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根据一项实验性研究结果，当红血球生成素被用于有视网膜病变的新生鼠时，他会增加视网膜的病理血管新生作用；这项研究数据发表于2月1日的临床研究期刊上，这不仅增加了红血球生成素的另外一个功能，也显示对癌症病患、与罹患其他与异常血管生长有关的疾病个体可能有不好的影响。
资深作者、麻州波士顿哈佛大学医学院眼科学助理教授Lois Smith医师表示，这个研究的一项重点是红血球生成素对于血管生长有影响，而不仅仅是对红血球而已。
红血球生成素是一种由肾脏制造用于刺激骨髓中红血球形成的醣蛋白荷尔蒙；基因重组DNA技术目前已经可以合成该蛋白质，这经常被用于治疗特定形式的贫血，例如接受透析或是化学治疗病患发生的贫血。
盖恩斯维尔佛州大学药理学与治疗学教授Maria B. Grant医师与同事在随后的一篇主编评论中表示，虽然红血球生成素最被广为人知的是它在血球生成过程中所扮演的角色，它可以使红血球前驱细胞增殖与分化，也牵涉到不同的非血液生长生化功能；这篇文献展示了红血球生成素的暂时表现对于神经血管视网膜损伤后，决定是否进行生理或是病理修复是关键性的。
主编们表示，目前这项研究的重要性在于其对于正在进行中临床治疗结果的应用性；此外，这项结果与我们对于其他牵涉到血管新生作用的疾病，其病理生成有关，例如伤口复原与癌症。
【红血球生成素的角色】
红血球生成素在血管新生作用与视网膜病变的角色目前正在研究中，目前显示它可以促进内皮细胞增殖与血管生长；红血球生成素也具有细胞保护的作用，且其能够保护血管细胞与神经细胞免于细胞凋亡；作者指出，在眼睛，罹患糖尿病视网膜增殖性病变病患，其水晶体内的红血球生成素浓度是增加的，老鼠的动物模式研究已经显示，抑制增殖期的红血球生成素可以抑制视网膜血管新生。
功能性红血球生成素缺乏已经被证实与发生视网膜病变风险增加有关，但是当贫血被治疗好后，其风险也会下降；Smith医师与其同事假设，缺乏红血球生成素可能与视网膜病变时一开始血管的损伤有关，且如果成真，接着在视网膜病变早期矫正这项缺陷将可以是有益的，且可以预防该疾病走到增殖期。然而，当组织中红血球生成素浓度是高的，使用这些制剂可能会加速血管的增殖。
研究者使用一种视网膜病变的老鼠动物模式，以氧气引发的血管损伤，之后跟随着缺氧造成的病理血管新生作用；他们发现，早期使用体外制造的红血球生成素可以避免视网膜血管损伤、与病理视网膜血管新生作用，且可以保护视网膜神经元免于缺氧造成的细胞凋亡；相反的，在视网膜病变血管新生期使用红血球生成素并不能保护血管，且可能恶化病理增殖作用。
Smith医师向Medscape肿瘤学表示，红血球生成素是一种正常表现于肾脏的荷尔蒙，但我们发现这也可以在视网膜制造；这在癌症上可能也是如此，局部可能也会制造红血球生成素。
【治疗癌症病患】
Smith医师表示，以红血球生成素治疗可能潜在地增加癌症病患的病理血管新生，这可能使得肿瘤的血管生长且恶化病况；然而，这将应该在癌症病患上检验。
作者写道，高剂量的红血球生成素已经被证实与肿瘤生长有关，且在没有仔细调整剂量与使用时机的情况下，治疗可能加剧病理血管新生；了解红血球生成素在血管新生的作用对于介入时机是很关键的。
Smith医师表示，我不认为我们的研究结果对肿瘤学家是决定性的，但这指出了研究的方向，需要进行治疗癌症病患贫血的研究。
Smith医师强调，其研究结果并未显示，以红血球生成素的治疗将会促进肿瘤生长，但却会促进血管增殖；她表示，我们仅是推测可能的应用；显然的，我们想要治疗极端贫血的病患，但我们的研究点燃了医师对于这些议题的重视。
这项研究由V. Kann Rasmussen基金会、NIH、波士顿儿童医院、年轻糖尿病基金会、以及预防失明研究组织的赞助。
Erythropoietin Can Influence Pathologic Proliferation of Blood Vessels, Possibly Influencing Tumor Growth
By Roxanne Nelson
Medscape Medical News
Results of an experimental study show that when erythropoietin was used in neonatal mice with retinopathy, it enhanced pathologic neovascularization of the retina. The data, which appear in the February 1 issue of the Journal of Clinical Investigation, not only add another function to erythropoietin, but suggest that cancer patients and other individuals with diseases related to abnormal blood vessel growth might be adversely affected.
"The important point of this study is that erythropoietin has an effect on blood vessel growth, and not just on erythrocytes," said senior author Lois Smith, MD, PhD, an associate professor of ophthalmology, Harvard Medical School, in Boston, Massachusetts.
Erythropoietin is a glycoprotein hormone produced by the kidney that stimulates the formation of erythrocytes in the bone marrow. Recombinant DNA technology has allowed it to be synthetically produced, and it is commonly used to treat certain types of anemia, such as that experienced by patients undergoing dialysis or chemotherapy.
Although erythropoietin is best known for its role in hematopoiesis as a factor that leads to the proliferation and differentiation of erythroid precursors, it is also involved in diverse nonhematopoietic biologic functions, write Maria B. Grant, MD, a professor of pharmacology and therapeutics at the University of Florida, Gainesville, and colleagues in an accompanying commentary. This paper demonstrates that the temporal expression of erythropoietin is critical in determining whether physiologic or pathologic repair occurs after neurovascular retinal injury.
"The importance of the current study is the applicability of the results to ongoing clinical therapies," write the editorialists. "Furthermore, the results could have relevance to our understanding of the pathogenetic basis of other diseases involving neovascularization, including wound healing and cancer."
Role of Erythropoietin
The role of erythropoietin on angiogenesis and retinopathy is beginning to be defined, and it has been shown to promote both endothelial cell proliferation and vessel growth. Erythropoietin also has cytoprotective capabilities and is able to protect vascular cells and neurons from apoptosis. The authors point out that, in the eyes, erythropoietin levels are increased in the vitreous of patients with proliferative diabetic retinopathy, and mouse studies have shown that inhibiting erythropoietin in the proliferative phase can inhibit retinal neovascularization.
Anemia with functional erythropoietin deficiency has been associated with an elevated risk of developing retinopathy, but when the anemia is corrected, the risk is lowered. Dr. Smith and colleagues hypothesized that the lack of erythropoietin might contribute to the initial loss of vessels in retinopathy and, if true, then correcting the deficiency during the early phase of retinopathy could be beneficial and prevent the proliferative stage of the disease. However, when tissue levels of erythropoietin are high, the use of the agent could exacerbate the proliferation of blood vessels.
The researchers used a mouse model of retinopathy that was characterized by oxygen-induced vascular loss followed by hypoxia-induced pathologic neovascularization. They found that the early use of exogenous erythropoietin prevented retinal vessel loss and pathologic retinal angiogenesis, and also protected retinal neurons from hypoxia-induced apoptosis. Conversely, the late use of erythropoietin during the neovascularization phase of retinopathy does not protect the vasculature, and also might exacerbate pathologic proliferation.
"Erythropoietin is a hormone normally expressed by the kidneys, but we found that it is also made in the retina," Dr. Smith told Medscape Oncology. "This may also be true in cancer, in that there is local production."
Treatment of Cancer Patients
Treatment with erythropoietin could potentially exacerbate pathologic angiogenesis in cancer patients. "It could make blood vessels in tumors grow and worsen the situation," said Dr. Smith. "However, it would need to be examined in that setting."
Higher doses of erythropoietin have been associated with tumor growth, and without careful dosing and timing, treatment might exacerbate pathologic angiogenesis, write the authors. Understanding the role of erythropoietin in angiogenesis is critical to timing its intervention.
"I don't think that our study is definitive for oncologists," said Dr. Smith, "But it points the way to studies that need to be done for treating anemia in cancer patients."
Dr. Smith emphasized that their study did not show that treatment with erythropoietin would cause tumors to grow, but only that it can cause blood vessels to proliferate. "We are just speculating on possible implications," she said. "Obviously, we want to treat a patient who is extremely anemic, but our study is bringing these issues to the attention of physicians."
The research was funded by the V. Kann Rasmussen Foundation, the NIH, Children's Hospital Boston, the Juvenile Diabetes Foundation, and the Research to Prevent Blindness organization.
J Clin Invest. 2008; 118:526-533 Abstract, 467-470 Abstract.