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دانلود رایگان مقاله افزایش واسکولاریزاسیون تومور با شیمی درمانی از طریق تشکیل سیگنالینگ شکاف

عنوان فارسی: افزایش واسکولاریزاسیون تومور با شیمی درمانی از طریق تشکیل سیگنالینگ شکاف اندوتلیال حاصل از تومور در سرطان پستان
عنوان انگلیسی: Chemotherapy enhances tumor vascularization via Notch signalingmediated formation of tumor-derived endothelium in breast cancer
تعداد صفحات مقاله انگلیسی : 13 تعداد صفحات ترجمه فارسی : ترجمه نشده
سال انتشار : 2016 نشریه : الزویر - Elsevier
فرمت مقاله انگلیسی : PDF کد محصول : E2304
محتوای فایل : PDF حجم فایل : 4 Mb
رشته های مرتبط با این مقاله: پزشکی و داروسازی
گرایش های مرتبط با این مقاله: ایمونولوژی، آسیب شناسی و خون شناسی
مجله: فارماکولوژی بیوشیمی - Biochemical Pharmacology
دانشگاه: دانشکده علوم دارویی، دانشگاه جیانگنان، چین
کلمات کلیدی: شیمی درمانی، سلول های سرطان پستان، سلول های اندوتلیال، شکاف سیگنالینگ
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چکیده

abstract

It is believed that tumor cells can give rise to endothelial cells and tumor endothelium has a neoplastic origin. Yet, the stimuli and underlying mechanism remain unclear. Here, we demonstrate that adriamycin or paclitaxel, first-line chemotherapy agent, induced breast cancer cells to generate morphological, phenotypical and functional features of endothelial cells in vitro. In xenografts models, challenges from adriamycin or paclitaxel induced cancer cells to generate the majority of microvessels. Importantly, in breast cancer specimens from patients with neoadjuvant anthracycline-based or taxane-based chemotherapy, tumor-derived endothelial microvessels, lined by EGFR-amplified or/and TP53+ -CD31+ endothelial cells, was significantly higher in patients with progressive or stable disease (PD/SD) than in those with a partial or complete response (PR/CR). Further, exposure to the Notch signaling inhibitor and gene silencing studies showed that Notch signaling inhibition or silencing Nothc4/Dll3 decreased endothelial markers and function of tumor-derived endothelial cells under chemotherapy treatment, which may be through VEGFR3. Thus, our findings demonstrate that chemotherapy induces functional tumor-derived endothelial microvessels by mediating Notch signaling and VEGF signaling, and may provide new targets for antiangiogenesis therapy in breast cancer.

بحث

4. Discussion

Although angiogenesis has become an important target in the treatment of breast cancer, anti-angiogenic agents have demonstrated limited activity and their underlying mechanism of action are still unknown. Here, we demonstrated that breast cancer cells in the context of chemotherapy are able to give rise to functional ECs in vascular networks mediated by Notch signaling in breast cancer. It is generally known that breast cancer shows intratumoral heterogeneity. The ability of cancer stem-like cells to directly contribute to the tumor vasculature by EC differentiation has been reported previously in breast cancer, and similar endothelial potential is shared by ovarian cancer [37], glioblastoma and lymphoma [12–14]. Thus, it is believed CSC of these tumors contributed to this endothelial transition but the origin or stimuli ofCSCs remains unclear. CSCs may be derived from normal stem cells, their high-self renewal ability enables them to accumulate a series of genetic and epigenetic changes that promote them into CSCs. However, in this study, we may provide another explanation of CSCs origin: induced by chemotherapies, both clinical samples from neoadjuvant chemotherapy of breast cancer and in vitro/ in vivo studies suggested the chemotherapy is able to induce normal tumor cells to give rise to endothelial cells through Notch pathways. Therefore, Our finding may explain the reason for failures in anti-angiogenesis therapy-combined neoadjuvant chemotherapy clinically: (1) Chemotherapy unveils the mesenchymal and CSCs features in tumor cells, thus enhance the tumor growth/metastasis by endowing anti-apoptosis ability to tumor cells from mesenchymal cells and CSCs; (2) chemotherapy promotes eNOS expression, VEGF secretion and NO release in those cancer cells, which is not only a feature of endothelial cells, but make tumor cells gaining of potent immunosuppressive capacity, a way of cancer cells to enter the blood circulation and metastasize to distant organ was offered; (3) chemotherapy enhanced the ability of cancer cells to organize into capillary-like structures by redifferentiation ability of mesenchymal cells and CSCs into endothelial, thus more nutrients and oxygen were provided to support tumor growth; (4) those mesenchyme or CSCs derived endothelial not only play an angiogenesis role, but also save the CSCs feature of hardly apoptosis when confront anti-angiogenic drugs.

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