Tumor associated macrophages (TAMs) are an important element of tumor stroma. They originate from blood monocytes attracted by chemokines and cytokines produced by tumor cells and, being instructed by tumor microenvironment, develop into potent tumor-supporting cell population. TAMs were demonstrated to directly stimulate tumor cell proliferation and to promote angiogenesis. Further TAMs provide for efficient immune escape by producing immunosuppressive cytokines and facilitate tumor dissemination by producing extracellular matrix remodeling enzymes. In renal cell carcinoma (RCC), numerous studies were performed for elucidation of the role of TAM in tumor progression. Using pan-macrophages marker CD68 and type 2 macrophage (M2) markers CD163 and CD206, it was demonstrated that increased density of TAMs is associated with poor survival of patients. Although most of the studies are focused on M2 population in RCC, several markers rather typical for type 1 macrophages (M1) were also characterized. Macrophages isolated from RCC tumors were shown to produce proinflammatory cytokines TNFα, IL-1β, IL-6, and CCL2. It can be concluded that RCC is an excellent example of a tumor with hybrid phenotype of TAMs that share both M1 and M2 properties. Moreover, TAMs seem to be an attractive therapeutic target as well. Further investigations are needed for identification of RCC-specific TAM markers with high predictive capacity and/or suitable for therapeutic targeting.

Recent research on cancer-associated microbial communities led to the accumulation of data on the interplay between bacteria, immune and tumor cells, the pathways of bacterial induction of carcinogenesis, and its meaningfulness for medicine. Microbial communities that have any kind of impact on tumor progression and microorganisms associated with tumors have been defined as oncobiome. Over the last decades, a number of studies were dedicated to Helicobacter pylori and its role in the progression of stomach tumors, so this correlation can be regarded as proven. Involvement of bacteria in the induction of lung cancer has been largely ignored for a long time, though some correlations between this type of cancer and lung microbiome were established. Despite the fact that in the present the microbial impact on lung cancer progression has many confirmations, the underlying mechanisms are poorly understood. Microorganisms can contribute to tumor initiation and progression through production of bacteriotoxins and other proinflammatory factors. The purpose of this review is to organize the available data on lung cancer microbiome and its role in malignant tumor progression.

The link between a lung tumor and the lung microbiome is a largely unexplored issue. To investigate the relationship between a lung microbiome and the phenotype of an inflammatory stromal infiltrate, we studied a cohort of 89 patients with non-small cell lung cancer. The microbiome was analyzed in tumor and adjacent normal tissue by 16S rRNA amplicon sequencing. Characterization of the tumor stroma was done using immunohistochemistry. We demonstrated that the bacterial load was higher in adjacent normal tissue than in a tumor (p = 0.0325) with similar patterns of taxonomic structure and alpha diversity. Lung adenocarcinomas did not differ in their alpha diversity from squamous cell carcinomas, although the content of Gram-positive bacteria increased significantly in the adenocarcinoma group (p = 0.0419). An analysis of an inflammatory infiltrate of tumor stroma showed a correlation of CD68, iNOS and FOXP3 with a histological type of tumor. For the first time we showed that high bacterial load in the tumor combined with increased iNOS expression is a favorable prognostic factor (HR = 0.1824; p = 0.0123), while high bacterial load combined with the increased number of FOXP3+ cells is a marker of poor prognosis (HR = 4.651; p = 0.0116). Thus, we established that bacterial load of the tumor has an opposite prognostic value depending on the status of local antitumor immunity.

The small G-protein ADP-ribosylation factor 6 (Arf6) belongs to the Ras GTPases superfamily and is mostly known for its actin remodeling functions and involvement in the processes of plasma membrane reorganization and vesicular transport. The majority of data indicates that Arf6 contributes to cancer progression through activation of cell motility and invasion. Alternatively, we found that the expression of a wild-type or a constitutively active Arf6 does not influence tumor cell motility and invasion but instead significantly stimulates cell proliferation and activates phospholipase D (PLD). Conversely the expression of a mutant Arf6 (Arf6N48I), that is, unable to interact with PLD has no effect on proliferation but promotes motility, invasion, and matrix degradation by uPA extracellular proteinase. Studying the mechanisms of Arf6-dependent stimulation of cell proliferation, we found some signaling pathways contributing to Arf6 promitogenic activity. Namely, we showed that Arf6 in a PLD-mTORC1-dependent manner activates S6K1 kinase, a well-known regulator of mitogen-stimulated translation initiation. Furthermore, we demonstrated an Arf6-dependent phosphorylation of mTORC1 downstream targets, 4E-BP1 and ribosomal S6 protein, confirming an existence of Arf6-PLD-mTORC1-S6K1/4E-BP1 signaling pathway and also demonstrated its impact on proliferation stimulation. Next, we found that Arf6 activation potentiates Erk1/2 and p38MAP kinases phosphorylation. Surprisingly, p38 opposite to Erk1/2 significantly contributes to Arf6-dependent proliferation increase promoting S6 ribosomal protein phosphorylation at Ser235/236 residues. Therefore, we demonstrated Arf6 proliferation stimulating activity and revealed PLD-mTORC1 and p38MAP kinase as Arf6 partners mediating promitogenic activity. These results highlight a new aspect of Arf6 functioning in cancer cell biology.

No abstract

Kidney cancer is one of the deadliest malignancies due to frequent late diagnosis (33 % or renal cell carcinoma are metastatic at diagnosis) and poor treatment options. There are two major subtypes of kidney cancer: renal cell carcinoma (RCC) and renal pelvis carcinoma. The risk factors for RCC, accounting for more than 90 % of all kidney cancers, are smoking, obesity, hypertension, misuse of pain medication, and some genetic diseases. The most common molecular markers of kidney cancer include mutations and epigenetic inactivation of von Hippel-Lindau (VHL) gene, genes of vascular endothelial growth factor (VEGF) pathway, and carbonic anhydrase IX (CIAX). The role of epigenetic pathways, including DNA methylation and chromatin structure remodeling, was also demonstrated. Immunologic properties of RCC enable this type of tumor to escape immune response effectively. An important role in this process is played by tumor-associated macrophages that demonstrate mixed M1/M2 phenotype. In this review, we discuss molecular and cellular aspects for RCC development and current state of knowledge allowing personalized approaches for diagnostics and prognostic prediction of this disease. A set of macrophage markers is suggested for the analysis of the association of macrophage phenotype and disease prognosis.

No abstract

Background. Tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) contribute significantly to the development of immunosuppressive properties of a tumor. In this study, we performed immunohistochemical analysis of immune cells of esophageal tumors stroma. Methods. Paraffin-embedded tissue specimens from 48 esophageal squamous cell carcinoma (ESCC) patients were retrospectively collected for immunohistochemical analysis of stromal cells. For staining of macrophages, CD68, CD163, CD206, PU.1, and iNOS were used. For T cell detection, CD8, CD3, and FOXP3 were used. Also, we performed staining for PD-L1 that can be expressed on TAMs and tumor cells. Clinicopathological and survival data were collected and analyzed using the χ2 and Fisher exact tests, Kaplan–Meier curves, and the log-rank test. The correlation analysis was performed with Spearman’s rank correlation coefficient. Results. We found that FOXP3 expression was associated with age (p=0.042) and iNOS expression was associated with the disease stage (p=0.044). In addition, FOXP3 and CD163 appeared to be markers of good prognosis (HR=0.4420, p=0.0325, and HR=0.4447, p=0.0456, respectively). Significant association between PU.1+ and CD68+ macrophages (r=0.833; p≤0.001) and between PU.1+ and CD163+ macrophages (r=0.500; p≤0.001) was established; positive association between PU.1 and CD206 expression was also observed (r=0.250; p=0.043). Conclusions. Large amounts of CD163+ macrophages and FOXP3+ Т cells appear to be markers of good prognosis of ESCC. The number of PU.1+ macrophages strongly correlates with the number of CD68+ macrophages; therefore, usage of PU.1 as a potential macrophage marker can be recommended for esophageal tumors.