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[ARVO2013]眼部肿瘤的发病机制及治疗
——以色列Hadassah大学J.Pe’er教授专访

玻璃体视网膜  作者:  J.Pe’er  2013/6/26 15:59:00
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内容概要:《国际眼科时讯》:抗血管内皮生长因子(VEGF)药物已经被用于治疗多种新生血管性疾病。您对目前的抗新生血管治疗有何见解?

  <International Ophthalmology Times>: Dr. Pe’er, anti-VEGF (anti- vascular endothelial growth factor) medicines have been used in the treatment of a variety of neovascular diseases. What is your opinion about the current anti-VEGF therapies?
        Prof.Pe’er  : In response to your question I would like to tell you a quick story. A story that actually combines my field of expertise, ocular oncology, VEGF, and anti-VEGF and all the treatments for vascular diseases of the retina. And this story will take us back twenty-two to 1991 and at that time no one in oncology knew about VEGF and actually at that time the original name of VEGF was PGF (placental growth factor) and it had been described just a few years earlier but no one yet knew the importance of VEGF to the field of ophthalmology and in general. So at that time I was working on research on melanoma and we found a kind of vascular petronas, specific vascular petronas but I will not go into details now that were important for the prognosis of melanoma. And when I went back home from sabbatical and worked on the melanoma I asked myself why did we have these vascular petronas. And then I looked for somebody to work with that would help me to solve the problem. So I got to know a researcher named from our medical school in Jerusalem named Eli Keshet. I call him the father of VEGF and systemic diseases. And I told him what I was looking for. I didn’t know him beforehand and he told me he didn’t really care about melanoma. He didn’t have space in his lab or any benches in his lab plus it wasn’t his field of research. Goodbye. So I asked him what his research was about. And he told me his research was a paper that was just accepted and there is a molecule called VEGF, the vascular endothelial growth factor. And this was twenty-two years ago. And I found in a cell culture near the stomata that when there is a hypoxia or less oxygen or an ischemia of tissue there is up-regulation of VEGF in these cells. And when there is hyperpoxia, more oxygen, there is down-regulation. This means that VEGF responds to the levels of oxygen. I couldn’t believe my ears because since 1948 we started looking for what we used to call the “X-Factor” that is expressed in systemic retinal diseases and is what causes all the trouble in diabetes, retinal diseases, venal occlusion and etc. and nobody could find it. And I was raised in a department where micosomes was the head of our department and this is in our heritage and I said to him, “look. I don’t know what you are doing but you have found something that could be very, very important for the field of ophthalmology.” And then I went back to my lab and I brought sections of retinoblastoma to him. Why retinoblastoma? Because in retinoblastoma almost always, we found in about ninety-nine percent, there is necrosis. There is cell death, tissue death because of not enough oxygen. Retinoblastoma is retinal tissue. It is sick retinal tissue but it is still retinal tissue. So it should respond to hypoxia or hyperpoxia like retinal tissue. I went to my lab on the spot and brought five sections of retinoblastoma and I thought let’s do intravitreal injection of VEGF. This means I wanted to find out whether and which cells produce VEGF. And it took about three days. I couldn’t sleep. I back went to the library and took the original paper by Michaelson, the prophecy of VEGF, from the library. It was a paper from 1948. At the time there was no such thing as molecular biology. But his experiments showed that there is a factor, some call it the “X-factor” but it causes systemic diseases such as diabetes, proliferative retinopathy, pre-proliferative retinopathy, maculopathy, carotid stenosis and etc. It the angiogenic factor that causes all the trouble. And it was BINGO. And after three days all the cells around the necrotic area, not the necrotic, dead ones because necrotic means dead cell, but the cells that were just around it and not dead yet but were suffered produced VEGF. We could tell because we checked the RNA. We checked the RNA that produced the protein. I could stop here and tell you all the rest is history but we didn’t stop here and we took eyes with venal closure and we developed a model for venal prematurity which is a disease in premature babies that also suffer from systemic retinal disease and we showed exactly which cells produce it. And we also showed that when the retina is detached and away from its blood supply, the outer cells produce VEGF but when the retina is in place and we have a disease of the vessels of the retina. The inner-retina supposedly produces the VEGF. By the way, the VEGF normal development is produced by clear cells not by sensory cells and actually these clear cells produce VEGF pull the development of the vascular but when you have sensory cells then any cell can develop it. It is a mess. If every cell could produce anything you would have a mess and nervous colorization and etc. And we were able to show all this. We had difficulty publishing it because when you have a new contribution it is difficult to get people to believe you and this and that. It took us one-and-a-half years to publish it. Luckily, I had the opportunity to present it in a meeting in approximately 1993 and at that time no one knew which cells produced what and what in the world VEGF was. In 1994, I remember there was an Ocular Oncology meeting in Geneva in which I gave two lectures one on my behalf and one on education. And at that time I said it will take time but instead of lasering the retina, which destroys the ischemic parts, to avoid the secretion of VEGF. That is what you do. So basically we were telling that that instead of lasering we would inject something called anti-VEGF. And by the way they had no idea what anti-VEGF was. And the people basically thought we were crazy. This was nineteen years ago.

  《国际眼科时讯》:抗血管内皮生长因子(VEGF)药物已经被用于治疗多种新生血管性疾病。您对目前的抗新生血管治疗有何见解?
           Prof.Pe’er:为了回答你的问题,我想先讲个小故事。这个故事结合了我的专业——眼部肿瘤、VEGF以及抗VEGF药物和所有视网膜新生血管性疾病的治疗。这个故事要追溯到22年前的1991年,那时候尚无肿瘤领域的专家认识VEGF,那时VEGF被称作PGF(胎盘生长因子)。VEGF在几年前被提出来,但是没有人意识到它在眼科学以及医学上的重要性。那时我正在进行脉络膜黑色素瘤方面的研究,发现了一种特殊的血管性因子,但是我没有继续深入研究。现在这种因子对于脉络膜黑色素瘤的预后非常重要。当我休假回家继续研究脉黑瘤时我问自己:为什么机体会有这些血管性因子?然后我请教了其他同事帮助解决这一问题。我去见了耶路撒冷医学院的一位科学家Eli Keshet。我称他为“VEGF和系统性疾病之父”。之前我并不认识他,我向他询问我的疑问。他说:“我并不关心脉络膜黑色素瘤,我的实验室没有地方可以坐,而且我也不研究这一领域,再见。”然后我又问他:“你的研究领域是什么?”他回答:“我的研究文章已经被接收,是关于一个叫做VEGF的分子,即血管内皮生长因子。”这是22年前的事情了。我在细胞培养时发现气孔的周围,也就是组织相对缺氧缺血的地方VEGF表达上调,氧气比较充足的环境下是下调的。这就意味着VEGF对含氧水平有反应。我都不相信我的耳朵,因为自从1948年我们一直在寻找曾经被称作“X因子”的物质,它在系统性视网膜疾病中表达,在糖尿病视网膜疾病以及血管阻塞性疾病等疾病中起作用,但是没有人发现这种因子。我按照我们的传统在科室中提出这一发现,科室主任说:“我不知道你们在做什么,但是你们发现了一种眼科领域非常非常重要的物质。”我回到我的实验室,把视网膜母细胞瘤组织拿给他。为什么选择视网膜母细胞瘤组织?因为眼肿瘤中99%的情况下我们会发现组织坏死、细胞凋亡,因为没有足够的氧气。视网膜肿瘤是一种病态的视网膜组织,但它依旧是视网膜组织,和视网膜组织一样对低氧或者高氧产生反应。我回到实验室拿了5个视网膜母细胞瘤组织,想要玻璃体腔注射VEGF。也就是说我想要观察细胞是否产生VEGF,都有哪些细胞产生。3天过去了,我都没有休息。我回到实验室找出Michaelson早期写的一篇文章,是1948年来自实验室的关于VEGF的预言。那时还没有分子生物学,但他的实验发现了一种叫做“X因子”的分子,能够引起系统性疾病,诸如糖尿病、视网膜增殖性疾病、糖尿病视网膜病增殖前期、黄斑病变、颈动脉狭窄等,这就是血管生成因子。3天后所有的细胞围绕坏死组织,这些细胞并没有坏死,但是产生了VEGF。我们检测了合成蛋白质的RNA。我的故事就讲到这里,但是并没有停止。我们把注意力放在静脉阻塞和新生儿视网膜病变等系统性视网膜疾病上,发现产生VEGF的细胞。当视网膜脱离缺少血供时,外层视网膜细胞就会产生VEGF,但是当视网膜在位产生了血管性疾病,据推测内侧视网膜细胞产生VEGF。VEGF是由明细胞而不是感觉细胞产生,促进血管内皮生长。如果有感觉细胞在,任何细胞都可以产生VEGF。如果每一个细胞都可以产生任何物质,将非常混乱。我们能够说明上述发现,但很难发表文章,因为当你发现一样新事物时,很难让别人相信。我们花费了一年半时间来发表。很幸运,我在1993年左右有机会在一次会议上发表这一看法,那时还没有人知道什么细胞产生了一种什么物质,VEGF是什么。1994年,在日内瓦眼肿瘤会议上,我做了两场演讲,一场是关于我所做的研究,另一场是教育性质的。我在会上提到,研究这一物质需要花费很长时间,但是它可以代替激光在视网膜疾病方面的应用(破坏缺血组织),减少VEGF的分泌。所以我可以说,注射抗VEGF药物可以代替激光治疗。但那时对于抗VEGF没有任何概念。那是19年前,人们都认为我们疯了。
 



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