Molecular mechanism of early metastatic breast cancer dissemination

Current cancer therapies generally assume cancers to progress linearly from primary to metastatic sites. The model postulates a stepwise accumulation of genetic and epigenetic alterations within the primary tumor, and therefore, primary tumors may be used as surrogate markers for disseminated cancer cells. However, this model is challenged by (i) the insufficient therapy success and (ii) the genomic disparity between disseminated cancer cells (DCCs) and their matched primary tumors when isolated at surgery. The genomic disparity suggests that metastatic dissemination may occur early during tumor formation, however the mechanisms of early metastatic spread are unknown so far. To uncover mechanisms of early metastatic dissemination we microdissected mammary tissue from a Her2-driven mouse model (Balb-NeuT) of breast cancer before and after microscopic invasion and performed gene expression analysis. Identified pathways were tested in a series of in vitro and in vivo experiments. Finally, the findings were validated in a panel of human breast cancer cell lines and investigation of more than 2000 patient samples. Gene expression profiling identified a distinct signature at the time point of maximal seeding when only pre-invasive mammary lesions could be identified. The morphology of pre-invasive lesions coincided with a transient time window of progesterone receptor (PgR) and Her2 co-expression. Upon functional testing progesterone-induced signaling triggered migration of stem-like cells from early lesions shortly after Her2 activation, but promoted proliferation in advanced primary tumor cells. The switch from migration to proliferation was regulated by elevated Her2 expression and increased cell density involving miRNA-regulated PgR down-regulation. The combined result was a differential response of cancer cells to progesterone and its paracrine-signal mediators Wnt4 and Rankl imposing stemness and migration at low and proliferation at high cellular density. Exploring human breast cancer cell lines we confirmed the observed phenotypes and mechanisms. Molecular-genetic and transcriptomic analysis of DCCs isolated from the bone marrow of breast cancer patients provided strong support for early metastatic dissemination. Finally, we identified a subtype of breast cancer mimicking the Balb-NeuT model closest. We identify microenvironmental signaling (PgR signaling), oncogenic signaling (Her2) and cellular density as central regulators of early dissemination and metastasis. In light of the patient-derived data we suggest that (i) dissemination is mostly early and (ii) clones that evolved over time at the primary site and became pre-dominant are less able to disseminate. We predict the findings not only to be relevant for Her2-driven cancers but for many other cancers as well

Effects of royal jelly on sterile skin cut repair

Introduction: Following injury, inflammatory response occurs and the cells below the dermis begin to increase collagen production, then, the epithelial tissue is regenerated. Royal jelly (RJ) has anti-inflammatory activity hence, the aim of this study was to examine the effect of RJ on the induction of sterile skin incision in Balb/C mice. Methods: In an experimental study 60 female Balb/C mice (8 weeks old) were anaesthetized with ether and a longitudinal para vertebral full thickness incision of 10 mm long was made. The animals were divided into six equal groups. Group 1 was considered as negative control. Group 2 (positive control) was treated topically with Nitrofurazon ointment, group 3 with RJ (200 mg/kg) every day, group 4 with RJ (200 mg/kg) every two days, group 5 with RJ (300 mg/kg) every day and group 6 with RJ (300 mg/kg) every two days. The wound length was measured with vernier capilar every two days up to full healing occurred and compared in different groups. Results: There was significant difference between groups 1 or 2 and other groups (p&lt;0.05). RJ promoted wound healing activity significantly in group 3, 5 compared to negative and positive control groups. There was no significant difference between the uses of 200 mg/kg and 300 mg/kg RJ (p&gt;0.05). Conclusion: The results of this study indicate that daily application of RJ possesses betters wound healing effects than Nitrofurazon and every two days usage of RJ.</p

An overview on the most important native medicinal plants against flour beetle

Contamination with pests is the main problems of stored food products and can defects them from harvest time until storage. Pests have high proliferation rate, global distribution, and sometimes damage foods up to a hundred percent. Nowadays plant materials are used for pest control in warehouses. Volatile essential oils are important compounds to combat fungal pathogens, insects, herbivores and pests in stored food products. Herbs and botanicals have insecticide and insect repellent properties and are good alternative to chemical insecticides. This paper was aimed to have an overview on the most important native medicinal plants against flour beetle. All required information was obtained by searching key words such as flour beetle, medicinal plant extracts or essential oils and Iran of published articles in authentic scientific databases such as Sciencedirect, Blackwell Wiley, Springer, Scopus, Pubmed, Google scholar and Scientific information database (SID) and Magiran. Eucalyptus globulus, Perovskia atriplicifolia, Azadirachta indica Adr. Juss, Artemisia sieberi Besser, Carum copticum C. B. Clarke, Cuminum cyminum L, Bunium persicum Boiss, Elletaria cardamomum Maton, Nerium oleander L, Lavandula officinalis L, Ferula assafoetida L, Rosmarinus officinalis L. Artemisia dracunculus L, Foeniculum vulgare, Satureja hortensis L, Zygophyllum fabago L, Delphinium persicum, Calotropis procera (Ait.) R. Br are the main medicinal plants can affect on flour beetle. They have various compounds and based on the results of phytochemical studies each of active compounds of medicinal plants could have potential anti pest effects against flour beetle. Therefore, it is recommended that all active ingredients are investigated in experimental and pharmacological studies and in case of positive effects, they used for production of natural anti pest compounds against the flour beetle

Omics Integration Analyses Reveal the Early Evolution of Malignancy in Breast Cancer

The majority of cancer evolution studies involve individual-based approaches that neglect the population dynamics necessary to build a global picture of cancer evolution for each cancer type. Here, we conducted a population-based study in breast cancer to understand the timing of malignancy evolution and its correlation to the genetic evolution of pathological stages. In an omics integrative approach, we integrated gene expression and genomic aberration data for pre-invasive (ductal carcinoma in situ; DCIS, early-stage) and post-invasive (invasive ductal carcinoma; IDC, late-stage) samples and investigated the evolutionary role of further genetic changes in later stages compared to the early ones. We found that single gene alterations (SGAs) and copy-number alterations (CNAs) work together in forward and backward evolution manners to fine-tune the signaling pathways operating in tumors. Analyses of the integrated point mutation and gene expression data showed that (i) our proposed fine-tuning concept is also applicable to metastasis, and (ii) metastases sometimes diverge from the primary tumor at the DCIS stage. Our results indicated that the malignant potency of breast tumors is constant over the pre- and post-invasive pathological stages. Indeed, further genetic alterations in later stages do not establish de novo malignancy routes; however, they serve to fine-tune antecedent signaling pathways

Evaluation of IL-17A and IL-17F genes polymorphism in Iranian dyspeptic patients

Helicobacter pylori (H.pylori) colonize the gastric mucosa of approximately 50 of the world's population that involved in chronic gastritis. The relationship between Hp colonization and gastric inflammation is widely accepted. Polymorphisms in inflammation related genes such as cytokines were thought to partly determine the outcome of Hp infection and progression of gastritis. Interleukin IL -17A and IL-17F are inflammatory cytokines expressed by a novel subset of CD4+ Th cells, play important function in inflammation. Aimed: we evaluate association of IL-17A G197A and IL-17F A7488G polymorphisms with gastritis, Polymorphonuclear (PMN) and Monoculear (MN) infiltration in related to Hp. Methods: According to rapid urease test, PCR 16srRNA, urea and histological examination of biopsies, patients were classified Hp-infected and Hp-uninfected. The histological severity of gastritis was graded from normal to severe based on the degree of MN cell and PMN leukocyte infiltration, chronic gastritis and chronic active gastritis. Polymorphism in IL-17A G197A and IL-17F A7488G were evaluated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: AG, GG, AG/AA carriers of IL-17A G197A and AA, GA, GG, GA/GG carriers of IL-17F A7488G polymorphisms were not associated with MN infiltration, PMN infiltration, chronic gastritis and Chronic active gastritis in Hp-infected and Hp-uninfected groups (p > 0.05). AA genotype of IL-17A G197A was related to chronic gastritis and PMN infiltration in Hp-uninfected group. Conclusion: IL-17A G197A substitution may be a risk factor for development gastritis in Hp-uninfected patients, also affect the pathway MN cell production pathways

Microenvironmental IL1 1 β promotes metastatic colonisation of breast cancer cells in the bone via activation of Wnt-dependent cancer stem cell activity

Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however cells may lie dormant for many years before bone metastases develop. Treatment for bone metastases is not curative, therefore new adjuvant therapies which prevent the colonisation of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are capable of metastasis, but the mechanism by which these colonise bone is unknown. Here, we establish that bone marrow-derived IL1β stimulates breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, leading to autocrine Wnt signalling and CSC colony formation. Importantly, we show that inhibition of this pathway prevents both CSC colony formation in the bone environment, and bone metastasis. These findings establish that targeting IL1β-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy to prevent breast cancer bone metastasis

Mechanism of early dissemination and metastasis in Her2+ mammary cancer

Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain dormant(1). Metastasis-initiating cells are thought to originate from a subpopulation present in progressed, invasive tumours(2). However, DCCs detected in patients before the manifestation of breast-cancer metastasis contain fewer genetic abnormalities than primary tumours or than DCCs from patients with metastases(3-5). These findings, and those in pancreatic cancer(6) and melanoma(7) models, indicate that dissemination might occur during the early stages of tumour evolution(3,8,9). However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown(8). Here we show that, in early lesions in mice and before any apparent primary tumour masses are detected, there is a sub-population of Her2(+) p-p38lop-Atf2loTwist1hiE-cadlo early cancer cells that is invasive and can spread to target organs. Intra-vital imaging and organoid studies of early lesions showed that Her2(+) eDCC precursors invaded locally, intravasated and lodged in target organs. Her2(+) eDCCs activated a Wnt-dependent epithelial-mesenchymal transition (EMT)-like dissemination program but without complete loss of the epithelial phenotype, which was reversed by Her2 or Wnt inhibition. Notably, although the majority of eDCCs were Twist1(hi)E-cadlo and dormant, they eventually initiated metastasis. Our work identifies a mechanism for early dissemination in which Her2 aberrantly activates a program similar to mammary ductal branching that generates eDCCs that are capable of forming metastasis after a dormancy phase