User:Arifa Aghajanova/sandbox

The theory of membrane and nuclear matrix pathology in the cancerogenesis. Aghajanova A.Kh. Azerbaijan Medical University, department pathological anatomy. aghajanovaarifa@gmail.com Abstract. Changes occurring in the plasma, nuclear membranes, especially the intranuclear matrix are the primary cause of cancer. These changes can be triggered by various factors: exposure to chemicals, viruses, radiation, mechanical damage, etc. Changes in the ratio of the lipid composition of cells, a change in the sphingomyelin / cholesterol ratio of the nuclear membrane and the nuclear matrix leads to DNA mutations. One of the possibilities is that under the influence of these factors the components of the membranes change, the ratio sphingomyelin /cholesterol. Such a seemingly insignificant change can affect the entire course of membrane biosynthesis, if it occurs in accordance with the principle of "membrane generates membranes." And this in turn can cause a whole chain of events that radically change the living conditions of the cell. Change the permeability of membranes and transport systems, as a result of change available hormone receptors, the working conditions of enzyme systems, etc., and these changes can have an even more far-reaching consequences, the till to the induction of new protein synthesis, RNA, DNA and mutations RNA and DNA. DNAs mutation leads to the occurrence of cancer. I believe that the change of membrane structures, especially of the nuclear matrix, is of primary importance cause of cancer, which leads to DNA mutations. Key words: theory, cancer, plasma membrane, nuclear membrane, nuclear matrix, sphingomyelin, cholesterol.

Introduction. Cancer is one of the most exciting problems of mankind. In the modern world, cancer is in second place among the causes of death. The problem of cancer for many years engaged in thousands of doctors, biochemists, physicists, virologists, toxicologists and chemists. But despite certain advances in the treatment of certain forms of cancer, too often the medicine is still powerless and is forced to retreat. It is possible that the problem of cancer can be solved completely only when the molecular nature of the disease is clarified. There are some of cancer theories, but none of them has received general recognition. Cancer is the result of the failure of an essential mechanism underlying life itself. Over the past two decades, we have learned more details about the molecular nature of life than in previous centuries [1].

Changes of the DNA in tumor can reveal in the development of cancer. The etiology of cancer is multifactorial, with genetic factors, chemical, physical and lifestyle factors interacting to cause DNA changes and then produce malignant neoplasm. Knowledge of DNA changes and nuclear matrix changes in cancer improves our understanding of cancer biology, helping to identify people at risk, promoting the ability to characterize malignant tumors, establishing treatment with regard to molecular changes of the disease and leading to the development of new methods of the treatments. Expanding the knowledge base is of great importance for all aspects of cancer treatment, prevention, and screening [ 2-4]. Tumors are overgrowths, clones within clones, of cells bearing cumulative genetic injuries, each of which confers growth advantages over the neighbor. Tumor cells typically have failure of division control, failure of senescence, and failure of proper apoptosis. Each of the many hundreds of known kinds of tumors appears to have a fairly typical pattern of genetic injury that is distinctive for it. Risk factors are known for various kinds of genetic injury, and various kinds of cancer. Oncogenes are DNA sequences within eukaryotic cells that seem to be involved in the development and maintenance of tumors. These genes direct the synthesis of proteins that under some conditions transform a normal cell into a cancer cell. By now, more different proto-oncogenes are known. Mutations in oncogenes and tumor suppressor genes, including: APC, beta catenin, Kras, BRAF, SMAD4, PTEN, p53 and bax in colon carcinomas [5,6]. BRAF commonly mutated in papillary thyroid carcinoma and melanoma [7, 8, 9]. C-abl is most cases of chronic myelogenous leukemia. Fumes are mutated in some hematopoietic neoplasm. The epidermal growth factor receptor family (EGFR/HER1, neu/HER2/erb2, erbB-2, erbB-3) is now very prominent because of the new biotechnology treatments. erbB-related cancers are mostly squamous cell carcinomas, and fms-related cancers are mostly hematopoietic cancers. The related neu (once erb2, now HER2) is amplified in many carcinomas, notably adenocarcinomas, especially of the breast [10,11,12]. Met proto-oncogene seems to be what produces lumens in mesenchyme and its tumors -synoviosarcomas, mesotheliomas, kidney tubules, and liver tubules [13]. Flk-1, a VEGF receptor (activated in glioblastoma, etc., must be why they elaborate those odd blood vessels. BRCA 1, 2 mutations seen in primary breast and ovary carcinomas [14,15,16]. PDGFR alpha is one of the receptors for platelet-derived growth factor. Mutations are common in medulloblastoma. Almost all pancreatic cancers, and many other cancers (especially adenocarcinomas) have mutations in codon 12 of K-ras. ras activation precedes malignant expression [17]. In Burkitt's lymphoma of B-cells, c-myc (chromosome 8) is moved next to the immunoglobulin gene (chromosome 14), i.e., the cell decides to multiply like crazy every time it is told to make antibodies.  myc genes are much amplified in neuroblastomas and oat cell lung carcinomas. raf, a family of serine-threonine kinase, is part of the signaling pathway that links most of the tyrosine kinases to the ras family. BRAF is mutated in around 15% of human cancers. Cyclin D1 itself (11q13, bcl-1, the PRAD-1 locus) is involved in the oldest known lymphoma translocation, in most parathyroid adenomas, and is amplified in around 20% of breast cancers [18]. The most common known genetic injury in human cancer is damage to the p53 gene, when defective, is now strongly linked all human cancers, especially the more anaplastic versions of each. p16INK4a is an inhibitor of cyclin-dependent kinase  which is very commonly deleted in lots of cancers. Apparently all renal cell carcinomas have lost the Von Hippel-Landau locus. Oat cell carcinomas also lack a portion of 3p; almost all other lung cancers lack a smaller chunk in the same place [19]. Von Recklinghausen's disease type I patients are heterozygous for a mutation on chromosome 17; the locus is "NF-1", and its protein product, "neurofibromin" characterized as a facilitator of hydrolysis of GTP by normal ras p21. Von Recklinghausen's disease type II patients are heterozygous for a mutation on chromosome 22, and their tumors and many spontaneous meningiomas and other nerve tumors are homozygous for this loss. Cell membrane structures and cancer. It is accelerating the pace of new research and new discoveries in the field of cancer. Many of them have shown that the transformation of a normal cell into a cancer cell is accompanied by serious changes in the structure and functioning of cell membranes [20, 21]. The basis of living matter is made up of high-molecular organic substances - proteins, nucleic acids and other substances. Biopolymers become living structures only when they are arranged in a certain order in space, interact in a certain way with each other. By separating the cell into a plurality of separate compartments, the membranes provide preservation in each compartment specific physical and chemical conditions. Therefore, on both sides of the membrane, environmental conditions such as acidity, temperature, concentration of solutes, electric potential, as a rule, are not the same. Membranes have a great influence on the processes occurring inside the cell, changing the activity of enzymes. Some enzymes are active only when they are attached to the membrane, others on the contrary are not active in this state and begin to act only after the membrane releases them into the cytoplasm. An important aspect of the enzymatic activity of membranes is associated with the coordination of many chemical reactions occurring in the cell. Membranes combine different enzymes into a uniform enzymatic container, in which each enzyme acts in strict harmony with the rest.Most of the membranes, in addition to these general functions, and perform special tasks.

The differences in the plasma membrane of normal and tumor cells were studied by many authors using electron microscopy, atomic force microscopy and immunohistochemistry. In cancer cells receptors easily move along the membrane, whereas in normal cells they do not show any tendency to change places. The reason for the increased mobility of receptors in malignant cells is simply that their membranes are filled with more liquid lipids [22, 23]. Differences in surface properties underlie one of the most important features of malignant growth — the lack of contact inhibition. At the same time, biochemical processes are beginning to change. There are important differences in the permeability of the membranes of cancer and normal cells. Majority cancer cells have a high permeability of cell membranes [24]. The inadequacy of mitochondrial membranes in cancer cells was confirmed by electron microscopy. In the cells of many tumor cells, the number of mitochondria is less than in normal cells, and the surface of their membranes is less developed. It has been proven that the number of mitochondria decreases and respiratory damage increases with increasing malignancy and tumor growth rate. The membrane of the endoplasmic reticulum in cancer cells also differ to some extent from the endoplasmic reticulum membrane of normal cells. In the cells of many tumors, the endoplasmic reticulum is less developed compared to the endoplasmic reticulum normal cells. In normal cells, most ribosome are attached to the membranes of the endoplasmic reticulum. In tumor cells attached ribosomes less, sometimes even absent and all ribosomes float freely in the cytoplasm. In many tumors also marked variations in the different enzymes that are attached to the membranes of the endoplasmic reticulum. Apparently all these defects are not guilty of the ribosome or enzymes and membranes themselves [25, 26, 27]. In normal cells, various lipids are always unevenly distributed between different types of membranes. Each membrane has its own special lipid composition. According to the characteristic features of the “lipid face”, mitochondria cannot be confused with the membranes of the endoplasmic reticulum, and the membrane of the nucleus with the plasma membrane. In cancer cells, these differences are aligned or almost absent, all membranes are the same. The alignment of the lipid composition of cell membranes is greater, the faster the tumor grows and the more malignant it is. Such a disorganization of the lipid composition may be responsible for many changes in the properties of the membranes of tumor cells [28].

Nuclear matrix support of DNA replication. In higher eukaryotic cells, DNA is tandemly arranged into 10(4) replicons that are replicated once per cell cycle during the S phase. To achieve this, DNA is organized into loops attached to the nuclear matrix. Each loop represents one individual replicon with the origin of replication localized within the loop and the ends of the replicon attached to the nuclear matrix at the bases of the loop. During late G1 phase, the replication origins are associated with the nuclear matrix and dissociated after initiation of replication in S phase. Clusters of several replicons are operated together by replication factories, assembled at the nuclear matrix. During replication, DNA of each replicon is spooled through these factories, and after completion of DNA synthesis of any cluster of replicons, the respective replication factories are dismantled and assembled at the next cluster to be replicated. Upon completion of replication of any replicon cluster, the resulting entangled loops of the newly synthesized DNA are resolved by topoisomerases present in the nuclear matrix at the sites of attachment of the loops [29-32].

The role of nuclear lipid composition. In the nucleus the lipid component is present in various subnuclear compartments playing different roles. In nuclear membrane and nuclear matrix, it regulates the fluidity, in chromatin it participates in signal transduction and in intranuclear complex it maintains the double/strand RNA structure influencing its transfer to the cytoplasm. The main problem facing was that the nuclear lipid could regulate cellular functions. It has been shown that in the nucleus there are energy-independent enzymes that allow lipid metabolism to occur independently from metabolism that occurs in other subcellular structures [33-37]. This can be realized through “mechanical” events related to DNA replication, mitosis, cytokinesis and “regulatory” events which control the transit of the cells through the various phases of cell cycle. Because the first hours after PH are characterized by DNA and RNA synthesis and the enzymes for sphingomyelin metabolism localized inside the nucleus are enzymatically active, we sought to demonstrate that intranuclear sphingomyelin cycle worked independently from that of the cell and nuclear membrane during the cell cycle [38, 39, 40]. It has been reported that the nuclear sphingomyelin is localized in nuclear membrane, nuclear matrix, chromatin, and nucleolus and that it has different roles in relation to its localization. In fact, in nuclear membrane and in the nuclear matrix, the sphingomyelin was responsible for the maintenance of normal fluidity in no stimulated cells [41, 42]. The modification of sphingomyelin content changed the fluidity of nuclear membrane, thus lipoproteins represents an attachment site for active chromatin and its plasticity influences nuclear function. In cell proliferation, the decrease of sphingomyelin could be responsible for the destabilization of the double-strand DNA, favoring its despiralization and new synthesis. Alternatively, the increase of sphingomyelin  could be responsible for the stabilization of the newly synthetized DNA. Thus nuclear lipid microdomein  has a specific role in nuclear function during cell life [43, 44, 45]. Presence of phospholipids and especially of sphingomyelin in chromatin, this became the object of long debate and of contradictory results. The general conclusion was that the presence of phospholipids may due to contamination during the isolation of chromatin. A decrease in sphingomyelin was observed at the beginning of the S-phase in regenerating liver or in cultured proliferating cells. These changes were due to the presence of sphingomyelinase and sphingomyelin synthase in the chromatin, the activity of which paralleled the variation in sphingomyelin content. The sphingomyelin was co-localized with RNA as shown by biochemical and electron microscopy methods. Isolated nuclear complexes after DNase and RNase digestion contained not only protein, but also RNA and sphingomyelin [46- 49].

Conclusion. Changes occurring in the plasma, nuclear membranes, especially the intranuclear matrix are the primary cause of cancer. These changes can be triggered by various factors: exposure to chemicals, viruses, radiation, mechanical damage, etc. Changes in the ratio of the lipid composition of cells, a change in the sphingomyelin / cholesterol ratio of the nuclear membrane and the nuclear matrix leads to DNA mutations. One of the possibilities is that under the influence of these factors the components of the membranes change, the ratio sphingomyelin /cholesterol. Such a seemingly insignificant change can affect the entire course of membrane biosynthesis, if it occurs in accordance with the principle of "membrane generates membranes." And this in turn can cause a whole chain of events that radically change the living conditions of the cell. Change the permeability of membranes and transport systems, as a result of change available hormone receptors, the working conditions of enzyme systems, etc., these changes can have an even more far-reaching consequences, the till to the induction of new protein synthesis, RNA, DNA and mutations RNA and DNA. DNAs mutation leads to the occurrence of cancer. I believe that the change of membrane structures, especially of the nuclear matrix, is of primary importance couse of cancer, which leads to DNA mutations.

Acknowledgements No funding or sponsorship was received for this study or publication of this article. The named author meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, takes responsibility for the integrity of the work as a whole, and has given final approval for the version to be published. References:

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