Molecular mechanisms of tumor growth

Abstract

Formation of properties promoting malignant transformation occurs even before the appearance of tumor cells at the level of inflammatory and precancerous processes. And the background of this formation is tumor cell’s genomic instability. Genetic instability manifests itself both in genetic structural changes that can be described as mutational process, and in epigenetic disturbances. Epigenetic changes are associated with DNA methylation, histone and

chromatin modification, appearance of new RNA molecules, and determine specific regulation and expression of genes in tumor area. As a result of genetic instability, mechanisms promoting malignant transformation of cells and tumor growth are formed and functioning. One of the main mechanisms is the ability to maintain chronic proliferation. Signaling system is changed in the tumor, and stimulation of cell growth and division occurs in the absence of external signals. Investigations of tumor cell’s genome demonstrated that somatic mutations do contribute to the activation of signaling systems. Tumor suppressor genes are the central regulators of cellular control and are associated with the activation of physiological aging and apoptosis program. Mechanisms allowing to ignore cellular proliferation suppression systems by suppressor genes do exist in tumor cells. Programmed cell death – apoptosis – acts as a natural barrier for tumor development. Tumor cells employ various opportunities for restricting and overcoming apoptosis, and several strategies employed by tumor cells for avoiding apoptosis are known. Unlimited replication potential is necessary for malignant cells in order to obtain cell number adequate for macroscopic tumor formation. This feature distinguishes them from normal cells that have limited number of division cycles. Decrease of telomeres length is the mechanism that restricts the replicative potential of normal cells and is disturbed in tumor cells. Another mechanism promoting tumor growth is neovascularization – formation of new blood vessels. In the course of tumor progression angiogenesis is always activated, and new blood vessels are formed that help to maintain the neoplasm’s growth. Tumors are transformed to pathologically high malignancy grade that is reflected in local invasion and distant metastasis. In time course tumor cells usually not only change their shape, but also lose the connection with other cells and extracellular matrix. As a result, multistep process of invasion and metastasizing often called invasion/metastasizing cascade arises. In the last years significant progress was achieved in the understanding of complicated invasion and metastasizing mechanisms, and genes regulating these processes were identified. The mechanism of epithelial-mesenchymal transition associated with epithelial cells transformation and acquiring of ability to invasion, apoptosis resistance and dissemination is now regarded to be one of the main regulators of invasion and metastasizing. Metastasizing process has two main phases: dissemination of cells to distant tissues, and adaptation of these cells to foreign tissue environment resulting in micrometastasis development to macroscopic tumors. In further decades intensive studies of the associations between inflammation and cancerogenesis revealed involvement of immune cells in neoplastic progression. Inflammation is found at early stages of neoplastic progression and apparently promotes the transition of incipient neoplasia to full-blown cancer. During chronic uncontrolled cell proliferation rearrangement of energetic metabolism for cell nutrition in the course of growth and division also occurs. The last years’ achievements of molecular oncology allow to reveal and evaluate the mechanisms promoting malignant transformation and tumor growth described in this paper, though many aspects still remain unclear.