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Cancers, Volume 8, Issue 6 (June 2016) – 7 articles

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702 KiB  
Review
S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction
by Mathias Dahlmann, Dennis Kobelt, Wolfgang Walther, Giridhar Mudduluru and Ulrike Stein
Cancers 2016, 8(6), 59; https://doi.org/10.3390/cancers8060059 - 20 Jun 2016
Cited by 72 | Viewed by 13248
Abstract
The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most [...] Read more.
The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of β-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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2271 KiB  
Review
Tomato as a Source of Carotenoids and Polyphenols Targeted to Cancer Prevention
by Raúl Martí, Salvador Roselló and Jaime Cebolla-Cornejo
Cancers 2016, 8(6), 58; https://doi.org/10.3390/cancers8060058 - 20 Jun 2016
Cited by 197 | Viewed by 16234
Abstract
A diet rich in vegetables has been associated with a reduced risk of many diseases related to aging and modern lifestyle. Over the past several decades, many researches have pointed out the direct relation between the intake of bioactive compounds present in tomato [...] Read more.
A diet rich in vegetables has been associated with a reduced risk of many diseases related to aging and modern lifestyle. Over the past several decades, many researches have pointed out the direct relation between the intake of bioactive compounds present in tomato and a reduced risk of suffering different types of cancer. These bioactive constituents comprise phytochemicals such as carotenoids and polyphenols. The direct intake of these chemoprotective molecules seems to show higher efficiencies when they are ingested in its natural biological matrix than when they are ingested isolated or in dietary supplements. Consequently, there is a growing trend for improvement of the contents of these bioactive compounds in foods. The control of growing environment and processing conditions can ensure the maximum potential accumulation or moderate the loss of bioactive compounds, but the best results are obtained developing new varieties via plant breeding. The modification of single steps of metabolic pathways or their regulation via conventional breeding or genetic engineering has offered excellent results in crops such as tomato. In this review, we analyse the potential of tomato as source of the bioactive constituents with cancer-preventive properties and the result of modern breeding programs as a strategy to increase the levels of these compounds in the diet. Full article
(This article belongs to the Special Issue Antioxidants in Cancer)
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766 KiB  
Review
Wnt Signaling in Renal Cell Carcinoma
by Qi Xu, Mirja Krause, Anatoly Samoylenko and Seppo Vainio
Cancers 2016, 8(6), 57; https://doi.org/10.3390/cancers8060057 - 17 Jun 2016
Cited by 73 | Viewed by 8338
Abstract
Renal cell carcinoma (RCC) accounts for 90% of all kidney cancers. Due to poor diagnosis, high resistance to the systemic therapies and the fact that most RCC cases occur sporadically, current research switched its focus on studying the molecular mechanisms underlying RCC. The [...] Read more.
Renal cell carcinoma (RCC) accounts for 90% of all kidney cancers. Due to poor diagnosis, high resistance to the systemic therapies and the fact that most RCC cases occur sporadically, current research switched its focus on studying the molecular mechanisms underlying RCC. The aim is the discovery of new effective and less toxic anti-cancer drugs and novel diagnostic markers. Besides the PI3K/Akt/mTOR, HGF/Met and VHL/hypoxia cellular signaling pathways, the involvement of the Wnt/β-catenin pathway in RCC is commonly studied. Wnt signaling and its targeted genes are known to actively participate in different biological processes during embryonic development and renal cancer. Recently, studies have shown that targeting this pathway by alternating/inhibiting its intracellular signal transduction can reduce cancer cells viability and inhibit their growth. The targets and drugs identified show promising potential to serve as novel RCC therapeutics and prognostic markers. This review aims to summarize the current status quo regarding recent research on RCC focusing on the involvement of the Wnt/β-catenin pathway and how its understanding could facilitate the identification of potential therapeutic targets, new drugs and diagnostic biomarkers. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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1479 KiB  
Article
Targeted Vaccination against Human α-Lactalbumin for Immunotherapy and Primary Immunoprevention of Triple Negative Breast Cancer
by Vincent K. Tuohy, Ritika Jaini, Justin M. Johnson, Matthew G. Loya, Dennis Wilk, Erinn Downs-Kelly and Suparna Mazumder
Cancers 2016, 8(6), 56; https://doi.org/10.3390/cancers8060056 - 16 Jun 2016
Cited by 23 | Viewed by 9384
Abstract
We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are “retired” from expression at immunogenic levels in normal tissues as we age, but are overexpressed in [...] Read more.
We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are “retired” from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. α-Lactalbumin is an example of a “retired” self-protein because its expression in normal tissues is confined exclusively to the breast during late pregnancy and lactation, but is also expressed in the vast majority of human triple negative breast cancers (TNBC)—the most aggressive and lethal form of breast cancer and the predominant form that occurs in women at high genetic risk including those with mutated BRCA1 genes. In anticipation of upcoming clinical trials, here we provide preclinical data indicating that α-lactalbumin has the potential as a vaccine target for inducing safe and effective primary immunoprevention as well as immunotherapy against TNBC. Full article
(This article belongs to the Special Issue Cancer Immunotherapies)
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Article
RASSF1A Site-Specific Methylation Hotspots in Cancer and Correlation with RASSF1C and MOAP-1
by Natalia Volodko, Mohamed Salla, Alaa Zare, El-Arbi Abulghasem, Krista Vincent, Matthew G.K. Benesch, Todd P.W. McMullen, Oliver F. Bathe, Lynne Postovit and Shairaz Baksh
Cancers 2016, 8(6), 55; https://doi.org/10.3390/cancers8060055 - 10 Jun 2016
Cited by 16 | Viewed by 6698
Abstract
Epigenetic silencing of RASSF1A is frequently observed in numerous cancers and has been previously reported. The promoter region of RASSF1A is predicted to have 75 CpG sites, and very few studies demonstrate how the methylation of these sites affects expression. In addition, the [...] Read more.
Epigenetic silencing of RASSF1A is frequently observed in numerous cancers and has been previously reported. The promoter region of RASSF1A is predicted to have 75 CpG sites, and very few studies demonstrate how the methylation of these sites affects expression. In addition, the expression relationship between RASSF1A and its downstream target, modulator of apoptosis 1 (MOAP-1), is poorly understood. In this study, we have explored the mRNA expression of RASSF1A, MOAP-1 and the well-characterized splice variant of RASSF1, RASSF1C, in cancer cell lines and primary tumors. We confirmed that the RASSF1A promoter is robustly methylated within a 32-CpG region in solid tumors and results in lower mRNA expression. The MOAP-1 promoter contains ~110 CpG sites, but was not found to be methylated in cancer cell lines when 19 predicted CpG sites were explored. Interestingly, MOAP-1 mRNA expression positively correlated with RASSF1A expression in numerous cancers, whereas RASSF1C expression remained the same or was increased in cell lines or tissues with epigenetic loss of RASSF1A. We speculate that MOAP-1 and RASSF1A may be more intimately connected than originally thought, and the expression of both are warranted in experimental designs exploring the biology of the RASSF1A/MOAP-1 molecular pathway. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)
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539 KiB  
Review
Control of Wnt Receptor Turnover by R-spondin-ZNRF3/RNF43 Signaling Module and Its Dysregulation in Cancer
by Huai-Xiang Hao, Xiaomo Jiang and Feng Cong
Cancers 2016, 8(6), 54; https://doi.org/10.3390/cancers8060054 - 8 Jun 2016
Cited by 111 | Viewed by 20285
Abstract
Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components [...] Read more.
Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components of the Wnt pathway is rather straightforward. However, it is difficult to identify tumors addicted to autocrine or paracrine Wnt signaling. Discovery of the R-spondin-ZNRF3/RNF43 signaling module and its genetic alterations in cancers represents a breakthrough in this area. Membrane E3 ligase ZNRF3 and RNF43 are critical negative feedback regulators of the Wnt pathway, which function through promoting ubiquitination and degradation of Wnt receptors. R-spondin proteins (RSPO1-4) serve as natural antagonists of ZNRF3/RNF43. To maintain strong and sustained Wnt/β-catenin signaling, cancers need to overcome ZNRF3/RNF43-mediated feedback inhibition. Indeed, mutations of RNF43/ZNRF3 and recurrent translocations of RSPO2/RSPO3 have recently been identified in various cancers. Significantly, genetic alterations in RNF43/ZNRF3/RSPO2/RSPO3 have shown promise as predictive biomarkers in pre-clinical models for the efficacy of upstream Wnt inhibitors. In this review, we will discuss the biology of the R-spondin-ZNRF3/RNF43 signaling module, cancer-associated alterations of this signaling module, and their value as biomarkers to identify Wnt-addicted tumors. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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173 KiB  
Letter
Letter to the Editor Re: Ogawa, Y. Cancers 2016, 8, 28
by Cameron J. Koch
Cancers 2016, 8(6), 53; https://doi.org/10.3390/cancers8060053 - 24 May 2016
Cited by 3 | Viewed by 3440
Abstract
We read with interest the recently published paper by Dr. Ogawa “Paradigm Shift in Radiation Biology/Radiation Oncology—Exploitation of the H2O2 Effect” for Radiotherapy Using Low-LET (Linear Energy Transfer) Radiation such as X-rays and High-Energy Electrons”.[...] Full article
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