Current Issue : July - September Volume : 2016 Issue Number : 3 Articles : 4 Articles
Background: Cancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and\ndevelopment. However, little research has been undertaken to evaluate the role of CAFs in endometrial cancer (EC)\nprogression. We aim to detect the functional contributions of CAFs to promote progression of EC.\nMethods: Stromal fibroblasts were isolated from endometrioid adenocarcinomas and normal endometrial tissues.\nThe conditioned media of cultured CAFs and normal fibroblasts (NFs) were collected to detect the level of stromal\ncell-derived factor-1alpha (SDF-1�±), macrophage chemoattractant protein-1 (MCP-1), migration inhibitory factor\n(MIF), colony stimulating factor-1 (CSF-1), and interleukin-1 (IL-1) by ELISA. The CAFs or NFs were cocultured with EC\ncell lines to determine the proliferation, migration, and invasion by MTT assays and transwell chambers. Xenograft\nmodels were used to observe tumor growth. Matrix metalloproteinases (MMP)-2 and MMP-9 activity was evaluated\nby zymography. AMD3100 (a chemokine receptor 4 (CXCR4) antagonist) was used to block the SDF-1/CXCR4 axis.\nNeutralizing antibodies were used to detect PI3K/Akt and MAPK/Erk pathways by western blotting. SDF-1�± and\nCXCR4 expressions were analyzed in xenotransplanted tumors and 348 cases by immunohistochemistry.\nResults: CAFs promoted proliferation, migration, and invasion as well as in vivo tumorigenesis of admixed EC\ncells significantly more than NFs by secreting SDF-1�±. These effects were significantly inhibited by AMD3100.\nCAFs promoted EC progression via the SDF-1�±/CXCR4 axis to activate the PI3K/Akt and MAPK/Erk signalings in a\nparacrine-dependent manner or increase MMP-2 and MMP-9 secretion in an autocrine-dependent manner. SDF-1�± and\nCXCR4 expression upregulation accompanied clinical EC development and progression. High SDF-1�± expression levels\nwere associated with deep myometrial invasion, lymph node metastasis, and poor prognosis in EC.\nConclusions: Our data indicated that CAFs derived from EC tissues promoted EC progression via the SDF-1/CXCR4 axis\nin a paracrine- or autocrine-dependent manner. SDF-1�± is a novel independent poor prognostic factor for EC patientsâ��\nsurvival. Targeting the SDF-1/CXCR4 axis might provide a novel therapeutic strategy for EC treatment....
Background. The beta-2 adrenergic receptor is expressed by neoplastic cells and is correlated with a wide spectrum of tumor cell\nmechanisms including proliferation, apoptosis, angiogenesis, migration, and metastasis. Objectives. The present study aimed to\nanalyze the expression of the beta-2 adrenergic receptor (...
Researchers have made considerable progress in last few decades in understanding mechanisms underlying pathogenesis of\nbreast cancer, its phenotypes, its molecular and genetic changes, its physiology, and its prognosis. This has allowed us to identify\nspecific targets and design appropriate chemical entities for effective treatment of most breast cancer phenotypes, resulting in\nincreased patient survivability. Unfortunately, these strategies have been largely ineffective in the treatment of triple negative\nbreast cancer (TNBC). Hormonal receptors lacking render the conventional breast cancer drugs redundant, forcing scientists\nto identify novel targets for treatment of TNBC. Two natural compounds, curcumin and resveratrol, have been widely reported\nto have anticancer properties. In vitro and in vivo studies show promising results, though their effectiveness in clinical settings\nhas been less than satisfactory, owing to their feeble pharmacokinetics. Here we discuss these naturally occurring compounds,\ntheir mechanism as anticancer agents, their shortcomings in translational research, and possible methodology to improve their\npharmacokinetics/pharmacodynamics with advanced drug delivery systems....
Background: The polycomb complex protein BMI-1 (BMI-1) is a putative oncogene reported to be overexpressed\nin multiple myeloma (MM). Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However,\ntherapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC-209, a novel\nsmall molecule inhibitor of BMI-1, for its activity in MM.\nMethods: BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publically\navailable gene expression profiling (GEP) data. The anti-MM activity of PTC-209 was investigated by viability testing,\ncell cycle analysis, annexin V and 7-AAD staining, quantification of cleaved poly(ADP-ribose) polymerase (PARP), JC-1\nas well as colony formation assays. Deregulation of central myeloma growth and survival genes was studied by\nquantitative PCR and flow cytometry, respectively. In addition, the impact of PTC-209 on in vitro osteoclast,\nosteoblast and tube formation was analysed.\nResults: We confirmed overexpression of BMI-1 in MM patients by using publically available GEP datasets. Of note,\nBMI-1 expression was further increased at relapse which translated into significantly shorter overall survival in\nrelapsed/refractory patients treated with bortezomib or dexamethasone.\nTreatment with PTC-209 significantly decreased viable cell numbers in human MM cell lines, induced a G1 cell cycle\narrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. The anti-MM\nactivity of PTC-209 was accompanied by a significant decrease of cyclin D1 (CCND1) and v-myc avian\nmyelocytomatosis viral oncogene homolog (MYC) expression as well as upregulation of cyclin-dependent kinase\ninhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). We also observed upregulation of NOXA\n(up to 3.6 �± 1.2-fold induction, P = 0.009) and subsequent downregulation of myeloid cell leukemia 1 (MCL-1)\nprotein levels, which likely mediates the apoptotic effects of PTC-209. Importantly, the anti-MM activity was upheld\nin the presence of stromal support or myeloma growth factors insulin-like growth factor 1 (IGF-1) and interleukin 6\n(IL-6).\nIn the MM microenvironment, PTC-209 impaired tube formation, impaired osteoclast development and decreased\nosteoblast formation in a dose-dependent manner (P < 0.01 at 1 �¼M, respectively). The latter might be attributed to\nan induction of DKK1 and was reversed by concurrent anti-DKK1 antibody treatment.\nConclusions: We confirmed overexpression of BMI-1 in MM highlighting its role as an attractive drug target and\nreveal therapeutic targeting of BMI-1 by PTC-209 as a promising novel therapeutic intervention for MM....
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