There are bon the basis of their own data presented a comparative analysis of the existing model of carcinogenesis and the author’s model in the work, as the development of Correa (1998). Author’s concept involves ethiotropics factors for all effects of neoplastics of any nature, causing activation of proliferative activity and apoptosis leading to the depletion of the Cambium tissue. The authors acknowledge neoplastical processes local changes that are not related to changes in the genome of cells and induced when control of effector immunocytes processes of cell proliferation and apoptosis leading to generalized changes in the body, and secondary immune deficiency. Author’s model of carcinogenesis based on data from the literature and own data involved in the formation of tumor blood stem cells migrated to the zone of damage may not initiate signalling molecules, and other effects, including the bioelectrical signals. The authors suggest that the local main damage cells even before the first clinical and morphological characteristics of leading cancer in humans, cause the start of generalized process violations in the regulation of differentiation and specialization of blood stem cells, circulating in the body, followed by the development of secondary immunodeficiency. Migration of blood stem cells, leaving them in the area damaged by the physiological tissue and inability to query a differentiation in the changed circumstances of the situation also involved a change of contact interactions. Reparative regeneration occurs with an attempt to close the defect without specialized tissue barrier function.
Relevance. According to Zur Hausen H. (2008–2012) as well as the majority of supporters of the virus theory of cancer, human papillomavirus (HPV) is now recognized as the primary etiologic agent of carcinogenesis. Narisawa-Saito M., Kiyono T. Et al. (2007–2012) indicate a high mortality from HPV infection, and believe that the human papilloma is the main cause of the development of neoplastic or malignant neoplasms of cervix; types 16 and 18, which relate to the high-risk strains of carcinogenesis, are present in more than 90 % cervical carcinomas. Many authors suggest that the viral genes HPV E6 and E7 play a major role in epithelial malignancy, as they contribute to the degradation of p53 and disrupt the complex formation of transcription factors, inducing multistage carcinogenesis. The availability of carcinogens, proliferation’s dependence on estrogen as well as WHO’s recognition of HbP being the cause of carcinogenesis in the stomach, provide grounds to believe that the solution to the mechanisms of carcinogenesis is to be found in the future. At the same time, the analysis of immune cells interaction in the mechanisms of neoplasia and the role of effector immune cells have been insufficiently studied. Spontaneous recovery in 98 % of papilloma virus cases, Hb pylori carrier state in 95 % at 10 % developing ulcers and 3 % getting cancer, suggests that the key pathogenetic process of oncogenesis is yet to be found.
The aim of our study is to analyze the concepts of oncogenesis and develop the author’s model based on an existing neoplasia algorithm provided by Correa (1998).
Materials and methods. Research data from 2000 to 2013 served as materials for the analysis, containing information on carcinogenesis in various human organs. We also used the results of own research of skin with human papillomavirus infection and reparative regeneration after the burn, as well as mucous membranes of the gastrointestinal tract of humans at ulcerative processes, metaplasia and cancer.
Own research results. The analysis of data on the regeneration process in the burn wound area showed that the migration of leukocytes and undifferentiated cells transforming into fibroblasts with protective and synthetic function for the formation of matrix and substrate for epithelial migration contribute to covering the tissue defect. In this case, restoration of an epithelial layer occurs through the restitution of the burn wound edges as well as through the cambium of hair follicles and sweat glands. It was found that burn wound’s infection with staphylococcus, despite its high pathogenicity and purulent fusion of tissue, results in reparative regeneration with repairing of epidermis at burns surface, even at significant decrease in patient’s immunity. At the same time, the reparative regeneration may be of pronounced hypertrophic character, or accompanied by the formation of poorly rendered normotrophic scar, in case burn wound area is minor. According to our data, in case of HPV infection, first there is an increase in mitotic activity of cambium keratinocytes of the basal and spinous layers, which is consistent with the results of Borgogna C., Lanfredini S., Peretti A., et al. (2014).
The epithelial layer’s adaptation to the HPV consists in amplified proliferative activity of epithelial and connective tissues, hyperkeratosis, as well as the formation of papillomas, represented with outgrowths of epidermis and underlying connective tissue. The HPV tropism to cambium cells and triggering of apoptosis in the epidermis as well as the subsequent destruction of cambium cells lead to the impossibility of restitution in the damage zone. In the absence of spontaneous recovery or in case of long-term infection with HPV, there is a formation of necrotic foci and later – cysts with blood infiltration. Cysts are characterized by the fact that the apical surface of skin retains shiny and corneous layers. There are no granular, tubercular and basal layers. The damage of cambial layer that has a regenerative potential leads to a lack of basement membrane, as it is a derivative of the basal cells and those of underlying connective tissue. Therefore, the basal part of the cyst has no clear outlines. In the epidermis adjacent to the lateral surface of the cyst, total apoptosis takes place. Cyst cells are presented with a pool of cells morphologically identical to blood cells in leukemia; they have numerous figures of abnormal divisions, such as holoschisis and polycentric mitosis. A portion of the fibroblast-like cyst cells produces fibers organizing the structure of cyst; from liquid, it acquires a more dense texture, filled with undifferentiated cells and intercellular substance. Regeneration results in closure of the defect without performing barrier and protective functions inherent in epithelial tissue. The lack of cambium, which generates growth factors of lymphocyte differentiation, leads to the impossibility of cells-migrants’ specialization. There is a decrease in the amount of CD68 cells in the area of expanding tumor as well as an increase in peripheral blood, CD68 cell migration from the epidermis to the connective tissue adjacent to the damage area, and the loss of epidermis restitution abilities, suggesting an explicit dysregulation in the epidermis regeneration process. Cystic formation, emerging in the zone of epidermis damage filled with cells-migrants with numerous abnormal mitoses and cells with morphological features of fibroblasts, show that carcinogenesis is not associated with dysregulation of gene expression and accumulation of epigenetic abnormalities in cambial keratinocytes.
One of the gastric carcinogenesis hypotheses provided by Chiariotti L., Angrisano T., Keller S., Florio E., Affinito O., Pallante P., Perrino C., Pero R. and Lembo F. (2013) suggests that Hb pylori interaction with gastric epithelial cells triggers epigenetic reprogramming, leading to genomic instability, just as in HPV infections, thereby causing tumor growth. Study of the dependence of stomach ulcers and malignancy development on strains with high pathogenicity genes, such as cagA and vacA associated with carcinogenesis, showed the same shifts of CD cells number in the local immune homeostasis of mucous membrane in the pyloric, fundal and cardial section of the stomach. In our opinion, this may indicate that the key role in the pathogenesis of gastric ulcers and carcinogenesis is played not by the pathogenic agents, but the state of local immune homeostasis of the gastric mucosa, providing barrier properties of the surface epithelium. Preceding carcinogenesis atrophy of the gastric mucosa indicates the common mechanisms of carcinogenesis in tissues of various organs, and does not endorse the view on the absence of apoptosis in tissue malignancy. In our studies, total apoptosis and atrophy precede carcinogenesis.
The work was submitted to International Scientific Conference «Present-day problems of science and education», Russia (Moscow), February, 25–27, 2014, came to the editorial office 14.02.2014.