Recent studies showed that changes to the gut microbiome alters the microbiome-derived metabolome, potentially promoting carcinogenesis in organs that are distal to the gut. In this study, we assessed the relationship between breast cancer and cadaverine biosynthesis. Cadaverine treatment of Balb/c female mice (500 nmol/kg p.o. q.d.) grafted with 4T1 breast cancer cells ameliorated the disease (lower mass and infiltration of the primary tumor, fewer metastases, and lower grade tumors). Cadaverine treatment of breast cancer cell lines corresponding to its serum reference range (100–800 nM) reverted endothelial-to-mesenchymal transition, inhibited cellular movement and invasion, moreover, rendered cells less stem cell-like through reducing mitochondrial oxidation. Trace amino acid receptors (TAARs), namely, TAAR1, TAAR8 and TAAR9 were instrumental in provoking the cadaverine-evoked effects. Early stage breast cancer patients, versus control women, had reduced abundance of the CadA and LdcC genes in fecal DNA, both responsible for bacterial cadaverine production. Moreover, we found low protein expression of E. coli LdcC in the feces of stage 1 breast cancer patients. In addition, higher expression of lysine decarboxylase resulted in a prolonged survival among early-stage breast cancer patients. Taken together, cadaverine production seems to be a regulator of early breast cancer.

Oncobiotic transformation of the gut microbiome may contribute to the risk of breast cancer. Recent studies have provided evidence that the microbiome secretes cytostatic metabolites that inhibit the proliferation, movement, and metastasis formation of cancer cells. In this study, we show that indolepropionic acid (IPA), a bacterial tryptophan metabolite, has cytostatic properties. IPA selectively targeted breast cancer cells, but it had no effects on non-transformed, primary fibroblasts. In cell-based and animal experiments, we showed that IPA supplementation reduced the proportions of cancer stem cells and the proliferation, movement, and metastasis formation of cancer cells. These were achieved through inhibiting epithelial-to-mesenchymal transition, inducing oxidative and nitrosative stress, and boosting antitumor immune response. Increased oxidative/nitrosative stress was due to the IPA-mediated downregulation of nuclear factor erythroid 2-related factor 2 (NRF2), upregulation of inducible nitric oxide synthase (iNOS), and enhanced mitochondrial reactive species production. Increased oxidative/nitrosative stress led to cytostasis and reductions in cancer cell stem-ness. IPA exerted its effects through aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR) receptors. A higher expression of PXR and AHR supported better survival in human breast cancer patients, highlighting the importance of IPA-elicited pathways in cytostasis in breast cancer. Furthermore, AHR activation and PXR expression related inversely to cancer cell proliferation level and to the stage and grade of the tumor. The fecal microbiome’s capacity for IPA biosynthesis was suppressed in women newly diagnosed with breast cancer, especially with stage 0. Bacterial indole biosynthesis showed correlation with lymphocyte infiltration to tumors in humans. Taken together, we found that IPA is a cytostatic bacterial metabolite, the production of which is suppressed in human breast cancer. Bacterial metabolites, among them, IPA, have a pivotal role in regulating the progression but not the initiation of the disease.

Background Forty percent of patients with gastric cancer have unnecessarily extended lymph node dissections with higher rates of morbidity and mortality than those in nonextended procedures. Successful sentinel lymph node (SLN) mapping may help to reduce the number of extended lymphadenectomies. Methods SLN mapping was investigated by a blue dyeonly method in patients with gastric cancer. The first cohort of patients (n = 16) were marked submucosally by an endoscopist and in the second cohort of patients (n = 23) a subserosal injection was performed by the surgeon. Results Thirty-nine patients, all Caucasians, underwent gastric resection or total gastrectomy with SLN biopsy using patent blue-dye mapping and modified D2 lymphadenectomy. The mapping procedure and the lymphadenectomy were supervised by the same surgeon. A total of 770 lymph nodes were removed and examined. The mean number of blue nodes was 4.3 per patient. In 22/23 cases at least one SLN showed tumor involvement. The sensitivity of SLN mapping was 95.7%, the false-negative rate was 4.3%, and the specificity was 100%. The negative predictive value was 93.8% and the positive predictive value was 100%. In cases of T1 and T2 tumors the sensitivity was 100%. We found the two marking methods (submucosal vs. subserosal) to be equivalent and there was no side-effect of the blue-dye mapping. Conclusions Our results suggest that SLN mapping with blue dye alone represents a safe procedure that seems to be adaptable for non-obese patients undergoing open surgery for gastric cancer in the Eastern European region. The procedure has high sensitivity and specificity, especially in cases of T1 and T2 tumors.

IntroductionRas guanine nucleotide exchange factors (RasGEFs) mediate the activation of the Ras signaling pathway that is over activated in many human cancers. The RasGRP3, an activator of H-Ras and R-Ras protein exerts oncogenic effects and the overexpression of the protein is observed in numerous malignant cancer types. Here, we investigated the putative alteration of expression and potential function of RasGRP3 in the formation and progression of human breast cancer.MethodsThe RasGRP3 and phosphoRasGRP3 expressions were examined in human invasive ductal adenocarcinoma derived samples and cell lines (BT-474, JIMT-1, MCF7, SK-BR-3, MDA-MB-453, T-47D) both in mRNA (Q-PCR) and protein (Western blot; immunohistochemistry) levels. To explore the biological function of the protein, RasGRP3 knockdown cultures were established. To assess the role of RasGRP3 in the viability of cells, annexin-V/PI staining and MitoProbe™ DilC1 (5) assay were performed. To clarify the function of the protein in cell proliferation and in the development of chemotherapeutic resistance, CyQuant assay was performed. To observe the RasGRP3 function in tumor formation, the Severe combined immunodeficiency (SCID) mouse model was used. To investigate the role of the protein in Ras-related signaling Q-PCR and Western blot experiments were performed.ResultsRasGRP3 expression was elevated in human breast tumor tissue samples as well as in multiple human breast cancer cell lines. Down-regulation of RasGRP3 expression in breast cancer cells decreased cell proliferation, induced apoptosis in MCF7 cells, and sensitized T-47D cells to the action of drugs Tamoxifen and trastuzumab (Herceptin). Gene silencing of RasGRP3 reduced tumor formation in mouse xenografts as well. Inhibition of RasGRP3 expression also reduced Akt, ERK1/2 and estrogen receptor alpha phosphorylation downstream from IGF-I insulin like growth factor-I (IGF-I) or epidermal growth factor (EGF) stimulation confirming the functional role of RasGRP3 in the altered behavior of these cells.ConclusionsTaken together, our results suggest that the Ras activator RasGRP3 may have a role in the pathological behavior of breast cancer cells and may constitute a therapeutic target for human breast cancer.

Two-dimensional photonic crystal structures (PCS) were fabricated using a one-step recording process, multi-beam interference in smart polymer nanocomposites incorporating SiO2 and Au nanoparticles sensitized to 532 nm laser radiation. It was shown, that PCS with different geometry can be recorded in thick nanocomposite layers. The typical two dimensional (2D) PCS have square structure with 2-8 µm period, being in good agreement with theoretical structures obtained by mathematical modeling of the recorded PCS. The peculiarities of the photo-polymerization of nanocomposites with plasmonic Au nanoparticles were analyzed on the basis of Surface Plasmon Resonance Imaging (SPRi) and Raman spectroscopy investigations and used for the interpretation of the recording process and periodic structure formation. Abstract Two-dimensional photonic crystal structures (PCS) were fabricated using a one-step recording process, multi-beam interference in smart polymer nanocomposites incorporating SiO 2 and Au nanoparticles sensitized to 532 nm laser radiation. It was shown, that PCS with different geometry can be recorded in thick nanocomposite layers. The typical two dimensional (2D) PCS have square structure with 2-8 µm period, being in good agreement with theoretical structures obtained by mathematical modeling of the recorded PCS. The peculiarities of the photopolymerization of nanocomposites with plasmonic Au nanoparticles were analyzed on the basis of Surface Plasmon Resonance Imaging (SPRi) and Raman spectroscopy investigations and used for the interpretation of the recording process and periodic structure formation.