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Intravasation is a key step in cancer metastasis during which tumor cells penetrate the vessel wall and enter circulation, thereby becoming circulating tumor cells and potential metastatic seeds. Understanding the molecular mechanisms of intravasation is critically important for the development of therapeutic strategies to prevent metastasis. In this article, we review current data on the mechanisms of cancer cell intravasation into the blood and lymphatic vessels. The entry of mature thymocytes into the circulation and of dendritic cells into the regional lymph nodes is considered as examples of intravasation under physiologically normal conditions. Intravasation in a pathophysiological state is illustrated by the reverse transendothelial migration of leukocytes into the bloodstream from the sites of inflammation mediated by the sphingosine 1-phosphate interaction with its receptors. Intravasation involves both invasion-dependent and independent mechanisms. In particular, mesenchymal and amoeboid cell invasion, as well as neoangiogenesis and vascular remodeling, are discussed to play a significant role in the entry of tumor cells to the circulation. Special attention is given to the contribution of macrophages to the intravasation via the CSF1/EGF (colony stimulating factor 1/epidermal growth factor) paracrine signaling pathway and the TMEM (tumor microenvironment of metastasis)-mediated mechanisms. Other mechanisms including intravasation of tumor cell clusters surrounded by the vessel wall elements, cooperative intravasation (entry of non-invasive tumor cells to the circulation following invasive tumor cells), and intravasation associated with the vasculogenic mimicry (formation of vascular channels by tumor cells) are also discussed. Novel intravasation-specific mechanisms that have not yet been described in the literature are suggested. The importance of targeted therapeutic strategies to prevent cancer intravasation is emphasized. [ABSTRACT FROM AUTHOR]

Intratumor heterogeneity inherent in the majority of human cancers is a major obstacle for a highly efficient diagnosis and successful prognosis and treatment of these diseases. Being a result of clonal diversity within the same tumor, intratumor heterogeneity can be manifested in variability of genetic and epigenetic status, gene and protein expression, morphological structure, and other features of the tumor. It is most likely that the appearance of this diversity is a source for the adaptation of the tumor to changes in microenvironmental conditions and/or a tool for changing its malignant potential. In any case, both processes result in the appearance of cell clones with different undetermined sets of hallmarks. In this review, we describe the heterogeneity of molecular disorders in various human tumors and consider modern viewpoints of its development including genetic and non-genetic factors of heterogeneity origin and the role of cancer stem cells and clonal evolution. We also systematize data on the contribution of tumor diversity to progression of various tumors and the efficiency of their treatment. The main problems are indicated in the diagnosis and therapy of malignant tumors caused by intratumor heterogeneity and possible pathways for their solution. Moreover, we also suggest the key goals whose achievement promises to minimize the problem of intratumor heterogeneity and to identify new prognostic, predictive, and target markers for adequate and effective treatment of cancer. [ABSTRACT FROM AUTHOR]

Aim. To investigate the expression of the TGFB1, TNF, CSF1, CSF2, VEGFA and HIF1A genes in the patients with invasive breast carcinoma of no special type considering the intratumoral morphological heterogeneity. Methods. The technology of laser capture microdissection PALM was used to isolate five types of morphological tumor structures from three patients with invasive carcinoma of no special type (IC NST), luminal A subtype, T1-2NxMx. The level of expression of the cytokine (TNF), growth factors (TGFB1, CSF1, CSF2, VEGFA) and the HIF1A genes was assessed in the samples obtained using quantitative real-time PCR. Results. The study demonstrated the absence of the expression of the growth factor CSF2 gene in tumor cells of IC NST, and the expression of the CSF1 gene, independent from the metastasis status and tumor structure type. The prevalence of the expression of the VEGFA and TGFB1 genes was revealed in the alveolar and solid structures along with the rare expression of the TNF gene. Conclusions. The expression of pre-metastatic niche genes in the tumors of patients with IC NST is heterogeneous. The hypoxia-mediated change in the cytokine gene expression may be expected in the alveolar and solid structures, which ultimately results in the formation of microenvironment, facilitating tumor growth and the formation of tumor metastatic potential. [ABSTRACT FROM AUTHOR]