Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix.

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.

Tumor-infiltrating monocytes/macrophages promote tumor invasion and migration by upregulating S100A8 and S100A9 expression in cancer cells.

Myeloid cells promote the development of distant metastases, but little is known about the molecular mechanisms underlying this process. Here we have begun to uncover the effects of myeloid cells on cancer cells in a mouse model of liver metastasis. Monocytes/macrophages, but not granulocytes, isolated from experimental liver metastases stimulated migration and invasion of MC38 colon and Lewis lung carcinoma cells. In response to conditioned media from tumor-infiltrating monocytes/macrophages, cancer cells upregulated S100a8 and S100a9 messenger RNA expression through an extracellular signal-related kinase-dependent mechanism. Suppression of S100A8 and S100A9 in cancer cells using short hairpin RNA significantly diminished migration and invasion in culture. Downregulation of S100A8 and S100A9 had no effect on subcutaneous tumor growth. However, colony size was greatly reduced in liver metastases with decreased invasion into adjacent tissue. In tissue culture and in the liver colonies derived from cancer cells with knockdown of S100A8 and S100A9, MMP2 and MMP9 expression was decreased, consistent with the reduction in migration and invasion. Our findings demonstrate that monocytes/macrophages in the metastatic liver microenvironment induce S100A8 and S100A9 in cancer cells, and that these proteins are essential for tumor cell migration and invasion. S100A8 and S100A9, however, are not responsible for stimulation of proliferation. This study implicates S100A8 and S100A9 as important mediators of tumor cell aggressiveness, and highlights the therapeutic potential of S100A8 and S100A9 for interference of metastasis.

Modeling of transcatheter aortic valve replacement: Patient specific vs general approaches based on finite element analysis.

BACKGROUND: There are two main methods used for transcatheter aortic valve replacement (TAVR) FEA modeling for medical devices development: patient specific and general approaches. Advantages and disadvantages of both approaches have never been compared in a single study. METHOD: Here we propose a bioinformatic algorithm to evaluate the accuracy of patient specific and generalized FEA approaches with regards to proximity configuration of the implanted stent reconstructed by computed tomography. In addition, in this study we also assessed the impact of the level of detail on FEA accuracy in the patient specific approach. RESULTS: Our results demonstrate that in certain cases, the generalized approach can ensure the same accuracy as the patient specific approach. Therefore, considering high cost effectiveness of the generalized approach, we identify it as more feasible in the context of TAVR. Furthermore, we suggest that high level of detail can improve the reproducibility of modeling results in the patient specific approach. CONCLUSIONS: Our findings may help medical engineers to better understand the peculiarities of both approaches and therefore make the right decision when choosing a particular approach for computer modeling. Future studies are required to validate our observations.

Macrophage migration inhibitory factor: a key cytokine and therapeutic target in colon cancer.

Macrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered, over 40 years ago. Since that time a burgeoning interest has developed in the role that MIF plays in both the regulation of normal physiology and the response to pathology. MIF is a pleotropic cytokine that functions to promote inflammation, drive cellular proliferation, inhibit apoptosis and regulate the migration and activation state of immune cells. These functions are particularly relevant for the development of cancer and it is notable that various solid tumours over express MIF. This includes tumours of the gastrointestinal tract and MIF appears to play a particularly prominent role in the development and progression of colonic adenocarcinoma. Here we review the role that MIF plays in colonic carcinogenesis through the promotion of colonic inflammation, as well as the progression of primary and metastatic colon cancer. The recent development of various antagonists and antibodies that inhibit MIF activity indicates that we may soon be able to classify MIF as a therapeutic target in colon cancer patients.

Computer-aided design of the human aortic root.

The development of computer-based 3D models of the aortic root is one of the most important problems in constructing the prostheses for transcatheter aortic valve implantation. In the current study, we analyzed data from 117 patients with and without aortic valve disease and computed tomography data from 20 patients without aortic valvular diseases in order to estimate the average values of the diameter of the aortic annulus and other aortic root parameters. Based on these data, we developed a 3D model of human aortic root with unique geometry. Furthermore, in this study we show that by applying different material properties to the aortic annulus zone in our model, we can significantly improve the quality of the results of finite element analysis. To summarize, here we present four 3D models of human aortic root with unique geometry based on computational analysis of ECHO and CT data. We suggest that our models can be utilized for the development of better prostheses for transcatheter aortic valve implantation.

[Role of infectious agents in the emergence of malignant tumors].

According to the data of the International Agency for Research on Cancer (IARC), at least 6 virus species (HPV, EBV, HHV-8/KSHV, HTLV-1, HBV, HCV), 4 helminthes species (Schistosoma haematobium and japonicum, Opisthorchis viverrini, Clonorchis sinensis) and I bacterium species (Helicobacter pylori) have been proved to be capable of causing the development of cancer. The analysis of the data available shows that Merkel cell polyomavirus (MCV), herpes simplex virus (HSV), John Cunningham polyomavirus (JCV), monkey virus 40 (SV40), cytomegalovirus (CMV), xenotropic murine leukemia virus (XMRV), Helicobacter bilis and hepaticus, Campylobacter jejuni, Fusobacterium varium, enteropathogenic Escherichia coli, enterotoxigenic Bacteroides fragilis, Bacteroides vulgatus, Prevotella spp., Streptococcus bovis and anginosus, Treponema denticola, Salmonella typhi, paratyphi and typhimurium, Borrelia burgdorferi, Bartonella spp., Mycobacterium tuberculosis, Chlamydia pneumoniae, trachomatis and psittaci, Neisseria gonorrhoeae, Propionibacterium acnes, Tropheryma whippelii, Schistosoma mansoni, Opistorchis felineus, Strongyloides stercoralis, Taenia solium, Candida spp., Paracoccidioides brasiliensis, Histoplasma capsulatum and Trichomonas vaginalis can also be potential etiological agents of cancer. Apparently, detection of new associations between infectious agents and risk of the development of cancer will facilitate progress in elaboration of prophylaxis measures, early diagnostic methods and, probably, methods of treatment of malignant tumors.