Gregersenkappel0569

Melanoma, a form of skin cancer, is one of the most common cancers in young men and women. Tumors require angiogenesis to provide oxygen and nutrients for growth. Pro-angiogenic molecules such as VEGF and anti-angiogenic molecules such as sFlt-1 control angiogenesis. In addition, the serum protein, Beta2 Glycoprotein I (β2-GPI) induces or inhibits angiogenesis depending on conformation and concentration. β2-GPI binds to proteins and negatively charged phospholipids on hypoxic endothelial cells present in the tumor microenvironment. We hypothesized that peptides derived from the binding domain of β2-GPI would regulate angiogenesis and melanoma growth. In vitro analyses determined the peptides reduced endothelial cell migration and sFlt-1 secretion. In a syngeneic, immunocompetent mouse melanoma model, β2-GPI-derived peptides also reduced melanoma growth in a dose-dependent response with increased sFlt-1 and attenuated vascular markers compared to negative controls. Importantly, administration of peptide with sFlt-1 antibody resulted in tumor growth. These data demonstrate the therapeutic potential of novel β2-GPI-derived peptides to attenuate tumor growth and endothelial migration is sFlt-1 dependent.Brain tumor is the leading cause of cancer related death in children. Clinically relevant animals are critical for new therapy development. To address the potential impact of animal gender on tumorigenicity rate, xenograft growth and in vivo drug responses, we retrospectively analyzed 99 of our established patient derived orthotopic xenograft mouse models (orthotopic PDX or PDOX). From 27 patient tumors, including 5 glioblastomas (GBMs), 11 medulloblastomas (MBs), 4 ependymomas (EPNs), 4 atypical teratoid/rhabdoid tumors (ATRTs) and 3 diffuse intrinsic pontine gliomas (DIPGs), that were directly implanted into matching locations in the brains of approximately equal numbers of male and female animals (n = 310) in age-matched (within 2-week age-difference) SCID mice, the tumor formation rate was 50.6 ± 21.5% in male and 52.7 ± 23.5% in female mice with animal survival times of 192.6 ± 31.7 days in male and 173.9 ± 34.5 days in female mice (P = 0.46) regardless of pathological diagnosis. Once established, PDOX tumors were serially subtransplanted for up to VII passage. Analysis of 1,595 mice from 59 PDOX models (18 GBMs, 18 MBs, 5 ATRTs, 6 EPNs, 7 DIPGs and 5 PENTs) during passage II and VII revealed similar tumor take rates of the 6 different tumor types between male (85.4 ± 15.5%) and female mice (84.7 ± 15.2%) (P = 0.74), and animal survival times were 96.7 ± 23.3 days in male mice and 99.7 ± 20 days in female (P = 0.25). A total of 284 mice from 7 GBM, 2 MB, 1 ATRT, 1 EPN, 2 DIPG and 1 PNET were treated with a series of standard and investigational drugs/compounds. The overall survival times were 106.9 ± 25.7 days in male mice, and 110.9 ± 31.8 days in female mice (P = 0.41), similar results were observed when different types/models were analyzed separately. In conclusion, our data demonstrated that the gender of SCID mice did not have a major impact on animal model development nor drug responses in vivo, and SCID mice of both genders are appropriate for use.Sulforaphane (SFN) is a compound derived from cruciferous plants shown to be effective in cancer prevention and suppression. Myeloid-derived suppressor cells (MDSCs) are known to inhibit anti-tumor immunity; however, whether SFN regulates the anti-tumor activity of MDSCs in breast cancer is still unknown. In the current study, we found that SFN blocked prostaglandin E2 (PGE2) synthesis in parental and doxorubicin (DOX)-resistant breast cancer 4T1 cell lines by activating NF-E2-related factor 2 (Nrf2). Nrf2-mediated reduction of PGE2 was dependent on the enhanced expression of heme oxygenase 1 (HO-1) and glutamate-cysteine ligase (GCLC), and decreased COX-2 expression in breast cancer cells. Moreover, our study further revealed that reduced PGE2 secretion from SFN-treated 4T1 cells triggered MDSCs to switch to an immunogenic phenotype, enhancing the anti-tumor activities of CD8+ T cells. Co-administration of SFN and DOX was more efficacious for the treatment of breast cancer in a mouse model than either agent alone, as evidenced by the significant decrease in tumor volume, MDSC expansion, and increase in cytotoxic CD8+ T cells. Taken together, our data indicate that SFN reverses the immunosuppressive microenvironment and is a potent adjuvant chemotherapeutic candidate in breast cancer.Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. selleck kinase inhibitor While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.