癌症是一种代谢性疾病 Warburg was Correct， Cancer is a Metabolic Disease

想要治愈癌症? 那就重新审视过去;“瓦伯格是正确的”，癌症是一种体质性疾病

Want to Cure Cancer Then Revisit the Past Warburg Was Correct Cancer Is a Metabolic Disease

作者：Robert L. Elliott, Xian P. Jiang, Jonathan F. Head

翻译：蓝山

●摘要

我想在这篇文章的开头就把它讲清楚。这是一个有争议的综述。然而，我认为是时候重新思考我们的癌症研究和治疗方法了。许多癌症研究人员，尤其是那些参与癌症基因组研究的人会不同意。我欢迎这种分歧，并希望它能在所有癌症研究和治疗学科之间激起一场诚实的辩论和对话。我确信，参与基础研究的人和治疗这种疾病的临床领域的人之间存在着巨大的脱节。所有领域的癌症研究人员都不应忽视肿瘤代谢在肿瘤发生、进展和转移中的作用。

关键词:宿主免疫力;线粒体功能障碍;Warburg效应;有氧发酵;肿瘤和线粒体铁代谢。

1 介绍(为什么发表这个综述?)

在参与癌症研究和乳腺癌患者治疗40多年后，我认为我们需要重新认证考虑如何对待和治疗这种疾病。我们需要回顾一下奥托·沃伯格(Otto Warburg)的过去和非凡的研究。回顾过去，我建议你们赶快学习托马斯·塞弗里德(Thomas Seyfried)的巨著。他和谢尔顿发表了一篇关于癌症作为一种代谢性疾病的论文[1]，最近，塞弗里德将他的《癌症作为一种代谢性疾病》由Wiley出版了[2]。我们必须重新思考我们的方法的原因是，自从理查德·尼克松(Richard M. Nixon)总统40多年前对癌症宣战以来，我们没有显著改善第四期癌症患者的生存期。

癌症是一种极其复杂的疾病，在每个宿主中都是相似但不同的。在肿瘤生物学或基因组突变方面，没有完全一致的实体瘤。事实上，我认为我们已经把复杂的疾病变得更加复杂，因为它强调了在肿瘤中发现的大量的基因突变。尽管这些基因发现很有趣，并将有助于一些个性化的特定疗法，但在我看来，这并不是最终的答案。因此，为了治疗癌症，我们需要确切地知道所有肿瘤的共同之处;不是有多少基因突变存在。在同一肿瘤中，突变可以是多种多样的，甚至在同一个肿瘤的不同于细胞之间。攻击主要的突变可能会消除这些细胞，但允许缺乏这种突变的细胞，继续生长、转移并最终杀死病人。

临床肿瘤学中忽视的另一个重要因素是宿主免疫。肿瘤学家治疗这种疾病(肿瘤生物学、突变、阶段)，忽视宿主对疾病的免疫力。肿瘤学家必须更加意识到宿主免疫对癌症的重要性。常规的癌症治疗是“三大”:1)手术，2)化疗和3)放射——这三种都损害并抑制宿主的特异性免疫。然而，在适当的个体免疫治疗中，“三巨头”实际上可以成为支持宿主免疫的伙伴。无论何种癌症治疗，都不能忽视宿主免疫[3]。

现在有确凿的证据表明，几乎所有癌症的主要特征都是细胞能量代谢受损，无论其来源是细胞还是组织。正常细胞从氧化磷酸化中获得可使用的能量，而大多数癌细胞依赖于低于基准水平的磷酸化来满足能量需求。

在20世纪30年代，Otto Warburg描述了线粒体功能障碍和肿瘤发生之间的联系。他观察到，在氧化磷酸化没有增加或偶尔会减少的情况下，糖酵解和乳酸盐的生产显著增加[4] [5]。这被称为“有氧发酵”或“Warburg效应”，在肿瘤细胞中有很好的记录。有氧发酵会使癌细胞的葡萄糖摄取显著增加，而乳酸的产生则会增加。这个“Warburg效应”是正电子发射断层扫描(PET SCAN)的基础，它使用放射性标记的葡萄糖成像发现体内的肿瘤。

Hanahan和Weinberg描述了癌细胞生理学的六种基本改变，它们可能是恶性细胞生长的基础[6]。这六种改变被描述为癌症的标志。这6个改变是:1)生长信号的自给自足性，2)抑制生长信号的不敏感性，3)凋亡的逃避，4)无限复制潜能，5)持续的血管生成(血管生成)，6)组织侵袭和转移。塞弗里德，其他人和我相信，除了这六种公认的癌症特征外，“Warburg效应”或有氧发酵也是大多数肿瘤的一个非常强健的代谢特征[7]-[12]。

　

另一种常见的异常代谢缺陷是肿瘤细胞铁代谢紊乱。我在最近的一篇文章[12]中详细讨论过这个问题，并将在以后的通信中再次讨论这个问题。我确信，线粒体功能紊乱(细胞呼吸功能受损)导致有氧发酵，也与肿瘤铁代谢和转录因子缺氧诱导因子-1 (HIF1-a)的稳定有关，HIF1-a在两者中都起着重要作用。

2 Warburg 效应在肿瘤细胞中的作用

这篇综述是强调癌症是一种代谢性疾病而不是现在流行的认为它是基因性疾病的观点。对于那些对科学和细节感兴趣的读者，我强烈推荐塞弗里德的书《癌症作为一种代谢疾病(关于癌症的起源、管理和预防)》[2]。我将试图讨论和总结他的一些重要观点，支持癌症作为一种代谢性疾病。然而，我不会深入研究异常代谢缺陷的硬科学和机制。研究表明，在所有癌症中，没有特定的基因突变或染色体异常[13]-[15]，但几乎所有的癌症，无论其细胞或组织的起源都表达了有氧发酵。这意味着癌细胞在氧气存在的情况下增加了葡萄糖的摄取。大多数癌症都表达了糖酵解的基因[7]-[18]。

毫无疑问，瓦伯格效应在癌症细胞中的起源是有争议的。沃伯格本人声称，有氧发酵是癌症细胞生理学问题的一种表现形式[5] [19]。Seyfried[1]指出，只有那些能够在间歇性呼吸损害中增加糖酵解的体细胞才能促进肿瘤的发生。由于能量衰竭，不能诱导糖酵解反应的细胞会因呼吸损伤而死亡。因此，在癌症中发现的最常见的表型是由受损的呼吸引起的有氧发酵。

在回顾了从许多人类和动物样本收集到的代谢数据后，Warburg确信，不可逆转的呼吸损害是导致癌症的主要原因[5] [19] [20]。然而，科学界抨击瓦伯格的理论过于简单化，并没有解释某些癌细胞正常呼吸的证据[21]-[29]。他们说，他的理论没有涉及肿瘤相关突变的作用或转移的进展。他们抱怨说，它也没有将不受抑制的细胞生长的分子机制直接与受损的呼吸联系起来。因此，癌症从一种代谢性疾病的概念代之以一种基因性疾病的概念。癌症是一种基因性疾病的概念在过去的几十年里一直主导着癌症研究。基因组研究人员虽然知道代谢缺陷，但在肿瘤发展过程中，肿瘤细胞的这些缺陷主要是由基因突变引起的[30]-[33]。越来越多证据质疑癌症的基因起源论而支持癌症是一种代谢性疾病。我们最近发表的一篇关于将分离的正常线粒体移植到癌细胞上的论文支持了癌症可能是由线粒体功能紊乱引起的代谢疾病的证据[34]。本研究表明，分离的正常乳腺线粒体容易进入乳腺癌细胞。这种细胞器移植到癌细胞中抑制增殖，增加药物敏感性，降低葡萄糖转运体III(GLUT3)的表达(图1-4)。

图1所示。MCF-7细胞与分离的JC-1染色MCF-12A线粒体共培养荧光显微图。

　

　

图2。在MCF-7和NCI/ADR-Res中加入MCF- 12A的线粒体如何抑制增殖。

　

图3。图中描述了MCF-12A线粒体与MCF-7乳腺癌细胞系的添加，以及由此产生的多柔比星的细胞毒性。

　

　

图4。MCF- 12A细胞外源性线粒体对乳腺癌MCF-7细胞中葡萄糖转运蛋白3 Mrna表达的影响(RT-PCR)。

　

　

Sebastian, Zwaans, Silberman和Gymrek等人最近发表的一篇论文支持了癌症是一种代谢疾病的概念[35]。他们提供了强有力的证据证明组蛋白去乙酰化酶SIRT6是一种抑制新陈代谢的肿瘤抑制因子。SIRT6缺失的细胞是致瘤性的，SIRT6 永久敲除的（immortalized knockout ）(KO)的小鼠胚胎成纤维细胞(MEFs)显示增加的葡萄糖摄取和乳酸生成(有氧糖酵解)。他们在SIRT6 (KO)和野生型(MEFs)中进行实验，证实SIRT6 (KO)细胞的肿瘤发生是独立于癌基因的。丙酮酸脱氢酶激酶(PDK)-1和乳酸脱氢酶(LDH)-一种蛋白水平在SIRT6 (KO)细胞中被上调，显示这些细胞是高度糖酵解的。他们的结论是，增强的糖酵解而非癌基因激活可能是SIRT6缺陷细胞中肿瘤发生的驱动力。他们的研究只是更多的证据表明，基因组不稳定是癌细胞代谢变化的下游，例如，有氧发酵[35]。

塞弗瑞德的目标是解决冲突，并提供证据，证明基因突变和癌症的特征，包括Warburg效应(有氧发酵)可以与能量代谢和受损呼吸联系起来。他认为，细胞呼吸受损出现在基因组不稳定之前并与肿瘤发生有关。与肿瘤发生相关的基因组不稳定性是细胞呼吸功能受损和线粒体功能障碍的下游。基因组的不稳定性导致进一步的呼吸损伤，增加了基因组的可变性和肿瘤的进展(影响变成了原因)。赛德弗里德的假设基于以下证据:核基因组的完整性主要取决于线粒体能量的稳态，而所有的细胞都需要持续水平的可用能量来维持生存能力。我相信瓦伯格是绝对正确的，尽管他并没有把他的影响与我们现在认为是癌症的标志联系起来。塞弗瑞德做了一项伟大的工作，对证据进行了审查，并建立了联系，并扩大了瓦伯格的观点，即能量代谢有多大可能被用于肿瘤治疗和预防。我相信Warburg和Seyfried是正确的，癌症是一种代谢性疾病。

3. 肿瘤和线粒体铁代谢

现在我将简要讨论肿瘤和线粒体的铁代谢。我认为，在线粒体中存在某种类型的铁硫簇生物合成缺陷，可能是引起线粒体呼吸损伤和异常能量产生的缺陷。换句话说，它可能是有氧发酵的推进器。我们已经研究了30多年的肿瘤铁代谢。希望这个关于肿瘤和线粒体铁代谢的讨论能激发像Seyfried这样的伟大研究人员尝试将其与有氧发酵和癌症代谢联系起来。

4. 肿瘤铁代谢异常

铁代谢可能是肿瘤发生代谢、线粒体功能障碍和肿瘤免疫抑制的主要原因[12]。铁(Fe)是对活细胞至关重要的金属[36]-[38]。血红素和血红素酶和蛋白质是必需的，它们对氧的运输和氧化磷酸化至关重要[39]。铁是核糖核苷酸还原酶的辅助因子，它是一种将核糖核苷酸转化为脱氧核糖核酸的酶，是DNA合成中的关键酶。这就要求核糖核苷酸还原酶的铁持续供应，以维持其活性[40] [41]。因此，铁与细胞增殖直接相关。

转铁蛋白是哺乳动物血液中的主要铁转运蛋白，是一种双叶糖蛋白。它将铁从吸收和储存的地点运输到铁的利用地点[42]。癌细胞在其细胞表面上明显地过度表达转铁蛋白受体。铁结合转铁蛋白特异性地与细胞表面转铁蛋白受体(TFR1)相互作用，促进铁在细胞内通过胞吞作用转运。整个(TF-TFR1)复合物内化，内胚层内的pH值由于内体膜中的质子泵而降低。酸性环境允许3价铁(Fe3+)原子从复合物的[43]中释放。通过铁还原酶将铁还原成亚铁态，然后由二价金属转运体(DMT1)从核内体转运到细胞质中。然后将(apo-TF-TFR1)复合物再循环到细胞表面，并将脱铁转运蛋白（apotransferrin）释放到血液中[44]。

1993年，我们报道了铁代谢在乳腺癌中的作用[45]。这是一种广泛的细胞化学、组织培养和超微结构研究。结果表明，铁贮存蛋白铁蛋白在细胞质中含量增加。它还证实，转铁蛋白可以作为一种载体，选择性地靶向肿瘤组织。我们之前报道了一种铂转移蛋白复合物(MPTC-63)的初步评估，作为一种潜在的非毒性乳腺癌治疗药物[46]。不可否认的是，铁在癌症的增殖、生长和发展过程中起着重要的作用。线粒体铁代谢是所有铁代谢的摇篮，现在我们将简要讨论线粒体铁代谢。

5.线粒体铁代谢

线粒体是铁代谢和铁硫(FeS)簇生物合成的重要场所，也是血红素合成的唯一场所。理查森、莱恩和贝克尔等人对线粒体铁的转运和线粒体与细胞浆之间铁代谢的整合做了大量的报道[47]。我认为一个在线粒体和细胞浆之间的铁代谢的一体化中，发生了一个缺陷发生，引发了呼吸损伤，促成有氧发酵和肿瘤发生。我为什么会这么想; 线粒体因其在能量生产、电子运输、氧气转运、脱氧核苷酸合成、活性氧、细胞凋亡等方面的关键作用而闻名。然而，很少有人意识到它是铁代谢的焦点。很少有人知道线粒体对铁吸收的调控，以及它是如何与其他细胞器和细胞质中的铁代谢结合的。线粒体铁转运蛋白的发现(mitoferrin 1和2)和储存(线粒体铁蛋白)揭示了线粒体中铁代谢与细胞浆[47]之间的确切联系。我认为，线粒体与细胞浆、线粒体铁的导入和铁代谢之间的铁的交流存在任何微小的缺陷，都可能导致线粒体呼吸损伤和基因组不稳定，从而导致肿瘤发生。

Veatch, McMurray, Nelson和Gottschling的一篇伟大的论文支持了这个概念[48]。他们发现线粒体功能障碍通过一个铁硫(FeS) 簇缺陷导致核基因组不稳定。mtDNA的缺失导致核基因组不稳定，导致细胞危机。这一危机不是由于缺乏呼吸作用，而是与线粒体膜电位的降低有关。他们发现了在发生这一危机的细胞中存在的一种铁硫(FeS) 簇生物合成的缺陷。因此，基因组不稳定性(突变)是在线粒体中被破坏的铁代谢的一种下游现象。他们的研究结果表明，线粒体功能障碍通过抑制含铁硫(FeS) 簇蛋白质的簇状蛋白质的产生来促进核基因组的不稳定性[48]。一个可能的问题是蛋白质Frataxin可能存在的缺陷，它是富含线粒体的组织中高度表达的一种重要蛋白质。Frataxin是一种内部线粒体膜和线粒体基质蛋白，参与(FeS) 簇和血红素生物合成[47]。线粒体铁代谢异常复杂，需要在未来重要的研究中进一步了解。

6. 结论

结论的第一点是，我强烈建议读者学习塞弗里德[1] [2]的精彩著作，特别是他的《癌症作为一种代谢性疾病》。对于不信者来说，很难反驳。证据支持一种普遍的假设，即癌症是一种能量代谢性疾病。塞弗里德和我认为，所有癌症的特征都可能与受损的线粒体功能有关。为了维持生存能力，癌细胞过渡到低于基准水平的氧化磷酸化，使用葡萄糖和谷氨酰胺作为能量底物。在这篇综述文章中，我确信瓦伯格对线粒体功能紊乱在恶性肿瘤中的作用是非常正确的。正是像塞弗里德这样的研究人员的工作，这些证据每天都在积累。我们希望通过我们正在做的关于线粒体细胞器移植的研究，为乳腺癌细胞系[34]提供更多的证据。我们目前正在设计一种体内模型。

罗伯特·l·艾略特(Robert L. Elliott)、西安P·江(Xian P. Jiang)、乔纳森·F(Jonathan F. Head)

未来的发现，只会让瓦伯格的贡献更加显著，尤其是在他工作的时代。这种交流是对他伟大的研究和观察的一种谦虚的赞扬。我尊敬他，现在塞弗里德为他们做出了巨大的贡献。希望这篇评论能激发更多的辩论和工作在这个领域，以改善治疗这种可怕的疾病。然而，我认为所有的癌症的全身治疗都应该得到宿主免疫系统的支持，以及辅助的代谢调理。所有大型癌症中心都应该有一个癌症的代谢调理部门。接下来的几年将会引发更多的争议，激烈的辩论和有趣的结果; 但是我相信癌症作为一种代谢性疾病将会赢得战争。

参考文献：

http://file.scirp.org/Html/8-8901908_44116.htm

Want to Cure Cancer Then Revisit the Past Warburg Was Correct Cancer Is a Metabolic Disease

　

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DOI: 10.4236/jct.2014.53036    3,537 Downloads   6,289 Views   Citations

Author(s)    Leave a comment Robert L. Elliott, Xian P. Jiang, Jonathan F. Head

Affiliation(s)

Elliott-Baucom-Head Breast Cancer Research and Treatment Center, Baton Rouge, USA.

　

ABSTRACT

I want to make it very clear at the beginning of this communication; this is a controversial opinion review. However, I believe it is time to rethink our approach to cancer research and therapy. Many cancer researchers, especially those involved in cancer genomic research will disagree. I welcome the disagreement and hope it will stimulate an honest debate and dialog between all disciplines of cancer research and treatment. I am convinced that a vast disconnection exists between those involved in basic research and those in the clinical arena that treat this disease. Cancer researchers in all areas should not ignore the role of cancer metabolism in tumorigenesis, progression and metastasis.

KEYWORDS

Host Immunity; Mitochondrial Dysfunction; Warburg Effect; Aerobic Fermentation; Tumor and Mitochondrial Iron Metabolism

http://www.scirp.org/journal/PaperInformation.aspx?PaperID=44116

　

1. Introduction (Why This Review?) After being involved in cancer research and treating breast cancer patients for over 40 years, I believe that we seriously need to reconsider how we approach and treat the disease. We need to revisit the past and the marvelous work of Otto Warburg. After reviewing the past, I suggest you fast forward to now and study the tremendous work of Thomas Seyfried. He and Shelton have published a great paper on cancer as a metabolic disease [1] , and recently Seyfried had his book on cancer as a Metabolic Disease released by Wiley [2] . The reason we must rethink our approach is because we have not significantly improved the survival of Stage IV cancer patients since President Richard M. Nixon declared war on cancer over 40 years ago. Cancer is an extremely complex disease, similar but different in each host. There is no solid tumor that is totally homogeneous in regard to tumor biology or genomic mutations. In fact, I believe that we have made a complex disease more complicated by the emphasis on the vast number of genetic mutations discovered in tumors. Though these genomic discoveries are interesting and will assist in some personalized specific therapies, it will in my opinion not be the final answer. Therefore, in order to cure cancer, we need to know exactly what is common to all tumors; not how many genetic mutations are present. Mutations can be numerous and even different from cell to cell in the same tumor. Attacking the predominant mutation may eliminate those cells but allow cells to lack that mutation to remain, grow, metastasize and ultimately kill the patient. Another important factor ignored in clinical oncology is host immunity. Oncologists treat the disease (tumor biology, mutations, stage) and ignore the immunity of the host harboring that disease. Oncologist must be more aware of the importance of host immunity in cancer. The routine cancer therapy is the “Big Three”: 1) surgery, 2) chemotherapy and 3) radiation—all three of which damage and depress host specific immunity. However, with proper specific individual immunotherapy the “Big Three” can actually be partners in supporting host immunity. Regardless of the type of cancer treatment, host immunity cannot be ignored [3] . There is now definitely emerging evidence that the main characteristic of nearly all cancers is impaired cellular energy metabolism regardless of cellular or tissue of origin. Normal cells derive their useable energy from oxidative phosphorylation, while most cancer cells become dependent on substrate level phosphorylation for energy demands. In the 1930s, Otto Warburg described a link between mitochondrial dysfunction and tumorigenesis. He observed a significant increase in glycolysis and lactate production in the presence of oxygen without an increase and an occasional decrease in oxidative phosphorylation [4] [5] . This became known as aerobic fermentation or the “Warburg Effect” and is well documented in tumor cells. Aerobic fermentation causes a marked increase in glucose uptake by cancer cells with an increased lactic acid production. This “Warburg Effect” is the basis for positron emission tomography (PET SCAN) which uses a radioactive labeled glucose analog for tumor imaging. Hanahan and Weinberg described six essential alterations in cell physiology that might underlie malignant cell growth [6] . These six alterations were described as the hallmarks of cancer. These six alterations were: 1) self-sufficiency in growth signals, 2) insensitivity to inhibitory growth signals, 3) evasion of apoptosis, 4) limitless replicative potential, 5) sustained vascularity (angiogenesis), and 6) tissue invasion and metastasis. Seyfried, others and I believe that in addition to these six recognized hallmarks of cancer, the “Warburg Effect” or aerobic fermentation is also a very robust metabolic hallmark of most tumors [7] -[12] . Another abnormal metabolic defect common to all cancers is dysfunction in tumor cellular iron metabolism. I discussed this in detail in a recent article [12] and will address it again later in this communication. I am convinced that mitochondrial dysfunction (impaired cellular respiration) leading to aerobic fermentation is also related to tumor iron metabolism and stabilization of the transcription factor Hypoxia Inducible factor-1alpha (HIF1-a), which plays a major role in both. 2. Warburg Effect in Tumor Cells This review is to emphasize the point that cancer is a metabolic disease rather than the now popular belief that it is genetic. For those readers interested in more science and detail on the subject, I highly recommend Seyfried’s book “Cancer as a Metabolic Disease (on the origin, management, and prevention of cancer)” [2] . I will attempt to discuss and summarize some of his very important points supporting cancer as a metabolic disease. However, I will not get into the hard science and mechanisms of the abnormal metabolic defects. It is stated that there are no specific gene mutations or chromosomal abnormality common to all cancers [13] -[15] , but nearly all cancers regardless of their cellular or tissue of origin express aerobic fermentation. This means that cancer cells have increased glucose uptake with increased lactic acid production in the presence of oxygen. The majority of cancers overexpress the genes for glycolysis [7] -[18] . There is no doubt that the origin of the Warburg effect in cancer cells is controversial. Warburg himself purposed that aerobic fermentation was a manifestation of a problem in cancer cell physiology, which was impaired cellular respiration [5] [19] . Seyfried [1] points out that only those body cells able to increase glycolysis during intermittent respiratory damage are capable of promoting tumorigenesis. The cells unable to induce glycolysis in response to respiratory damage will perish due to energy failure. Therefore, a most common phenotype found in cancer is aerobic fermentation, arising from damaged respiration. After reviewing the metabolic data collected from many human and animal samples, Warburg postulated with confident certainty that irreversible respiratory damage was the main cause of cancer [5] [19] [20] . However, the scientific community attacked Warburg’s theory as too simplistic and not explaining the evidence of apparent normal respiration in some cancer cells [21] -[29] . They stated that his theory did not address the role of tumorassociated mutations or the progression of metastasis. They complained that it also did not link the molecular mechanisms of uninhibited cell growth directly to damaged respiration. Therefore, the concept of cancer as a metabolic disease was replaced with the view that cancer was a genetic disease. The concept that cancer is a genetic disease has dominated cancer research for the past several decades. The genomic researchers though aware of the metabolic defects felt these defects in cancer cells arose primarily from genomic mutability during tumor progression [30] -[33] . There is now much emerging evidence that questions the genetic origin of cancer and supports data that cancer is a metabolic disease. Our recent paper on transplantation of isolated normal mitochondria to cancer cells support the evidence that cancer is probably a metabolic disease caused by mitochondrial dysfunction [34] . This study demonstrated that isolated normal mammary mitochondria easily enter breast cancer cells. This organelle transplantation into cancer cells inhibits proliferation, increases drug sensitivity and decreases the expression of glucose transporter III (Glut III) (Figures 1-4).Figure 1. Fluorescent micrograph of MCF-7 cells co-cultured with isolated JC-1 stained MCF-12A mitochondria.Figure 2. Graph of how the mitochondria of MCF- 12A inhibit the proliferation when added to the cancer cell lines MCF-7 and NCI/ADR-Res.Figure 3. Graph depicting the addition of MCF-12A mitochondria to the MCF-7 breast cancer cell line and the resulting increase in the cytotoxicity of doxorubicin.Figure 4. Effect of exogenous mitochondria of MCF- 12A cells on Mrna expression of glucose transporter 3 in breast cancer MCF-7 cells (RT-PCR). A recent paper by Sebastian, Zwaans, Silberman and Gymrek et al. supports the concept that cancer is a metabolic disease [35] . They present strong evidence that the Histone Deacetylase SIRT6 is a tumor suppressor that controls metabolism. SIRT6 deficient cells are tumorigenic and SIRT6 immortalized knockout (KO) mouse embryonic fibroblast (MEFs) showed increased glucose uptake and lactate production (aerobic glycolysis). They performed experiments in SIRT6 (KO) and wild type (WT) (MEFs) and confirmed that tumorigenesis in SIRT6 (KO) cells is oncogene independent. Pyruvate dehyrogenase kinase (PDK)-1 and lactate dehydrogenase (LDH)- A protein levels are upregulated in SIRT6 (KO) cells showing that these cells are highly glycolytic. They concluded that the enhanced glycolysis rather than oncogene activation was probably the driving force for tumorigenesis in SIRT6 deficient cells. Their work is just more evidence that genomic instability is downstream of the metabolic changes in cancer cells, such as, aerobic fermentation (the glycolytic phenotype) [35] . Seyfried’s goal is to resolve the conflict and provide evidence that genomic mutability and the hallmarks of cancer, including the Warburg effect (aerobic fermentation) can be linked to energy metabolism and damaged respiration. He believes that impaired cellular respiration precedes the genome instability that is associated with tumorigenesis. The genome instability that is associated with tumorigenesis is downstream of impaired cellular respiration and mitochondrial dysfunction. The genome instability contributes to further respiratory damage, increased genome mutability and tumor progression (effects become causes). Seyfried bases his hypothesis on evidence that nuclear genome integrity is mostly dependent on homeostasis of mitochondrial energy and that all cells require a continuous level of useable energy to maintain viability. I believe Warburg was definitely correct, though he did not link his effect to what we now recognize as the hallmarks of cancer. Seyfried does a great job reviewing the evidence and making the connection and expanding Warburg’s ideas of how impaired energy metabolism might be exploited for tumor therapy and prevention. I believe that Warburg and Seyfried are correct, and that Cancer is a Metabolic Disease. ARE YOU HERE? IF NOT WAKE UP! 3. Tumor and Mitochondrial Iron Metabolism Now I am going to discuss briefly tumor and mitochondrial iron metabolism. I believe that some type of defect in iron sulfur (FeS) cluster biosynthesis in the mitochondria might be the defect that initiates mitochondrial respiratory damage and abnormal energy production. In other words, it might be the promoter of aerobic fermentation. We have been working on tumor iron metabolism for over 30 years. Hopefully, this discussion of tumor and mitochondrial iron metabolism will stimulate great researchers like Seyfried to attempt to link it to aerobic fermentation and cancer metabolism. 4. Tumor Iron Metabolism Abnormal iron metabolism could be the main culprit in tumorigenesis as it is involved in tumor metabolism, mitochondrial dysfunction and tumor immuno-suppression [12] . Iron (Fe) is an essential metal vital for living cells [36] -[38] . It is required by heme and—heme enzymes and proteins, which are essential for oxygen transport and oxidative phosphorylation [39] . Iron is a cofactor for ribonucleotide reductase, an enzyme that converts ribonucleotides to deoxyribonucelotides, and thus a key enzyme in DNA synthesis. This requires a continuous supply of iron for ribonucleotide reductase to maintain its activity [40] [41] . Therefore, iron is directly associated with cell proliferation. Transferrin (TF), a bilobed glycoprotein is the chief iron transport protein in mammalian blood. It transports iron from sites of absorption and storage to sites of iron utilization [42] . Cancer cells markedly overexpress on their cell surface transferrin receptors. Iron bound (TF) specifically interacts with the cell surface transferrin receptor (TFR1) that promotes the transport of iron across the cell membrane by endocytosis. The entire (TF-TFR1) complex is internalized and the pH within the endosome decreases due to a proton pump in the endosomal membrane. The acidic environment allows ferric (Fe3+) atoms to release from the complex [43] . The ferric is reduced to the ferrous state by a ferrireductase and then transported out of the endosome into the cytoplasm by the divalent metal transporter (DMT1). The (apo-TF-TFR1) complex is then recycled to the cell surface and apotransferrin is released into the bloodstream [44] . In 1993, we reported on the role of iron metabolism in breast carcinoma [45] . This was an extensive cytochemical, tissue culture, and ultrastructural study. It demonstrated that the iron storage protein ferritin was increased and located in the cytoplasm. It also confirmed that transferrin could be used as a carrier to target toxic therapy selectively to tumor tissue. We had previously reported preliminary evaluation of a platinum transferrin complex (MPTC-63) as a potential nontoxic therapy for breast cancer [46] . It is undeniable that iron plays a significant role in the proliferation, growth and progression of cancer. Mitochondrial iron metabolism is the cradle of all iron metabolism and now we will briefly address mitochondrial iron metabolism. 5. Mitochondrial Iron Metabolism Mitochondria are essential for iron metabolism and a site for iron sulfur (FeS) cluster biosynthesis and the only site of heme synthesis. Richardson, Lane and Becker et al, have done a great job reporting on mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and the cytosol [47] . It is somewhere in the integration of iron metabolism between the mitochondrion and the cytosol that I believe a defect takes place that initiates respiratory damage contributing to aerobic fermentation and tumorigenesis. Why might I think that; because the mitochondrion is well known for its key role in energy production, electron transport, oxygen transport, deoxynucleotide synthesis, reactive oxygen species, and apoptosis. However, little is appreciated that it is a focal point of iron metabolism. There is very little known about the regulation of iron uptake by the mitochondrion and how this is merged with iron metabolism in other organelles and the cytosol. The discovery of proteins involved in mitochondrial iron transport (mitoferrin 1 and 2) and storage (mitochondrial ferritin) has revealed a definite communication between iron metabolism in the mitochondrion and the cytosol [47] . I believe that any minor defect in the communication of iron between the mitochondrion and the cytosol, mitochondrial iron import and iron metabolism could lead to mitochondrial respiratory damage and genomic instability and thus contribute to tumorigenesis. A great paper by Veatch, McMurray, Nelson and Gottschling support this concept [48] . They showed that mitochondrial dysfunction leads to nuclear genome instability via an iron an iron-sulphur (FeS) cluster defect. The loss of mtDNA leads to nuclear genome instability which causes a cellular crisis. The crisis is not mediated by absence of respiration, but correlates with a reduction in the mitochondrial membrane potential. They identified a defect in (FeS) cluster biogenesis in cells undergoing this crisis. Therefore, genomic instability (mutations) arises as a downstream epiphenomenon of disturbed iron metabolism in mitochondria. Their results suggest mitochondrial dysfunction stimulates nuclear genome instability by inhibiting the production of (FeS) cluster— containing proteins, which are required for maintenance of nuclear genome integrity [48] . A possible problem is a probable defect involving the protein Frataxin, which is a vital protein highly expressed in tissues rich in mitochondria. Frataxin is an inner mitochondrial membrane and mitochondrial matrix protein that is involved in (FeS) cluster and heme biogenesis as well as iron storage [47] . Mitochondrial iron metabolism is extremely complicated and there is much more to learn from future important needed research. 6. Conclusions The first point to make in this conclusion is that I highly recommend that the readers study the marvelous work of Seyfried [1] [2] especially his book on cancer metabolism published by Wiley. For non-believers it will be difficult to refute. The evidence supports a general hypothesis that cancer is a disease of energy metabolism. Seyfried and I believe that all of the hallmarks of cancer can be linked to impaired mitochondrial function. To maintain viability, cancer cells transition to substrate level phosphorylation uses glucose and glutamine as energy substrates. The road traveled on this review has convinced me that Warburg was remarkably correct about the role of mitochondrial dysfunction in malignancy. The evidence is accumulating every day, thanks to the work of researchers like Seyfried. We hope to soon contribute more evidence by the work we are doing on mitochondrial organelle transplantation of isolated normal mammary mitochondria into breast cancer cell lines [34] . We are presently designing an in vivo model. Robert L. Elliott, Xian P. Jiang, Jonathan F. Head The future discoveries will only make even more remarkable the contributions of Warburg especially in the era he worked. This communication is a humble tribute to his great research and observations. I honor him and now Seyfried for their tremendous contributions. Hopefully, this review will stimulate more debate and work in this area to improve therapy for this dreaded disease. However, I believe that all systemic therapy for cancer should be complemented with support of the host immune system, and an adjunctive metabolic approach. All large cancer centers should have a metabolic unit. The next few years will breed more controversy, heated debate and interesting results; but I believe that cancer as a metabolic disease will win the war. References

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Abbreviations HIF-1a: Hypoxia inducible factor 1-alpha Glut III: Glucose transporter III (PDK)1: pyruvate dehydrogenase kinase 1 LDH-A: lactate dehydrogenase FeS: iron sulfur cluster TF: Transferrin TFR1: Transferrin receptor 1 TF-TFR1: Transferrin-transferrin receptor 1 complex DMT1: divalent metal transporter 1

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