indicated that overexpression of DDR2 contributes to breast cancer invasion and lymph node metastasis. Taken together, these findings indicate beclin-1 expression in the stroma might be important for shaping the breast cancer microenvironment and thus could be a potent molecular target in patients with invasive ductal carcinoma of the breast.
我们研究了在乳腺浸润性导管癌中自噬体形成的关键调节因子Beclin-1的病理生物学特性，特别关注癌症微环境。免疫组织化学显示，在115例浸润性导管癌中，癌细胞和基质间充质细胞分别有68例和38例表达Beclin-1。仅癌细胞或基质细胞中Beclin-1的表达与患者预后无关。相反，癌细胞中Beclin-1缺失而基质间充质细胞中Beclin-1过表达与局部癌症复发、术后淋巴结转移及无病生存率低相关。对乳腺癌细胞和间充质基质细胞的共培养物进行了全面的基因表达分析，后者要么表达Beclin-1，要么通过小干扰RNA（siRNA）使其Beclin-1缺失。值得注意的是，与乳腺癌细胞共培养的间充质细胞中，siRNA介导的Beclin-1下调降低了各种促炎细胞因子、其受体和胶原受体的水平。定量逆转录聚合酶链反应分析证实，基质Beclin-1表达的降低会降低白细胞介素-1β（IL-1β）和胶原受体盘状结构域受体2（DDR2）的表达。微环境中的IL-1β被认为在肿瘤侵袭中起重要作用。最近的研究还表明，DDR2的过表达有助于乳腺癌的侵袭和淋巴结转移。综上所述，这些发现表明基质中Beclin-1的表达可能对塑造乳腺癌微环境很重要，因此可能是乳腺浸润性导管癌患者的一个有效的分子靶点。
