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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]

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]

Aim      To analyze fatal outcomes of myocardial infarction (MI) in patients after COVID-19.Material and methods  Data of pathoanatomical protocols and case histories of 612 patients managed in clinics of the Siberian State Medical University from 01.01.2020 through 31.12.2021 were studied. 68 (11%) of these patients were transferred to the clinics from respiratory hospitals for rehabilitation after the novel coronavirus infection. The main condition for hospitalization was a negative polymerase chain reaction (PCR) test for SARS-CoV-2 virus RNA. 544 (89%) of patients had no history of COVID-19. The incidence of MI was 14% (7/68) in patients after COVID-19 and 10% (74/544) in patients who have not had it. In pathoanatomical protocols and case histories of 81 patients diagnosed with MI, macroscopic and histological changes in the heart, pericardial cavity, coronary arteries, and laboratory results were evaluated. Statistical analysis was performed with a STATISTICA version 10.0 software package.Results The patients after COVID-19 had a lower percentage stenosis, more frequent coronary artery thrombosis, and a positive D-dimer. According to our data, MI emerged 10.0 (2.0; 21.0) days after admission to the hospital, had a larger area, always was transmural, and rapidly resulted in death; the time of necrotic changes in all cases did not exceed 24 h. Upon admission to the hospital, the PCR test for SARS-CoV-2 virus RNA was negative, and acute inflammatory changes were stopped at the previous stage of hospitalization.Conclusion      The risk of coronary thrombosis in patients after COVID-19 remains after the relief of acute inflammatory response and elimination of the infectious agent, thereby creating a risk of MI, that often leads to a fatal outcome.

Aim: To identify gene expression profiles involved in drug resistance of different morphological structures (tubular, alveolar, solid, trabecular, and discrete) presented in breast cancer., Material and Methods: Ten patients with luminal breast cancer have been included. A laser microdissection-assisted microarrays and qRT-PCR were used to perform whole-transcriptome profiling of different morphological structures, to select differentially expressed drug response genes, and to validate their expression., Results: We found 27 differentially expressed genes (p < 0.05) encoding drug uptake (SLC1A3, SLC23A2, etc.) and efflux (ABCC1, ABCG1, etc.) transporters, drug targets (TOP2A, TYMS, and Tubb3), and proteins that are involved in drug detoxification (NAT1 and ALDH1B1), cell cycle progression (CCND1, AKT1, etc.), apoptosis (CASP3, TXN2, etc.), and DNA repair (BRCA1 and USP11). Each type of structures showed an individual gene expression profile related to resistance and sensitivity to anticancer drugs. However, most of the genes (19/27; p < 0.05) were expressed in alveolar structures. Functional enrichment analysis showed that drug resistance is significantly associated with alveolar structures. Other structures demonstrated the similar number (10-13 out of 27) of expressed genes; however, the spectrum of resistance and sensitivity to different anticancer drugs varied., Conclusion: Different morphological structures of breast cancer show individual expression of drug resistance genes.

Breast cancer (BC) demonstrates considerable intratumoral morphological heterogeneity. The aim of this work was to evaluate the relationship among different morphological structures, the rate of metastasis, and efficacy of neoadjuvant chemotherapy (NAC) in NAC-treated ( n = 427) and NAC-naïve ( n = 249) BC patients. We also studied the involvement of an epithelial-mesenchymal transition (EMT) in the development of the intratumoral morphological heterogeneity of BC. We found a significant association between the intratumoral morphological heterogeneity and the rate of BC metastasis and response to NAC, which, in most cases, correlated with the presence of alveolar and trabecular structures. In particular, the rate of lymph node metastasis in tumors containing alveolar and trabecular structures was higher compared to that in tumors lacking such structures. NAC-treated patients with alveolar and trabecular structures had a high distant metastasis rate and a low metastasis-free survival rate. Furthermore, alveolar and trabecular structures were found to be associated with a lack of response to NAC. Interestingly, the association between alveolar structures and a high distant metastasis rate was found only in NAC-unresponsive patients, whereas the association between trabecular structures and an increased distant metastasis was revealed in responders. Alveolar structures were associated with chemoresistance only in patients with lymph node metastases, whereas trabecular structures were associated with chemoresistance only in patients without lymph node metastases. In general, increased intratumoral morphological diversity correlated with considerable chemoresistance and a high metastasis rate of BC. We found variable expressions of epithelial ( EPCAM and CDH1 ) and mesenchymal ( ITGA5 , ITGB5 , CDH2 , CDH11 , TGFb2 , ZEB1 , MMP2 , DCN , MST1R ) markers and, thus, different EMT manifestations in different morphological structures. Therefore, intratumoral morphological heterogeneity of BC may serve as an indicator of the metastatic potential and tumor chemosensitivity.

Cancer invasion and the ability of malignant tumor cells for directed migration and metastasis have remained a focus of research for many years. Numerous studies have confirmed the existence of two main patterns of cancer cell invasion: collective cell migration and individual cell migration, by which tumor cells overcome barriers of the extracellular matrix and spread into surrounding tissues. Each pattern of cell migration displays specific morphological features and the biochemical/molecular genetic mechanisms underlying cell migration. Two types of migrating tumor cells, mesenchymal (fibroblast-like) and amoeboid, are observed in each pattern of cancer cell invasion. This review describes the key differences between the variants of cancer cell migration, the role of epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and amoeboid- mesenchymal transitions, as well as the significance of different tumor factors and stromal molecules in tumor invasion. The data and facts collected are essential to the understanding of how the patterns of cancer cell invasion are related to cancer progression and therapy efficacy. Convincing evidence is provided that morphological manifestations of the invasion patterns are characterized by a variety of tissue (tumor) structures. The results of our own studies are presented to show the association of breast cancer progression with intratumoral morphological heterogeneity, which most likely reflects the types of cancer cell migration and results from different activities of cell adhesion molecules in tumor cells of distinct morphological structures.

In order to understand invasive/adhesive and drug resistant properties of intratumor morphological heterogeneity of breast cancer, we compared the expression of genes responsible for the cell adhesion and for the drug resistance between distinct morphological structures of breast tumors. Tubular (hollow-like), alveolar (morula-like), trabecular, solid structures/patterns, and discrete (small) groups of tumor cells were isolated from invasive carcinoma of no special type (n=3) and invasive micropapillary carcinoma (n=1) of the breast using laser microdissection. The gene expression of cadherins, catenins, integrins, ABC transporters, GSTP1, and drug targets was analyzed using qRT-PCR. Expression of catenin genes was identified in almost all structures. In contrast, the expression of cadherin and integrin genes significantly varied depending on the morphological variant. Cadherin expression declined in the row: solid - alveolar and trabecular structures - discrete groups of tumor cells. Expression of integrins declined in the row: solid and alveolar - trabecular structures - discrete groups of tumor cells. For drug resistance genes, trabecular structures more often demonstrated activity of genes coding for ABC transporters compared to other morphological variants. These results indicate that intratumoral morphological heterogeneity in breast cancer correlates with expression profile of adhesion and drug resistance genes reflecting different patterns of invasive growth and responsiveness to chemotherapy.

Multi-drug resistance (MDR) is a condition when there is broad cross-resistance of cells to various agents which are different in structure and effect. Modern perceptions on mechanisms of MDR development in malignant tumors have been considered, in particular, in tre-ating breast cancer. Physiological functions and contribution to MDR development of ABC-transporter protein families have been described. The role of activation of glutathione system enzymes and apoptosis-regulating proteins in MDR formation has been shown.