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Cancers, Volume 9, Issue 1 (January 2017)

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Cover Story (view full-size image) Current biomarkers often require invasive excision of the tumour for profiling, do not allow [...] Read more.
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Open AccessReview
Stromal Androgen Receptor in Prostate Cancer Development and Progression
Received: 30 November 2016 / Revised: 13 January 2017 / Accepted: 16 January 2017 / Published: 22 January 2017
Cited by 12 | Viewed by 3841 | PDF Full-text (2226 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, [...] Read more.
Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, it has been becoming increasingly apparent that changes in AR signalling in the surrounding stroma can dramatically influence tumour cell behavior. This is reflected in the consistent finding of a strong association between stromal AR expression and patient outcomes. In this review, we explore the relationship between AR signalling in fibroblasts/myofibroblasts and prostate cancer cells in the primary site, and detail the known functions, actions, and mechanisms of fibroblast AR signaling. We conclude with an evidence-based summary of how androgen action in stroma dramatically influences disease progression. Full article
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Open AccessReview
Epigenomic Regulation of Androgen Receptor Signaling: Potential Role in Prostate Cancer Therapy
Received: 30 November 2016 / Revised: 2 January 2017 / Accepted: 11 January 2017 / Published: 16 January 2017
Cited by 7 | Viewed by 4198 | PDF Full-text (1343 KB) | HTML Full-text | XML Full-text
Abstract
Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, [...] Read more.
Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome. This has permitted better understanding of the underlying regulatory mechanisms of AR during carcinogenesis and revealed the importance of epigenetic modifiers. In screening for new epigenomic modifiying drugs, we identified SD-70, and found that this demethylase inhibitor is effective in CRPC cells in combination with current therapies. The aim of this review is to explore the role of epigenetic modifications as biomarkers for detection, prognosis, and risk evaluation of PCa. Furthermore, we also provide an update of the recent findings on the epigenetic key processes (DNA methylation, chromatin modifications and alterations in noncoding RNA profiles) involved in AR expression and their possible role as therapeutic targets. Full article
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Open AccessReview
Exosomes in Cancer Diagnostics
Received: 29 November 2016 / Revised: 6 January 2017 / Accepted: 9 January 2017 / Published: 12 January 2017
Cited by 68 | Viewed by 3822 | PDF Full-text (220 KB) | HTML Full-text | XML Full-text
Abstract
Exosomes are endosome derived extracellular vesicles of 30–120 nm size ranges. Exosomes have been identified as mediators of cell-to-cell communication by transferring bioactive molecules such as nucleic acids, proteins and lipids into recipient cells. While exosomes are secreted by multiple cell types, cancer [...] Read more.
Exosomes are endosome derived extracellular vesicles of 30–120 nm size ranges. Exosomes have been identified as mediators of cell-to-cell communication by transferring bioactive molecules such as nucleic acids, proteins and lipids into recipient cells. While exosomes are secreted by multiple cell types, cancer derived exosomes not only influence the invasive potentials of proximally located cells, but also affect distantly located tissues. Based on their ability to alter tumor microenvironment by regulating immunity, angiogenesis and metastasis, there has been growing interest in defining the clinical relevance of exosomes in cancers. In particular, exosomes are valuable sources for biomarkers due to selective cargo loading and resemblance to their parental cells. In this review, we summarize the recent findings to utilize exosomes as cancer biomarkers for early detection, diagnosis and therapy selection. Full article
Open AccessReview
AR-Signaling in Human Malignancies: Prostate Cancer and Beyond
Received: 29 November 2016 / Revised: 4 January 2017 / Accepted: 5 January 2017 / Published: 11 January 2017
Cited by 13 | Viewed by 2239 | PDF Full-text (263 KB) | HTML Full-text | XML Full-text
Abstract
In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of [...] Read more.
In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types. Full article
Open AccessEditorial
Acknowledgement to Reviewers of Cancers in 2016
Received: 10 January 2017 / Revised: 10 January 2017 / Accepted: 10 January 2017 / Published: 10 January 2017
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Abstract
The editors of Cancers would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.[...] Full article
Open AccessReview
Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer
Received: 14 November 2016 / Revised: 31 December 2016 / Accepted: 1 January 2017 / Published: 8 January 2017
Cited by 14 | Viewed by 4988 | PDF Full-text (1312 KB) | HTML Full-text | XML Full-text
Abstract
Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for [...] Read more.
Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for profiling, do not allow monitoring of the response to treatment and stratify patients into broad heterogeneous groups leading to inconsistent treatment responses. Here we explore and describe the benefits of using circulating biomarkers (nucleosomes and/or modifications to nucleosomes) as a non-invasive method for detecting cancer and monitoring response to treatment. Nucleosomes (DNA wound around eight core histone proteins) are responsible for compacting our genome and their composition and post-translational modifications are responsible for regulating gene expression. Here, we focus on breast and colorectal cancer as examples where utilizing circulating nucleosomes as biomarkers hold real potential as liquid biopsies. Utilizing circulating nucleosomes as biomarkers is an exciting new area of research that promises to allow both the early detection of cancer and monitoring of treatment response. Nucleosome-based biomarkers combine with current biomarkers, increasing both specificity and sensitivity of current tests and have the potential to provide individualised precision-medicine based treatments for patients. Full article
(This article belongs to the collection Histone Modification in Cancer)
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Open AccessArticle
Expression and Clinical Significance of Androgen Receptor in Triple-Negative Breast Cancer
Received: 10 November 2016 / Revised: 2 January 2017 / Accepted: 4 January 2017 / Published: 6 January 2017
Cited by 12 | Viewed by 2637 | PDF Full-text (760 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Triple-negative breast cancer (TNBC) has a poor prognosis because of frequent recurrence. Androgen receptor (AR) is involved in the pathogenesis of breast cancer, but its role is not clearly defined. The aim of this study was to explore the expression of AR [...] Read more.
Background: Triple-negative breast cancer (TNBC) has a poor prognosis because of frequent recurrence. Androgen receptor (AR) is involved in the pathogenesis of breast cancer, but its role is not clearly defined. The aim of this study was to explore the expression of AR and its relationship with clinicopathologic features in TNBC. Methods: This study investigated 1036 cases of sporadic invasive breast carcinoma. Immunohistochemical assays were performed to determine the expression of AR in 190 TNBC samples. The relationships between AR expression and clinicopathologic data and prognosis were analyzed. Results: In 190 TNBC cases, the prognosis of AR-positive patients was significantly better (p = 0.019, log-rank) than AR-negative patients, and in multivariate analysis, AR expression was an independent indicator of good prognosis (p = 0.039, hazard ratio = 0.36). In patients with disease relapse, AR positivity was significantly correlated with better prognosis (p = 0.034, log-rank). Conclusions: AR expression may be useful as a subclassification marker for prognosis in TNBC. Full article
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Open AccessArticle
Stabilization of Nucleosomes by Histone Tails and by FACT Revealed by spFRET Microscopy
Received: 10 November 2016 / Revised: 19 December 2016 / Accepted: 22 December 2016 / Published: 6 January 2017
Cited by 10 | Viewed by 3011 | PDF Full-text (1550 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A correct chromatin structure is important for cell viability and is tightly regulated by numerous factors. Human protein complex FACT (facilitates chromatin transcription) is an essential factor involved in chromatin transcription and cancer development. Here FACT-dependent changes in the structure of single nucleosomes [...] Read more.
A correct chromatin structure is important for cell viability and is tightly regulated by numerous factors. Human protein complex FACT (facilitates chromatin transcription) is an essential factor involved in chromatin transcription and cancer development. Here FACT-dependent changes in the structure of single nucleosomes were studied with single-particle Förster resonance energy transfer (spFRET) microscopy using nucleosomes labeled with a donor-acceptor pair of fluorophores, which were attached to the adjacent gyres of DNA near the contact between H2A-H2B dimers. Human FACT and its version without the C-terminal domain (CTD) and the high mobility group (HMG) domain of the structure-specific recognition protein 1 (SSRP1) subunit did not change the structure of the nucleosomes, while FACT without the acidic C-terminal domains of the suppressor of Ty 16 (Spt16) and the SSRP1 subunits caused nucleosome aggregation. Proteolytic removal of histone tails significantly disturbed the nucleosome structure, inducing partial unwrapping of nucleosomal DNA. Human FACT reduced DNA unwrapping and stabilized the structure of tailless nucleosomes. CTD and/or HMG domains of SSRP1 are required for this FACT activity. In contrast, previously it has been shown that yeast FACT unfolds (reorganizes) nucleosomes using the CTD domain of SSRP1-like Pol I-binding protein 3 subunit (Pob3). Thus, yeast and human FACT complexes likely utilize the same domains for nucleosome reorganization and stabilization, respectively, and these processes are mechanistically similar. Full article
(This article belongs to the collection Histone Modification in Cancer)
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Open AccessReview
The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia
Received: 26 October 2016 / Revised: 14 December 2016 / Accepted: 23 December 2016 / Published: 3 January 2017
Cited by 8 | Viewed by 2044 | PDF Full-text (526 KB) | HTML Full-text | XML Full-text
Abstract
While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena [...] Read more.
While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. Full article
(This article belongs to the collection Histone Modification in Cancer)
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Open AccessReview
Retroareolar Carcinomas in Breast Ultrasound: Pearls and Pitfalls
Received: 10 October 2016 / Revised: 26 December 2016 / Accepted: 26 December 2016 / Published: 30 December 2016
Cited by 1 | Viewed by 2949 | PDF Full-text (11541 KB) | HTML Full-text | XML Full-text
Abstract
Breast Ultrasound (US) is an important tool for both screening and diagnostic examinations. Although breast US has benefitted from significant recent technical improvements, its use for the retroareolar region is known to be more challenging than for other locations. The retroareolar location was [...] Read more.
Breast Ultrasound (US) is an important tool for both screening and diagnostic examinations. Although breast US has benefitted from significant recent technical improvements, its use for the retroareolar region is known to be more challenging than for other locations. The retroareolar location was defined by Giess et al. in 1998 as the region where any lesion is situated at less than two cm from the nipple and/or involves the nipple-areolar complex on mammogram. Understanding of the complex anatomy and physiology of the nipple-areolar region is important to avoid misinterpretation and misdiagnosis. The ability for the breast imager to manage difficulties related to the retroareolar area is paramount by adjusting settings (compounding, frequency, Doppler) and utilizing specific manoeuvers. Cases illustrating difficulties encountered in diagnosis of retroareolar carcinomas are presented. Full article
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Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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