Background: CD47 is a widely expressed receptor that regulates cellular responses to stress. Results: CD47 regulates metabolic pathways required to control glucose metabolism, oxidative stress, DNA repair, and energetics after exposure to ionizing radiation. Conclusion: CD47 broadly limits the capacity of cells and tissues to survive and recover from damage caused by ionizing radiation. Significance: CD47-targeted therapeutics could be global regulators of cell metabolism.
Purpose: To evaluate whether (a) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like receptor 3 (TLR3) and/or TLR3 signaling; (b) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with cell growth and migration; and (c) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo. Experimental Design: We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3 regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice were implanted with human pancreatic cancer and/ or melanoma cells and the effects of C10 on tumor growth were evaluated. Results: We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of transcription 3 activation. Conclusions: C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma.Pancreatic cancer and malignant melanoma are difficult to treat and have poor prognoses. The American Cancer Society estimates that 37,680 people will have been diagnosed with pancreatic cancer in 2008, with an expected death rate of 92%. It is the fourth leading cause of cancer deaths in the United States and has an overall survival rate of <4%; most die within 6 months to 1 year from time of diagnosis. Malignant melanoma exceeds many other types of cancers in lost "years of life" because it is most prevalent in younger individuals. The poor prognosis is attributable to a highly invasive nature, metastases before discovery, and a poor response to chemotherapeutic and/or surgical intervention. Uncovering a potentially effective treatment for both carcinoma of the pancreas and malignant melanoma is therefore of importance, particularly if the therapy has a novel molecular basis and is applicable to both.The Wingless (Wnt) family of secreted glycoproteins control early developmental processes including cellular migration, differentiation, and proliferation (reviewed in ref. 1). "Canonical" Wnts modulate cell growth by increasing β-catenin levels, β-catenin nuclear localization, and binding...
Elevated CD47 expression in some cancers is associated with decreased survival and limited clearance by phagocytes expressing the CD47 counterreceptor SIRPa. In contrast, elevated CD47 mRNA expression in human melanomas was associated with improved survival. Gene-expression data were analyzed to determine a potential mechanism for this apparent protective function and suggested that high CD47 expression increases recruitment of natural killer (NK) cells into the tumor microenvironment. The CD47 ligand thrombospondin-1 inhibited NK cell proliferation and CD69 expression in vitro. Cd47 À/À NK cells correspondingly displayed augmented effector phenotypes, indicating an inhibitory function of CD47 on NK cells. Treating human NK cells with a CD47 antibody that blocks thrombospondin-1 binding abrogated its inhibitory effect on NK cell proliferation. Similarly, treating wild-type mice with a CD47 antibody that blocks thrombos-pondin-1 binding delayed B16 melanoma growth, associating with increased NK cell recruitment and increased granzyme B and interferon-g levels in intratumoral NK but not CD8 þ T cells. However, B16 melanomas grew faster in Cd47 À/À than in wild-type mice. Melanoma-bearing Cd47 À/À mice exhibited decreased splenic NK cell numbers, with impaired effector protein expression and elevated exhaustion markers. Proapoptotic gene expression in Cd47 À/À NK cells was associated with stress-mediated increases in mitochondrial proton leak, reactive oxygen species, and apoptosis. Global geneexpression profiling in NK cells from tumor-bearing mice identified CD47-dependent transcriptional responses that regulate systemic NK activation and exhaustion. Therefore, CD47 positively and negatively regulates NK cell function, and therapeutic antibodies that block inhibitory CD47 signaling can enhance NK immune surveillance of melanomas.
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