白花丹醌通过VEGFR2-RAS信号通路抑制肿瘤血管新生以及LGR4通过调节肿瘤干细胞促进乳腺癌发生发展的机制研究
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摘要
本人在攻读博士学位期间的研究分为两部分,分别从药物开发及基因治疗两个不同方向阐述了本人在肿瘤治疗方面的研究成果。第一部分讨论了中草药单体白花丹醌通过抗血管新生抑制肿瘤的机制研究,第二部分讨论了LGR4/GPR48通过影响肿瘤干细胞从而调节乳腺癌发生发展的研究。
1.血管新生是在已生成血管的基础上,通过内皮细胞的增殖、迁移以及与周围环境的交流与协调,最终形成新的血管的多步骤过程.由于血管新生是几乎所有肿瘤发生发展的共性,针对其开发的药物尤其具有临床价值。
白花丹醌是从中草药白花丹中提取出来的黄色针状结晶,先前的研究表明其具有抗病毒、抗生育、抗凝血以及抗肿瘤的功效,最近也有研究表明其在抗动脉粥样硬化以及抗炎中的作用,但其在肿瘤血管新生中的相关研究尚未有人报道。因此在本研究的第一部分,我们发现白花丹醌能抑制由VEGF诱导的内皮细胞的生长及迁移等生物学功能,并且在鸡胚尿囊膜和小鼠角膜的血管新生经典实验中有着明显的抗血管新生功效。在结肠癌和前列腺癌的裸鼠荷瘤实验中,白花丹醌进一步的抑制了体内肿瘤血管新生。在白花丹醌影响血管新生的分子机理探索的过程中,我们发现白花丹醌显著地抑制了内皮细胞在VEGF诱导下F-actin应力纤维的形成,而调节这种应力纤维的一条重要信号通路就是Rac-PAK1-LIMK-Cofilin通路,另外我们也发现白花丹醌对内皮细胞的生长也有强烈的抑制作用,其中紧密相关的信号通路是MEK-ERK/JNK通路。这两条通路的共同上游是Ras蛋白,在内皮细胞中Ras蛋白又由VEGFR2所调控。因此我们检验了白花丹醌在这个信号级联反应中的作用,并证明了白花丹醌能够通过抑制VEGFR2的磷酸化从而抑制由VEGF活化的Ras下游的信号,并进一步影响内皮细胞迁移及生长,最终抑制肿瘤血管新生。因此,白花丹醌很可能成为抗肿瘤的候选药物。
2.肿瘤干细胞是肿瘤研究领域的新理论,该理论认为肿瘤的发生与转移都是有赖于存在于肿瘤细胞群体中极少部分的获得了干细胞特性的肿瘤细胞。该理论对于临床治疗药物耐受性,抗辐射性以及许多肿瘤的休眠行为提供了很好的解释。这个由干细胞驱动的肿瘤形成的理论引起了很多讨论与问题,包括是否在靶向快速分裂细胞的抗肿瘤治疗同时靶向到那些缓慢自我更新的肿瘤干细胞。因此最近对于肿瘤干细胞的特征的研究更多的集中在鉴定出那些使得肿瘤干细胞对于治疗干预更敏感更易受到攻击的信号通路。
G蛋白偶联受体是一大类膜结合蛋白家族,其中包括的蛋白都具有七次跨膜的结构,并承担将胞外刺激转导到胞内的功能。这类蛋白广泛地参与了对于包括免疫系统、神经系统发育等在内的生理病理过程的调控,因此GPCR已经成为现今50-60%的疾病治疗药物的直接或间接靶点。越来越多的实验及临床数据发现肿瘤细胞能够将GPCR的正常生理功能劫为己用,从而促进自己的生长,逃避免疫识别,增加自己的营养和氧气供应,侵入周围组织并最终散播到另外的器官。因此,调控GPCR以及其下游靶点可能为新的抗肿瘤策略以及肿瘤诊断与防治提供了新的机会。
LGR4/GPR48是G蛋白偶联受体大家族里的一员,在我们实验室研制的LGR4基因敲除小鼠中,发现了在骨发育,眼睛发育,肾功能以及雄性生殖系统中的缺陷,最近发表的文章提示LGR4在乳腺及前列腺发育中也起到调节作用,但是至今鲜有对LGR4在肿瘤中的研究。基于我们实验室初步的研究证明,LGR4在乳腺癌的发生发展中起到促进作用,但是否LGR4的这种对乳腺癌的促进作用是通过对肿瘤于细胞的调节而达到的尚未可知。所以我们通过将LGR4基因敲出老鼠与乳腺癌肿瘤干细胞小鼠模型进行杂交,发现将LGR4敲除之后,由WNT1驱动的肿瘤形成以及转移受到了明显的抑制,且存在于肿瘤中的以CD90+CD24+作为表面标志的乳腺癌肿瘤干细胞的功能被强烈抑制了。而存在于LGR4表达缺失的WNT1肿瘤中的肿瘤干细胞的发生频率也受到大幅度下调,其自我更新、分化及肿瘤再造功能都降低了。并且LGR4的下调能促进肿瘤细胞对化疗药物的敏感性。
因此,LGR4很有可能通过调节肿瘤干细胞而促进乳腺癌的发生发展,并很可能成为乳腺癌治疗的很好的靶点。
To better elaborate my research achievements from the aspects of drug development and gene therapy, my research work was divided into two distinct parts. In the first part,by which mechanism, plumbagin, the Chinese herb monomer, inhibits tumor growth through anti-angiogenesis function was discussed; in the second part, how LGR4/GPR48regulate breast cancer initiation and progression through cancer stem cell was lucubrated.
1. Angiogenesis is the multi-process composing of endothelial cell proliferation, migration and interaction as well as corporation with the environments based on the existing vessels. Because angiogenesis is the commonality for all the tumor development, drugs designed to target angiogenesis are of high clinical value.
Plumbagin is a crystal compound isolated from some Chinese herbs such as plumbaginaceae, Ebenaceae and Droseraceae. Previous studies showed its antibacterial, antifertility, anticoagulant and anti-cancer properties. And, recent studies reported its antiatherosclerotic and anti-inflammation effects as well. However its function in tumor angiogenesis has not yet been reported. So in the first part, I discovered that plumbagin can specifically inhibit endothelial cell proliferation and VEGF-induced migration. Furthermore, in chick embryo chorioallantoic membrane and mouse corneal assay, plumbagin exhibits strong anti-angiogenesis effect. In the human colon cancer and prostate cancer xenograft assays, plumbagin inhibits angiogenesis in vivo. To explore the underlined molecular mechanism, we found that plumbagin significantly decreased the ability of endothelial cell to from F-actin stress fiber under the VEGF induction. One of the most important signal pathways that cause this phenomenon is Rac-PAK1-LIMK-Cofilin pathway. Besides, plumbagin also regulates the proliferation of endothelial cells, which is controlled by MEK-ERK/JNK pathway. Both of these two pathways have the common upper stream regulator Ras, which is controlled by VEGFR2. Hence, we tested the role of plumbagin in this cascade, and proved that plmbagin can inhibit the phosphorylation of VEGFR2in the endothelial cells and down-regulate the VEGF activation for downstream signals of Ras pathway, then affects endothelial cell migration and proliferation, and ultimately inhibits tumor angiogenesis. Based on our study, plumbagin could be an anti-cancer drug candidate.
2. Cancer stem study is a new field for cancer research, and it is believed that the carcinomas originate from so called cancer stem cell population upon the oncogenic hit. This theory also provides new explanation on drug resistance, anti-radioactivity properties of cancer cells. Inevitably, some discussions and questions were raised up coming with the new theory, including whether the cancer treatment should switch from the traditional to the newly merging one. As a result, more research has been done to target on signaling pathways that are unique for cancer stem cell.
G coupled protein family consists of proteins that are characterized by a7transmembarane domain, and it function as a signal transducer. The loss of function of these proteins will lead to multiple human diseases, so50%to60%drugs approved by FDA are designed to specifically target this particular family. Numerous studies have found that tumor cell can take advantage GPCR signaling to overcome the obstacles preventing them from grow wild, and invade other organs through circulation by getting the nutrients and oxygen they need to survive. Therefore, it is important to unravel the mechanism under the regulation of GPCR family, and the success to do so will definitely help us get new strategy to diagnose and eventually win the battle against cancer.
LGR4/GPR48belongs to GPCR family, and we have found that the deletion of LGR4in mouse model led to severe development defect in bone, eye, renal and reproduction system. Our most recent paper also points out the importance of LGR4mammary gland development. However, the function of LGR4in cancer including breast cancer is barely known. Base on the data we have so far, we can conclude that LGR4must play a role in breast cancer, but the mechanism still not clear. To address this question, we crossed LGR4null/ko mouse with WNT1driven mouse tumor model. Interestingly, the progression of tumor, and the function of cells labeled by CD90+CD24+, the marker for breast cancer stem cell, are significantly suppressed in WNT+LGR4-/-LGR4mice. We also proved that the cancer stem cells population sorted from Wntl+LGR4-/-mice have poorer ability in self-renewal, in ivtro differentiation and in vivo tumor regeneration. Altogether, LGR4could be an essential pathway for cancer stem cell, therefore it has potential to become a promising drug target.
1.血管新生是在已生成血管的基础上,通过内皮细胞的增殖、迁移以及与周围环境的交流与协调,最终形成新的血管的多步骤过程.由于血管新生是几乎所有肿瘤发生发展的共性,针对其开发的药物尤其具有临床价值。
白花丹醌是从中草药白花丹中提取出来的黄色针状结晶,先前的研究表明其具有抗病毒、抗生育、抗凝血以及抗肿瘤的功效,最近也有研究表明其在抗动脉粥样硬化以及抗炎中的作用,但其在肿瘤血管新生中的相关研究尚未有人报道。因此在本研究的第一部分,我们发现白花丹醌能抑制由VEGF诱导的内皮细胞的生长及迁移等生物学功能,并且在鸡胚尿囊膜和小鼠角膜的血管新生经典实验中有着明显的抗血管新生功效。在结肠癌和前列腺癌的裸鼠荷瘤实验中,白花丹醌进一步的抑制了体内肿瘤血管新生。在白花丹醌影响血管新生的分子机理探索的过程中,我们发现白花丹醌显著地抑制了内皮细胞在VEGF诱导下F-actin应力纤维的形成,而调节这种应力纤维的一条重要信号通路就是Rac-PAK1-LIMK-Cofilin通路,另外我们也发现白花丹醌对内皮细胞的生长也有强烈的抑制作用,其中紧密相关的信号通路是MEK-ERK/JNK通路。这两条通路的共同上游是Ras蛋白,在内皮细胞中Ras蛋白又由VEGFR2所调控。因此我们检验了白花丹醌在这个信号级联反应中的作用,并证明了白花丹醌能够通过抑制VEGFR2的磷酸化从而抑制由VEGF活化的Ras下游的信号,并进一步影响内皮细胞迁移及生长,最终抑制肿瘤血管新生。因此,白花丹醌很可能成为抗肿瘤的候选药物。
2.肿瘤干细胞是肿瘤研究领域的新理论,该理论认为肿瘤的发生与转移都是有赖于存在于肿瘤细胞群体中极少部分的获得了干细胞特性的肿瘤细胞。该理论对于临床治疗药物耐受性,抗辐射性以及许多肿瘤的休眠行为提供了很好的解释。这个由干细胞驱动的肿瘤形成的理论引起了很多讨论与问题,包括是否在靶向快速分裂细胞的抗肿瘤治疗同时靶向到那些缓慢自我更新的肿瘤干细胞。因此最近对于肿瘤干细胞的特征的研究更多的集中在鉴定出那些使得肿瘤干细胞对于治疗干预更敏感更易受到攻击的信号通路。
G蛋白偶联受体是一大类膜结合蛋白家族,其中包括的蛋白都具有七次跨膜的结构,并承担将胞外刺激转导到胞内的功能。这类蛋白广泛地参与了对于包括免疫系统、神经系统发育等在内的生理病理过程的调控,因此GPCR已经成为现今50-60%的疾病治疗药物的直接或间接靶点。越来越多的实验及临床数据发现肿瘤细胞能够将GPCR的正常生理功能劫为己用,从而促进自己的生长,逃避免疫识别,增加自己的营养和氧气供应,侵入周围组织并最终散播到另外的器官。因此,调控GPCR以及其下游靶点可能为新的抗肿瘤策略以及肿瘤诊断与防治提供了新的机会。
LGR4/GPR48是G蛋白偶联受体大家族里的一员,在我们实验室研制的LGR4基因敲除小鼠中,发现了在骨发育,眼睛发育,肾功能以及雄性生殖系统中的缺陷,最近发表的文章提示LGR4在乳腺及前列腺发育中也起到调节作用,但是至今鲜有对LGR4在肿瘤中的研究。基于我们实验室初步的研究证明,LGR4在乳腺癌的发生发展中起到促进作用,但是否LGR4的这种对乳腺癌的促进作用是通过对肿瘤于细胞的调节而达到的尚未可知。所以我们通过将LGR4基因敲出老鼠与乳腺癌肿瘤干细胞小鼠模型进行杂交,发现将LGR4敲除之后,由WNT1驱动的肿瘤形成以及转移受到了明显的抑制,且存在于肿瘤中的以CD90+CD24+作为表面标志的乳腺癌肿瘤干细胞的功能被强烈抑制了。而存在于LGR4表达缺失的WNT1肿瘤中的肿瘤干细胞的发生频率也受到大幅度下调,其自我更新、分化及肿瘤再造功能都降低了。并且LGR4的下调能促进肿瘤细胞对化疗药物的敏感性。
因此,LGR4很有可能通过调节肿瘤干细胞而促进乳腺癌的发生发展,并很可能成为乳腺癌治疗的很好的靶点。
To better elaborate my research achievements from the aspects of drug development and gene therapy, my research work was divided into two distinct parts. In the first part,by which mechanism, plumbagin, the Chinese herb monomer, inhibits tumor growth through anti-angiogenesis function was discussed; in the second part, how LGR4/GPR48regulate breast cancer initiation and progression through cancer stem cell was lucubrated.
1. Angiogenesis is the multi-process composing of endothelial cell proliferation, migration and interaction as well as corporation with the environments based on the existing vessels. Because angiogenesis is the commonality for all the tumor development, drugs designed to target angiogenesis are of high clinical value.
Plumbagin is a crystal compound isolated from some Chinese herbs such as plumbaginaceae, Ebenaceae and Droseraceae. Previous studies showed its antibacterial, antifertility, anticoagulant and anti-cancer properties. And, recent studies reported its antiatherosclerotic and anti-inflammation effects as well. However its function in tumor angiogenesis has not yet been reported. So in the first part, I discovered that plumbagin can specifically inhibit endothelial cell proliferation and VEGF-induced migration. Furthermore, in chick embryo chorioallantoic membrane and mouse corneal assay, plumbagin exhibits strong anti-angiogenesis effect. In the human colon cancer and prostate cancer xenograft assays, plumbagin inhibits angiogenesis in vivo. To explore the underlined molecular mechanism, we found that plumbagin significantly decreased the ability of endothelial cell to from F-actin stress fiber under the VEGF induction. One of the most important signal pathways that cause this phenomenon is Rac-PAK1-LIMK-Cofilin pathway. Besides, plumbagin also regulates the proliferation of endothelial cells, which is controlled by MEK-ERK/JNK pathway. Both of these two pathways have the common upper stream regulator Ras, which is controlled by VEGFR2. Hence, we tested the role of plumbagin in this cascade, and proved that plmbagin can inhibit the phosphorylation of VEGFR2in the endothelial cells and down-regulate the VEGF activation for downstream signals of Ras pathway, then affects endothelial cell migration and proliferation, and ultimately inhibits tumor angiogenesis. Based on our study, plumbagin could be an anti-cancer drug candidate.
2. Cancer stem study is a new field for cancer research, and it is believed that the carcinomas originate from so called cancer stem cell population upon the oncogenic hit. This theory also provides new explanation on drug resistance, anti-radioactivity properties of cancer cells. Inevitably, some discussions and questions were raised up coming with the new theory, including whether the cancer treatment should switch from the traditional to the newly merging one. As a result, more research has been done to target on signaling pathways that are unique for cancer stem cell.
G coupled protein family consists of proteins that are characterized by a7transmembarane domain, and it function as a signal transducer. The loss of function of these proteins will lead to multiple human diseases, so50%to60%drugs approved by FDA are designed to specifically target this particular family. Numerous studies have found that tumor cell can take advantage GPCR signaling to overcome the obstacles preventing them from grow wild, and invade other organs through circulation by getting the nutrients and oxygen they need to survive. Therefore, it is important to unravel the mechanism under the regulation of GPCR family, and the success to do so will definitely help us get new strategy to diagnose and eventually win the battle against cancer.
LGR4/GPR48belongs to GPCR family, and we have found that the deletion of LGR4in mouse model led to severe development defect in bone, eye, renal and reproduction system. Our most recent paper also points out the importance of LGR4mammary gland development. However, the function of LGR4in cancer including breast cancer is barely known. Base on the data we have so far, we can conclude that LGR4must play a role in breast cancer, but the mechanism still not clear. To address this question, we crossed LGR4null/ko mouse with WNT1driven mouse tumor model. Interestingly, the progression of tumor, and the function of cells labeled by CD90+CD24+, the marker for breast cancer stem cell, are significantly suppressed in WNT+LGR4-/-LGR4mice. We also proved that the cancer stem cells population sorted from Wntl+LGR4-/-mice have poorer ability in self-renewal, in ivtro differentiation and in vivo tumor regeneration. Altogether, LGR4could be an essential pathway for cancer stem cell, therefore it has potential to become a promising drug target.
引文
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