Balzanelli Mario G, Distratis Pietro, Lazzaro Rita, Pham Van Hung, Del Prete Raffaele, Mosca Adriana, Inchingolo Francesco, Aityan Sergey K, Santacroce Luigi, Nguyen Kieu C D, Gargiulo Isacco Ciro
SET-118, Department of Pre-Hospital and Emergency, SG Giuseppe Moscati Hospital, 74120 Taranto, Italy.
International Research Institute of Genetics and Immunology, Ho Chi Minh City 70000, Vietnam.
Diagnostics (Basel). 2023 Feb 20;13(4):813. doi: 10.3390/diagnostics13040813.
Life is based on a highly specific combination of atoms, metabolism, and genetics which eventually reflects the chemistry of the Universe which is composed of hydrogen, oxygen, nitrogen, sulfur, phosphorus, and carbon. The interaction of atomic, metabolic, and genetic cycles results in the organization and de-organization of chemical information of that which we consider as living entities, including cancer cells. In order to approach the problem of the origin of cancer it is therefore reasonable to start from the assumption that the sub-molecular level, the atomic structure, should be the considered starting point on which metabolism, genetics, and external insults eventually emanate. Second, it is crucial to characterize which of the entities and parts composing human cells may live a separate life; certainly, this theoretical standpoint would consider mitochondria, an organelle of "bacteria" origin embedded in conditions favorable for the onset of both. This organelle has not only been tolerated by immunity but has also been placed as a central regulator of cell defense. Virus, bacteria, and mitochondria are also similar in the light of genetic and metabolic elements; they share not only equivalent DNA and RNA features but also many basic biological activities. Thus, it is important to finalize that once the cellular integrity has been constantly broken down, the mitochondria like any other virus or bacteria return to their original autonomy to simply survive. The Warburg's law that states the ability of cancers to ferment glucose in the presence of oxygen, indicates mitochondria respiration abnormalities may be the underlying cause of this transformation towards super cancer cells. Though genetic events play a key part in altering biochemical metabolism, inducing aerobic glycolysis, this is not enough to impair mitochondrial function since mitochondrial biogenesis and quality control are constantly upregulated in cancers. While some cancers have mutations in the nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle, enzymes that produce oncogenic metabolites, there is also a bio-physic pathway for pathogenic mitochondrial genome mutations. The atomic level of all biological activities can be considered the very beginning, marked by the electron abnormal behavior that consequently affects DNA of both cells and mitochondria. Whilst the cell's nucleus DNA after a certain number of errors and defection tends to gradually switch off, the mitochondria DNA starts adopting several escape strategies, switching-on a few important genes that belong back at their original roots as independent beings. The ability to adopt this survival trick, by becoming completely immune to current life-threatening events, is probably the beginning of a differentiation process towards a "super-power cell", the cancer cells that remind many pathogens, including virus, bacteria, and fungi. Thus, here, we present a hypothesis regarding those changes that first begin at the mitochondria atomic level to steadily involve molecular, tissue and organ levels in response to the virus or bacteria constant insults that drive a mitochondria itself to become an "immortal cancer cell". Improved insights into this interplay between these pathogens and mitochondria progression may disclose newly epistemological paradigms as well as innovative procedures in targeting cancer cell progressive invasion.
生命基于原子、新陈代谢和遗传学的高度特定组合,最终反映了由氢、氧、氮、硫、磷和碳组成的宇宙化学。原子、代谢和遗传循环的相互作用导致了我们视为生命实体(包括癌细胞)的化学信息的组织与解构。因此,为了解决癌症起源的问题,从这样的假设出发是合理的,即亚分子水平,也就是原子结构,应该是被考虑的起点,新陈代谢、遗传学和外部损伤最终都源于此。其次,至关重要的是要确定构成人类细胞的哪些实体和部分可以独立存在;当然,这种理论观点会考虑线粒体,一种起源于“细菌”的细胞器,处于有利于两者发生的条件中。这个细胞器不仅被免疫系统所容忍,还被置于细胞防御的核心调节位置。从遗传和代谢元素的角度来看,病毒、细菌和线粒体也很相似;它们不仅具有等效的DNA和RNA特征,还具有许多基本的生物学活性。因此,重要的是要确定一旦细胞完整性不断被破坏,线粒体就会像任何其他病毒或细菌一样回归其原始自主性以简单地生存。瓦伯格定律指出癌症在有氧存在的情况下发酵葡萄糖的能力,表明线粒体呼吸异常可能是这种向超级癌细胞转变的潜在原因。虽然遗传事件在改变生物化学代谢、诱导有氧糖酵解方面起着关键作用,但这并不足以损害线粒体功能,因为癌症中线粒体的生物发生和质量控制一直在上调。虽然一些癌症在核编码的线粒体三羧酸(TCA)循环中有突变,这些酶会产生致癌代谢物,但也存在致病性线粒体基因组突变的生物物理途径。所有生物活动的原子水平可以被视为起点,其特征是电子的异常行为,进而影响细胞和线粒体的DNA。虽然细胞的核DNA在经历一定数量的错误和缺陷后往往会逐渐关闭,但线粒体DNA开始采取几种逃避策略,开启一些属于其原始独立状态的重要基因。通过对当前危及生命的事件完全免疫来采用这种生存技巧的能力,可能是向“超级细胞”分化过程的开始,这种癌细胞让人联想到许多病原体,包括病毒、细菌和真菌。因此,在这里,我们提出一个假设,即那些首先在线粒体原子水平开始的变化,会随着病毒或细菌的持续攻击,稳步涉及分子、组织和器官水平,从而驱使线粒体本身成为一个“不朽的癌细胞”。对这些病原体与线粒体进展之间相互作用的深入了解,可能会揭示新的认识论范式以及针对癌细胞进行性侵袭的创新方法。