Semaphorin 4F as a Critical Regulator of Neuro-Epithelial Interactions and a Biomarker of Aggressive Prostate Cancer

“Semaphorin 4F (S4F) has roles in embryological axon guidance and is expressed in adults. S4F is involved in cancer-induced neurogenesis. METHODS: Prostate cells were transfected with S4F retrovirus. Cells and controls were used for a BrdU incorporation assay (proliferation) and in vitro scratch and matrigel transwell chamber invasion assay (migration). Monoclonal antibodies were developed using baculovirus expressed recombinant GST-S4F and used to immunostain tissue microarrays. Slides were imaged using deconvolution and analyzed using tissue segmentation. Data was correlated with clinico-pathological parameters, other biomarkers and survival analysis performed. Heterogeneity of S4F expression was analyzed with unsupervised clustering algorithms. RESULTS: Proliferation rates measured by BrdU incorporation were higher in all S4F transfected cells. S4F over-expression was associated with increased motility of the cancer cells. S4F expression was over expressed in HGPIN / PCa than normal epithelium. S4F expression correlated with seminal vesicle invasion. Patients with high values of S4F in PCa cytoplasm are at significantly higher risk of biochemical recurrence, by univariate and multivariate analysis. S4F cytoplasmic expression in PCa cells also correlates with nerve density in PCa and perineural invasion diameter. Correlations were identified with NFkB and inversely with apoptosis in PNI. CONCLUSION: This data demonstrates that S4F is significantly involved in human PCa progression. S4F is a key regulator of the interactions between nerves in the tumor microenvironment and cancer cells. Because of the importance of cancer nerve interaction in the biology of cancer and its clinical implication, S4F can be considered a major therapeutic target.”


Why Melanoma Strikes Redheads

People with red hair and very fair skin are 10 to 100 times more likely to get melanoma—and new research pins this on a mutated protein. The normal protein, called MC1R, helps suppress tumors. But, in a lab, cells with the mutant protein divided abnormally fast after exposure to ultraviolet (UV) radiation, which is a risk factor for melanoma. This abnormal cell division is driven by a known cancer pathway, opening the way to developing targeted treatments for redheads with melanomas. Underscoring the urgency, the researchers found that this cancer pathway was even more active in cells with both the mutant ‘redhead’ protein and the BRAF mutation found in nearly 70% of melanomas.


Pharmacological Inactivation of Skp2 SCF Ubiquitin Ligase Restricts Cancer Stem Cell Traits and Cancer Progression

“Skp2 E3 ligase is overexpressed in numerous human cancers and plays a critical role in cell-cycle progression, senescence, metabolism, cancer progression, and metastasis. In the present study, we identified a specific Skp2 inhibitor using high-throughput in silico screening of large and diverse chemical libraries. This Skp2 inhibitor selectively suppresses Skp2 E3 ligase activity, but not activity of other SCF complexes. It also phenocopies the effects observed upon genetic Skp2 deficiency, such as suppressing survival and Akt-mediated glycolysis and triggering p53-independent cellular senescence. Strikingly, we discovered a critical function of Skp2 in positively regulating cancer stem cell populations and self-renewal ability through genetic and pharmacological approaches. Notably, Skp2 inhibitor exhibits potent antitumor activities in multiple animal models and cooperates with chemotherapeutic agents to reduce cancer cell survival. Our study thus provides pharmacological evidence that Skp2 is a promising target for restricting cancer stem cell and cancer progression.”


Pharmacological Inactivation of Skp2 SCF Ubiquitin Ligase Restricts Cancer Stem Cell Traits and Cancer Progression

“Skp2 E3 ligase is overexpressed in numerous human cancers and plays a critical role in cell-cycle progression, senescence, metabolism, cancer progression, and metastasis. In the present study, we identified a specific Skp2 inhibitor using high-throughput in silico screening of large and diverse chemical libraries. This Skp2 inhibitor selectively suppresses Skp2 E3 ligase activity, but not activity of other SCF complexes. It also phenocopies the effects observed upon genetic Skp2 deficiency, such as suppressing survival and Akt-mediated glycolysis and triggering p53-independent cellular senescence. Strikingly, we discovered a critical function of Skp2 in positively regulating cancer stem cell populations and self-renewal ability through genetic and pharmacological approaches. Notably, Skp2 inhibitor exhibits potent antitumor activities in multiple animal models and cooperates with chemotherapeutic agents to reduce cancer cell survival. Our study thus provides pharmacological evidence that Skp2 is a promising target for restricting cancer stem cell and cancer progression.”


Prostate Cancer Might Need a Little Help from the Nerves


For many years, researchers have known that cancers need a system of support to grow and metastasize. The so-called tumor microenvironment—the still normal tissue in which tumors grow, the blood vessels that feed this tissue (and the tumor), and the immune cells found in most tissues—is co-opted by the cancer cells to change in such a way as to support their growth. Analysis of the tumor microenvironment and how it affects the tumor (and vice versa) is the focus of intense research. Continue reading…


Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State

“Ribosome biogenesis is commonly up-regulated to satisfy the increased anabolic demands associated with malignant transformation and tumor growth. Many different oncogenic signaling pathways converge on the ribosome to increase translational flux. Despite the detailed understanding of ribosome regulation in cancer, it is not clear whethethe net translational activity of the ribosome can itself regulate transcriptional programs that support and promote the malignant state.”


Molecular Pathways: Inflammation-Associated Nitric-Oxide Production as a Cancer-Supporting Redox Mechanism and a Potential Therapeutic Target

“It is widely accepted that many cancers express features of inflammation, driven by both microenvironmental cells and factors, and the intrinsic production of inflammation-associated mediators from malignant cells themselves. Inflammation results in intracellular oxidative stress, with the ultimate biochemical oxidants composed of reactive nitrogens and oxygens. Although the role of inflammation in carcinogensis is well accepted, we now present data that inflammatory processes are also active in the maintenance phase of many aggressive forms of cancer. The oxidative stress of inflammation is proposed to drive a continuous process of DNA adducts and crosslinks, as well as posttranslational modifications to lipids and proteins that we argue support growth and survival. In this Perspective we introduce data on the emerging science of inflammation-driven posttranslational modifications on proteins responsible for driving growth, angiogenesis, immunosuppression, and inhibition of apoptosis. Examples include data from human melanoma, breast, head and neck, lung, and colon cancers.”


Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State

“Ribosome biogenesis is commonly up-regulated to satisfy the increased anabolic demands associated with malignant transformation and tumor growth. Many different oncogenic signaling pathways converge on the ribosome to increase translational flux. Despite the detailed understanding of ribosome regulation in cancer, it is not clear whethethe net translational activity of the ribosome can itself regulate transcriptional programs that support and promote the malignant state.”


Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State

“Ribosome biogenesis is commonly up-regulated to satisfy the increased anabolic demands associated with malignant transformation and tumor growth. Many different oncogenic signaling pathways converge on the ribosome to increase translational flux. Despite the detailed understanding of ribosome regulation in cancer, it is not clear whethethe net translational activity of the ribosome can itself regulate transcriptional programs that support and promote the malignant state.”