KAI1 suppresses HIF-1α and VEGF expression by blocking CDCP1-enhanced Src activation in prostate cancer

<p>Abstract</p> <p>Background</p> <p>KAI1 was initially identified as a metastasis-suppressor gene in prostate cancer. It is a member of the tetraspan transmembrane superfamily (TM4SF) of membrane glycoproteins. As part of a tetraspanin-enriched microdomain (TEM), KAI1 inhibits tumor metastasis by negative regulation of Src. However, the underlying regulatory mechanism has not yet been fully elucidated. CUB-domain-containing protein 1 (CDCP1), which was previously known as tetraspanin-interacting protein in TEM, promoted metastasis via enhancement of Src activity. To better understand how KAI1 is involved in the negative regulation of Src, we here examined the function of KAI1 in CDCP1-mediated Src kinase activation and the consequences of this process, focusing on HIF-1 α and VEGF expression.</p> <p>Methods</p> <p>We used the human prostate cancer cell line PC3 which was devoid of KAI1 expression. Vector-transfected cells (PC3-GFP clone #8) and KAI1-expressing PC3 clones (PC3-KAI1 clone #5 and #6) were picked after stable transfection with KAI1 cDNA and selection in 800 <it>μ</it>g/ml G418. Protein levels were assessed by immunoblotting and VEGF reporter gene activity was measured by assaying luciferase activitiy. We followed tumor growth <it>in vivo </it>and immunohistochemistry was performed for detection of HIF-1, CDCP1, and VHL protein level.</p> <p>Results</p> <p>We demonstrated that Hypoxia-inducible factor 1α (HIF-1α) and VEGF expression were significantly inhibited by restoration of KAI1 in PC3 cells. In response to KAI1 expression, CDCP1-enhanced Src activation was down-regulated and the level of von Hippel-Lindau (VHL) protein was significantly increased. In an <it>in vivo </it>xenograft model, KAI1 inhibited the expression of CDCP1 and HIF-1α.</p> <p>Conclusions</p> <p>These novel observations may indicate that KAI1 exerts profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1-mediated Src activation, followed by VHL-induced HIF-1α degradation and, ultimately, decreased VEGF expression.</p

Spatial Modulation of Primate Inferotemporal Responses by Eye Position

Background: A key aspect of representations for object recognition and scene analysis in the ventral visual stream is the spatial frame of reference, be it a viewer-centered, object-centered, or scene-based coordinate system. Coordinate transforms from retinocentric space to other reference frames involve combining neural visual responses with extraretinal postural information. Methodology/Principal Findings: We examined whether such spatial information is available to anterior inferotemporal (AIT) neurons in the macaque monkey by measuring the effect of eye position on responses to a set of simple 2D shapes. We report, for the first time, a significant eye position effect in over 40 % of recorded neurons with small gaze angle shifts from central fixation. Although eye position modulates responses, it does not change shape selectivity. Conclusions/Significance: These data demonstrate that spatial information is available in AIT for the representation of objects and scenes within a non-retinocentric frame of reference. More generally, the availability of spatial information in AIT calls into questions the classic dichotomy in visual processing that associates object shape processing with ventra

Effects of the total replacement of fish-based diet with plant-based diet on the hepatic transcriptome of two European sea bass (Dicentrarchus labrax) half-sibfamilies showing different growth rates with the plant-based diet

Background: Efforts towards utilisation of diets without fish meal (FM) or fish oil (FO) in finfish aquaculture have been being made for more than two decades. Metabolic responses to substitution of fishery products have been shown to impact growth performance and immune system of fish as well as their subsequent nutritional value, particularly in marine fish species, which exhibit low capacity for biosynthesis of long-chain poly-unsaturated fatty acids (LC-PUFA). The main objective of the present study was to analyse the effects of a plant-based diet on the hepatic transcriptome of European sea bass (Dicentrarchus labrax). Results: We report the first results obtained using a transcriptomic approach on the liver of two half-sibfamilies of the European sea bass that exhibit similar growth rates when fed a fish-based diet (FD), but significantly different growth rates when fed an all-plant diet (VD). Overall gene expression was analysed using oligo DNA microarrays (GPL9663). Statistical analysis identified 582 unique annotated genes differentially expressed between groups of fish fed the two diets, 199 genes regulated by genetic factors, and 72 genes that exhibited diet-family interactions. The expression of several genes involved in the LC-PUFA and cholesterol biosynthetic pathways was found to be up-regulated in fish fed VD, suggesting a stimulation of the lipogenic pathways. No significant diet-family interaction for the regulation of LC-PUFA biosynthesis pathways could be detected by microarray analysis. This result was in agreement with LC-PUFA profiles, which were found to be similar in the flesh of the two half-sibfamilies. In addition, the combination of our transcriptomic data with an analysis of plasmatic immune parameters revealed a stimulation of complement activity associated with an immunodeficiency in the fish fed VD, and different inflammatory status between the two half-sibfamilies. Biological processes related to protein catabolism, amino acid transaminations, RNA splicing and blood coagulation were also found to be regulated by diet, while the expression of genes involved in protein and ATP synthesis differed between the half-sibfamilies. Conclusions: Overall, the combined gene expression, compositional and biochemical studies demonstrated a large panel of metabolic and physiological effects induced by total substitution of both FM and FO in the diets of European sea bass and revealed physiological characteristics associated with the two half-sibfamilies

Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment

Cancer cells show a broad spectrum of bioenergetic states, with some cells using aerobic glycolysis while others rely on oxidative phosphorylation as their main source of energy. In addition, there is mounting evidence that metabolic coupling occurs in aggressive tumors, between epithelial cancer cells and the stromal compartment, and between well-oxygenated and hypoxic compartments. We recently showed that oxidative stress in the tumor stroma, due to aerobic glycolysis and mitochondrial dysfunction, is important for cancer cell mutagenesis and tumor progression. More specifically , increased autophagy/mitophagy in the tumor stroma drives a form of parasitic epithelial-stromal metabolic coupling. These findings explain why it is effective to treat tumors with either inducers or inhibitors of autophagy, as both would disrupt this energetic coupling. We also discuss evidence that glutamine addiction in cancer cells produces ammonia via oxidative mitochondrial metabolism. Ammonia production in cancer cells, in turn, could then help maintain autophagy in the tumor stromal compartment. In this vicious cycle, the initial glutamine provided to cancer cells would be produced by autophagy in the tumor stroma. Thus, we believe that parasitic epithelial-stromal metabolic coupling has important implications for cancer diagnosis and therapy, for example, in designing novel metabolic imaging techniques and establishing new targeted therapies. In direct support of this notion, we identified a loss of stromal caveolin-1 as a marker of oxidative stress, hypoxia, and autophagy in the tumor microenvironment, explaining its powerful predictive value. Loss of stromal caveolin-1 in breast cancers is associated with early tumor recurrence, metastasis, and drug resistance, leading to poor clinical outcome

Challenging the standard of care in advanced melanoma: focus on pembrolizumab

Raghad M Abdul-Karim,1 C Lance Cowey2&ndash;4 1Baylor Sammons Cancer Center, 2Melanoma and Genitourinary Oncology Program, Baylor University Medical Center, Sammons Cancer Center Texas Oncology,3Baylor Skin Malignancy Research and Treatment Center, Baylor University Medical Center, 4Developmental Therapeutics Program, US Oncology Research, Dallas, TX, USA Abstract: The last several years have seen a dramatic rise in the number of effective therapies that have been shown to improve survival outcomes for patients with advanced melanoma. Among these treatments are the immune checkpoint inhibitors, a new class of immunotherapy, that have demonstrated the ability to improve both response rates and survival outcomes. Pembrolizumab, an immune checkpoint inhibitor that blocks the negative regulatory PD-1 receptor on T-cell lymphocytes, has shown improved efficacy compared to standard therapies with an acceptable tolerability profile. Additionally, this agent is being evaluated in adjuvant and combination trial strategies that have great potential to further advance outcomes. This review focuses on the advances that pembrolizumab has made in melanoma and what studies are upcoming that could change the future of melanoma treatment yet again. Keywords: keytruda, MK-3475, immune checkpoint inhibitor, PD-1 inhibitor, adjuvant therapy, combination therapies, immunotherap