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Cancers, Volume 5, Issue 4 (December 2013) – 28 articles , Pages 1199-1747

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310 KiB  
Opinion
The Clinical Potential of Circulating Tumor Cells; The Need to Incorporate a Modern “Immunological Cocktail” in the Assay
by Jonathan W. Uhr
Cancers 2013, 5(4), 1739-1747; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041739 - 13 Dec 2013
Cited by 5 | Viewed by 5015
Abstract
The accepted clinical assay, CellSearch®, and lab-on-a-chip tests for capturing circulating tumor cells are antibody-mediated. Attempts to improve their sensitivity have relied upon physical changes in the instruments. There have been no significant advances in improving the antibody-mediated portion of the [...] Read more.
The accepted clinical assay, CellSearch®, and lab-on-a-chip tests for capturing circulating tumor cells are antibody-mediated. Attempts to improve their sensitivity have relied upon physical changes in the instruments. There have been no significant advances in improving the antibody-mediated portion of the capture. Modern immunologic engineering offers major possibilities for improving the sensitivity and other features of the assay. These include obtaining univalent antibody fragments such as scFvs with picomolar binding affinity and sufficient specificity; altering them to enhance their range of potential contact with target antigens; using antibodies directed against different epitopes on epithelial, mesenchymal or organ-specific cell surface markers to allow simultaneous binding and investigating non-antibody binding molecules as substitutes for antibody. These maneuvers could markedly improve the ability of current assays to improve patient care and might result in an acceptable test for detecting cancer earlier in high risk patients. Full article
(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)
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Review
Circulating Tumor Cell Detection and Capture by Photoacoustic Flow Cytometry in Vivo and ex Vivo
by Ekaterina I. Galanzha and Vladimir P. Zharov
Cancers 2013, 5(4), 1691-1738; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041691 - 10 Dec 2013
Cited by 105 | Viewed by 15957
Abstract
Despite progress in detecting circulating tumor cells (CTCs), existing assays still have low sensitivity (1–10 CTC/mL) due to the small volume of blood samples (5–10 mL). Consequently, they can miss up to 103–104 CTCs, resulting in the development of barely [...] Read more.
Despite progress in detecting circulating tumor cells (CTCs), existing assays still have low sensitivity (1–10 CTC/mL) due to the small volume of blood samples (5–10 mL). Consequently, they can miss up to 103–104 CTCs, resulting in the development of barely treatable metastasis. Here we analyze a new concept of in vivo CTC detection with enhanced sensitivity (up to 102–103 times) by the examination of the entire blood volume in vivo (5 L in adults). We focus on in vivo photoacoustic (PA) flow cytometry (PAFC) of CTCs using label-free or targeted detection, photoswitchable nanoparticles with ultrasharp PA resonances, magnetic trapping with fiber-magnetic-PA probes, optical clearance, real-time spectral identification, nonlinear signal amplification, and the integration with PAFC in vitro. We demonstrate PAFC’s capability to detect rare leukemia, squamous carcinoma, melanoma, and bulk and stem breast CTCs and its clusters in preclinical animal models in blood, lymph, bone, and cerebrospinal fluid, as well as the release of CTCs from primary tumors triggered by palpation, biopsy or surgery, increasing the risk of metastasis. CTC lifetime as a balance between intravasation and extravasation rates was in the range of 0.5–4 h depending on a CTC metastatic potential. We introduced theranostics of CTCs as an integration of nanobubble-enhanced PA diagnosis, photothermal therapy, and feedback through CTC counting. In vivo data were verified with in vitro PAFC demonstrating a higher sensitivity (1 CTC/40 mL) and throughput (up to 10 mL/min) than conventional assays. Further developments include detection of circulating cancer-associated microparticles, and super-rsesolution PAFC beyond the diffraction and spectral limits. Full article
(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)
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Review
Circulating Tumor Cells in Prostate Cancer
by Brian Hu, Holly Rochefort and Amir Goldkorn
Cancers 2013, 5(4), 1676-1690; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041676 - 04 Dec 2013
Cited by 43 | Viewed by 10251
Abstract
Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, [...] Read more.
Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, CTC analysis has been shifting from enumeration to more sophisticated molecular characterization of captured cells, which serve as a “liquid biopsy” of the tumor, reflecting molecular changes in an individual’s malignancy over time. Here we will review the main CTC studies in advanced and localized prostate cancer, highlighting the important gains as well as the challenges posed by various approaches, and their implications for advancing prostate cancer management. Full article
(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)
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Review
Long Non-Coding RNAs Embedded in the Rb and p53 Pathways
by Murugan Subramanian, Matthew F. Jones and Ashish Lal
Cancers 2013, 5(4), 1655-1675; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041655 - 04 Dec 2013
Cited by 31 | Viewed by 17547
Abstract
In recent years, long non-coding RNAs (lncRNAs) have gained significant attention as a novel class of gene regulators. Although a small number of lncRNAs have been shown to regulate gene expression through diverse mechanisms including transcriptional regulation, mRNA splicing and translation, the physiological [...] Read more.
In recent years, long non-coding RNAs (lncRNAs) have gained significant attention as a novel class of gene regulators. Although a small number of lncRNAs have been shown to regulate gene expression through diverse mechanisms including transcriptional regulation, mRNA splicing and translation, the physiological function and mechanism of action of the vast majority are not known. Profiling studies in cell lines and tumor samples have suggested a potential role of lncRNAs in cancer. Indeed, distinct lncRNAs have been shown to be embedded in the p53 and Rb networks, two of the major tumor suppressor pathways that control cell cycle progression and survival. Given the fact that inactivation of Rb and p53 is a hallmark of human cancer, in this review we discuss recent evidence on the function of lncRNAs in the Rb and p53 signaling pathways. Full article
(This article belongs to the Special Issue Cell Cycle Deregulation in Cancers)
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Article
Butylated Hydroxyanisole Blocks the Occurrence of Tumor Associated Macrophages in Tobacco Smoke Carcinogen-Induced Lung Tumorigenesis
by Yan Zhang, Swati Choksi and Zheng-Gang Liu
Cancers 2013, 5(4), 1643-1654; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041643 - 04 Dec 2013
Cited by 8 | Viewed by 6620
Abstract
Tumor-associated macrophages (TAMs) promote tumorigenesis because of their proangiogenic and immune-suppressive functions. Here, we report that butylated hydroxyanisole (BHA) blocks occurrence of tumor associated macrophages (TAMs) in tobacco smoke carcinogen-induced lung tumorigenesis. Continuous administration of butylated hydroxyanisole (BHA), a ROS inhibitor, before or [...] Read more.
Tumor-associated macrophages (TAMs) promote tumorigenesis because of their proangiogenic and immune-suppressive functions. Here, we report that butylated hydroxyanisole (BHA) blocks occurrence of tumor associated macrophages (TAMs) in tobacco smoke carcinogen-induced lung tumorigenesis. Continuous administration of butylated hydroxyanisole (BHA), a ROS inhibitor, before or after NNK treatment significantly blocked tumor development, although less effectively when BHA is administered after NNK treatment. Strikingly, BHA abolished the occurrence of F4/80+ macrophages with similar efficiency no matter whether it was administered before or after NNK treatment. Detection of cells from bronchioalveolar lavage fluid (BALF) confirmed that BHA markedly inhibited the accumulation of macrophages while slightly reducing the number of lymphocytes that were induced by NNK. Immunohistological staining showed that BHA specifically abolished the occurrence of CD206+ TAMs when it was administered before or after NNK treatment. Western blot analysis of TAMs markers, arginase I and Ym-1, showed that BHA blocked NNK-induced TAMs accumulation. Our study clearly demonstrated that inhibiting the occurrence of TAMs by BHA contributes to the inhibition of tobacco smoke carcinogen-induced tumorigenesis, suggesting ROS inhibitors may serve as a therapeutic target for treating smoke-induced lung cancer. Full article
(This article belongs to the Special Issue Tumor Associated Macrophages)
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Review
Towards the Biological Understanding of CTC: Capture Technologies, Definitions and Potential to Create Metastasis
by Ana M.C. Barradas and Leon W.M.M. Terstappen
Cancers 2013, 5(4), 1619-1642; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041619 - 04 Dec 2013
Cited by 75 | Viewed by 10223
Abstract
Circulating Tumor Cells (CTC) are rare cells originated from tumors that travel into the blood stream, extravasate to different organs of which only a small fraction will develop into metastasis. The presence of CTC enumerated with the CellSearch system is associated with a [...] Read more.
Circulating Tumor Cells (CTC) are rare cells originated from tumors that travel into the blood stream, extravasate to different organs of which only a small fraction will develop into metastasis. The presence of CTC enumerated with the CellSearch system is associated with a relative short survival and their continued presence after the first cycles of therapy indicates a futile therapy in patients with metastatic carcinomas. Detailed characterization of CTC holds the promise to enable the choice of the optimal therapy for the individual patients during the course of the disease. The phenotype, physical and biological properties are however not well understood making it difficult to assess the merit of recent technological advancements to improve upon the capture of CTC or to evaluate their metastatic potential. Here we will discuss the recent advances in the classification of CTC captured by the CellSearch system, the implications of their features and numbers. Latest capture platforms are reviewed and placed in the light of technology improvements needed to detect CTC. Physical properties, phenotype, viability and proliferative potential and means to assess their proliferation and metastatic capacity will be summarized and placed in the context of the latest CTC capture platforms. Full article
(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)
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Review
Role of Met Axis in Head and Neck Cancer
by Yiru Xu and Gary J. Fisher
Cancers 2013, 5(4), 1601-1618; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041601 - 26 Nov 2013
Cited by 8 | Viewed by 5734
Abstract
Head and neck cancer is the sixth most common type of cancer worldwide. Despite advances in aggressive multidisciplinary treatments, the 5-year survival rate for this dreadful disease is only 50%, mostly due to high rate of recurrence and early involvement of regional lymph [...] Read more.
Head and neck cancer is the sixth most common type of cancer worldwide. Despite advances in aggressive multidisciplinary treatments, the 5-year survival rate for this dreadful disease is only 50%, mostly due to high rate of recurrence and early involvement of regional lymph nodes and subsequent metastasis. Understanding the molecular mechanisms responsible for invasion and metastasis is one of the most pressing goals in the field of head and neck cancer. Met, also known as hepatocyte growth factor receptor (HGFR), is a member of the receptor protein tyrosine kinase (RPTK) family. There is compelling evidence that Met axis is dysregulated and plays important roles in tumorigenesis, progression, metastasis, angiogenesis, and drug resistance in head and neck cancer. We describe in this review current understanding of Met axis in head and neck cancer biology and development of therapeutic inhibitors targeting Met axis. Full article
(This article belongs to the Special Issue MET in Cancer)
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Article
Surrogates of Long-Term Vitamin D Exposure and Ovarian Cancer Risk in Two Prospective Cohort Studies
by Jennifer Prescott, Kimberly A. Bertrand, Elizabeth M. Poole, Bernard A. Rosner and Shelley S. Tworoger
Cancers 2013, 5(4), 1577-1600; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041577 - 22 Nov 2013
Cited by 11 | Viewed by 5599
Abstract
Experimental evidence and ecologic studies suggest a protective role of vitamin D in ovarian carcinogenesis. However, epidemiologic studies using individual level data have been inconsistent. We evaluated ultraviolet (UV)-B radiation, vitamin D intake, and predicted plasma 25-hydroxyvitamin D [25(OH)D] levels as long-term surrogates [...] Read more.
Experimental evidence and ecologic studies suggest a protective role of vitamin D in ovarian carcinogenesis. However, epidemiologic studies using individual level data have been inconsistent. We evaluated ultraviolet (UV)-B radiation, vitamin D intake, and predicted plasma 25-hydroxyvitamin D [25(OH)D] levels as long-term surrogates of vitamin D exposure within the Nurses’ Health Study (NHS) and NHSII. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for risk of overall ovarian cancer and by histologic subtype using Cox proportional hazards models. Between 1976 and 2010 in NHS and 1989 and 2011 in NHSII, we identified a total of 1,225 incident epithelial ovarian cancer cases (NHS: 970, NHSII: 255) over 4,628,648 person-years of follow-up. Cumulative average UV-B exposure was not associated with ovarian cancer risk in NHS (Ptrend = 0.08), but was associated with reduced risk in NHSII (highest vs. lowest category RR = 0.67; 95% CI: 0.50, 0.89; Ptrend < 0.01). When stratified by histologic subtype, UV-B flux was positively associated with risk of serous tumors in NHS (Ptrend < 0.01), but inversely associated in NHSII (Ptrend = 0.01). Adjusted for confounders, ovarian cancer risk was not associated with vitamin D intake from food or supplements or with predicted 25(OH)D levels. Our study does not strongly support a protective role for vitamin D in ovarian cancer risk. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
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Article
Aberrant Promoter Hypermethylation of RASSF Family Members in Merkel Cell Carcinoma
by Antje M. Richter, Tanja Haag, Sara Walesch, Peter Herrmann-Trost, Wolfgang C. Marsch, Heinz Kutzner, Peter Helmbold and Reinhard H. Dammann
Cancers 2013, 5(4), 1566-1576; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041566 - 18 Nov 2013
Cited by 20 | Viewed by 6882
Abstract
Merkel cell carcinoma (MCC) is one of the most aggressive cancers of the skin. RASSFs are a family of tumor suppressors that are frequently inactivated by promoter hypermethylation in various cancers. We studied CpG island promoter hypermethylation in MCC of RASSF2, RASSF5A, RASSF5C [...] Read more.
Merkel cell carcinoma (MCC) is one of the most aggressive cancers of the skin. RASSFs are a family of tumor suppressors that are frequently inactivated by promoter hypermethylation in various cancers. We studied CpG island promoter hypermethylation in MCC of RASSF2, RASSF5A, RASSF5C and RASSF10 by combined bisulfite restriction analysis (COBRA) in MCC samples and control tissue. We found RASSF2 to be methylated in three out of 43 (7%), RASSF5A in 17 out of 39 (44%, but also 43% in normal tissue), RASSF5C in two out of 26 (8%) and RASSF10 in 19 out of 84 (23%) of the cancer samples. No correlation between the methylation status of the analyzed RASSFs or between RASSF methylation and MCC characteristics (primary versus metastatic, Merkel cell polyoma virus infection, age, sex) was found. Our results show that RASSF2, RASSF5C and RASSF10 are aberrantly hypermethylated in MCC to a varying degree and this might contribute to Merkel cell carcinogenesis. Full article
(This article belongs to the Special Issue Merkel Cell Carcinoma)
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Review
Interplay of Stem Cell Characteristics, EMT, and Microtentacles in Circulating Breast Tumor Cells
by Monica Charpentier and Stuart Martin
Cancers 2013, 5(4), 1545-1565; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041545 - 14 Nov 2013
Cited by 47 | Viewed by 9864
Abstract
Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with [...] Read more.
Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease. Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential. Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation. Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs), which aid in reattachment. CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis. Full article
(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)
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Review
Exosomes in Prostate Cancer: Putting Together the Pieces of a Puzzle
by Carolina Soekmadji, Pamela J. Russell and Colleen C. Nelson
Cancers 2013, 5(4), 1522-1544; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041522 - 11 Nov 2013
Cited by 62 | Viewed by 12388
Abstract
Exosomes have been shown to act as mediators for cell to cell communication and as a potential source of biomarkers for many diseases, including prostate cancer. Exosomes are nanosized vesicles secreted by cells and consist of proteins normally found in multivesicular bodies, RNA, [...] Read more.
Exosomes have been shown to act as mediators for cell to cell communication and as a potential source of biomarkers for many diseases, including prostate cancer. Exosomes are nanosized vesicles secreted by cells and consist of proteins normally found in multivesicular bodies, RNA, DNA and lipids. As a potential source of biomarkers, exosomes have attracted considerable attention, as their protein content resembles that of their cells of origin, even though it is noted that the proteins, miRNAs and lipids found in the exosomes are not a reflective stoichiometric sampling of the contents from the parent cells. While the biogenesis of exosomes in dendritic cells and platelets has been extensively characterized, much less is known about the biogenesis of exosomes in cancer cells. An understanding of the processes involved in prostate cancer will help to further elucidate the role of exosomes and other extracellular vesicles in prostate cancer progression and metastasis. There are few methodologies available for general isolation of exosomes, however validation of those methodologies is necessary to study the role of exosomal-derived biomarkers in various diseases. In this review, we discuss “exosomes” as a member of the family of extracellular vesicles and their potential to provide candidate biomarkers for prostate cancer. Full article
(This article belongs to the Special Issue Exosomes in Cancer Development)
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Article
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment
by Santosh Kumar Upadhyay, Alissa Verone, Suzanne Shoemaker, Maochun Qin, Song Liu, Moray Campbell and Pamela A. Hershberger
Cancers 2013, 5(4), 1504-1521; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041504 - 08 Nov 2013
Cited by 34 | Viewed by 7693
Abstract
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations [...] Read more.
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDRhigh) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDRlow and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH)2D3 sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH)2D3 induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH)2D3-mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH)2D3 opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH)2D3 may prevent lung cancer progression in a molecularly defined subset of NSCLC patients. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
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Article
Heterogeneity of Mesenchymal Markers Expression—Molecular Profiles of Cancer Cells Disseminated by Lymphatic and Hematogenous Routes in Breast Cancer
by Aleksandra Markiewicz, Magdalena Książkiewicz, Barbara Seroczyńska, Jarosław Skokowski, Jolanta Szade, Marzena Wełnicka-Jaśkiewicz and Anna J. Zaczek
Cancers 2013, 5(4), 1485-1503; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041485 - 08 Nov 2013
Cited by 8 | Viewed by 8309
Abstract
Breast cancers can metastasize via hematogenous and lymphatic routes, however in some patients only one type of metastases are detected, suggesting a certain proclivity in metastatic patterns. Since epithelial-mesenchymal transition (EMT) plays an important role in cancer dissemination it would be worthwhile to [...] Read more.
Breast cancers can metastasize via hematogenous and lymphatic routes, however in some patients only one type of metastases are detected, suggesting a certain proclivity in metastatic patterns. Since epithelial-mesenchymal transition (EMT) plays an important role in cancer dissemination it would be worthwhile to find if a specific profile of EMT gene expression exists that is related to either lymphatic or hematogenous dissemination. Our study aimed at evaluating gene expression profile of EMT-related markers in primary tumors (PT) and correlated them with the pattern of metastatic spread. From 99 early breast cancer patients peripheral blood samples (N = 99), matched PT (N = 47) and lymph node metastases (LNM; N = 22) were collected. Expression of TWIST1, SNAI1, SNAI2 and VIM was analyzed in those samples. Additionally expression of CK19, MGB1 and HER2 was measured in CTCs-enriched blood fractions (CTCs-EBF). Results were correlated with each other and with clinico-pathological data of the patients. Results show that the mesenchymal phenotype of CTCs-EBF correlated with poor clinico-pathological characteristics of the patients. Additionally, PT shared more similarities with LNM than with CTCs-EBF. Nevertheless, LNM showed increased expression of EMT-related markers than PT; and EMT itself in PT did not seem to be necessary for lymphatic dissemination. Full article
(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)
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Review
Tumor Metabolism of Malignant Gliomas
by Peng Ru, Terence M. Williams, Arnab Chakravarti and Deliang Guo
Cancers 2013, 5(4), 1469-1484; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041469 - 08 Nov 2013
Cited by 54 | Viewed by 14429
Abstract
Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming [...] Read more.
Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation. Full article
(This article belongs to the Special Issue Glioblastoma)
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Review
Bevacizumab for Glioblastoma—A Promising Drug or Not?
by Motoo Nagane and Ryo Nishikawa
Cancers 2013, 5(4), 1456-1468; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041456 - 07 Nov 2013
Cited by 5 | Viewed by 5901
Abstract
Two double blind, placebo-controlled, and randomized phase III studies were conducted, and the results including OS’s were reported at the ASCO Meeting in June 2013, which was the beginning of confusion surrounding this topic. This is a review article not only summarizing the [...] Read more.
Two double blind, placebo-controlled, and randomized phase III studies were conducted, and the results including OS’s were reported at the ASCO Meeting in June 2013, which was the beginning of confusion surrounding this topic. This is a review article not only summarizing the previous evidence, but also looking beyond. Full article
(This article belongs to the Special Issue Glioblastoma)
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Discussion
The Inverse Relationship between 25-Hydroxyvitamin D and Cancer Survival: Discussion of Causation
by Trude E. Robsahm, Gary G. Schwartz and Steinar Tretli
Cancers 2013, 5(4), 1439-1455; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041439 - 05 Nov 2013
Cited by 33 | Viewed by 6559
Abstract
Cancer mortality rates vary inversely with geographic latitude and solar ultraviolet-B doses. This relationship may be due to an inhibitory role of vitamin D on cancer development. The relationship between vitamin D and cancer appears to be stronger for studies of cancer mortality [...] Read more.
Cancer mortality rates vary inversely with geographic latitude and solar ultraviolet-B doses. This relationship may be due to an inhibitory role of vitamin D on cancer development. The relationship between vitamin D and cancer appears to be stronger for studies of cancer mortality than incidence. Because cancer mortality reflects both cancer incidence and survival, the difference may be due to effects of vitamin D on cancer survival. Here we review analytic epidemiologic studies investigating the relation between vitamin D, measured by circulating levels of 25-hydroxyvitamin D (25-OHD), and cancer survival. A relationship between low 25-OHD levels and poor survival is shown by most of the reviewed studies. This relationship is likely to be causal when viewed in light of most criteria for assessing causality (temporality, strength, exposure-response, biological plausibility and consistency). A serum level of 25-OHD around 50 nmol/L appears to be a threshold level. Conversely, there are several mechanisms whereby cancer could lower serum levels of 25-OHD. The severity of disease at the time of diagnosis and time of serum sampling are key factors to clarify the temporal aspect of these relationships. Evidence that vitamin D supplementation could retard the disease process or prolong survival time would be key evidence, but is difficult to generate. However, recent clinical trial results in prostate cancer support a role for vitamin D in this regard. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
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Review
The Protective Role of Vitamin D Signaling in Non-Melanoma Skin Cancer
by Daniel D. Bikle and Yan Jiang
Cancers 2013, 5(4), 1426-1438; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041426 - 05 Nov 2013
Cited by 19 | Viewed by 7159
Abstract
Although the epidemiologic evidence that adequate vitamin D nutrition protects against non-melanoma skin cancer (NMSC) is limited, recent evidence that the vitamin D receptor (VDR) is protective is compelling. The role of vitamin D signaling in limiting the proliferation while promoting the differentiation [...] Read more.
Although the epidemiologic evidence that adequate vitamin D nutrition protects against non-melanoma skin cancer (NMSC) is limited, recent evidence that the vitamin D receptor (VDR) is protective is compelling. The role of vitamin D signaling in limiting the proliferation while promoting the differentiation of keratinocytes, the major cell in the epidermis from which NMSC are derived, is well known. However, recent findings that mice lacking the VDR are predisposed to skin cancer has brought to the fore the question of how the VDR is protective. In this review we will look first at the role of vitamin D signaling in regulating the proliferation and differentiation of keratinocytes. We will examine two pathways, β-catenin (CTNNB) and hedgehog (HH), that are regulated by vitamin D signaling and may contribute to the dysregulated proliferation and differentiation in the absence of VDR. We will then examine the failure of VDR deficient keratinocytes to repair DNA damaged by UVB. Finally we will examine the change in long non-coding RNA (LncRNA) expression in VDR null keratinocytes that in other cells is associated with malignant transformation, a potential newly appreciated mechanism by which vitamin D signaling is protective against NMSC. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
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Article
Investigation of siRNA Nanoparticle Formation Using Mono-Cationic Detergents and Its Use in Gene Silencing in Human HeLa Cells
by Yuma Yamada, Ryosuke Suzuki and Hideyoshi Harashima
Cancers 2013, 5(4), 1413-1425; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041413 - 01 Nov 2013
Cited by 4 | Viewed by 5883
Abstract
The focus of recent research has been on the development of siRNA vectors to achieve an innovative gene therapy. Most of the conventional vectors are siRNA nanoparticles complexed with cationic polymers and liposomes, making it difficult to release siRNA. In this study, we [...] Read more.
The focus of recent research has been on the development of siRNA vectors to achieve an innovative gene therapy. Most of the conventional vectors are siRNA nanoparticles complexed with cationic polymers and liposomes, making it difficult to release siRNA. In this study, we report on the use of MCD, a quaternary ammonium salt detergent containing a long aliphatic chain (L-chain) as an siRNA complexation agent using human HeLa cells (a model cancer cell). We prepared siRNA nanoparticles using various MCDs, and measured the diameters and zeta-potentials of the particles. The use of an MCD with a long L-chain resulted in the formation of a positively charged nanoparticle. In contrast, a negatively charged nanoparticle was formed when a MCD with a short L-chain was used. We next evaluated the gene silencing efficiency of the nanoparticles using HeLa cells expressing the luciferase protein. The results showed that the siRNA/MCD nanoparticles showed a higher gene silencing efficiency than Lipofectamine 2000. We also found that the efficiency of gene silencing is a function of the length of the alkyl chain in MCD and zeta-potential of the siRNA/MCD nanoparticles. Such information provides another viewpoint for designing siRNA vectors. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
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573 KiB  
Review
Immune-Checkpoint Blockade and Active Immunotherapy for Glioma
by Brian J. Ahn, Ian F. Pollack and Hideho Okada
Cancers 2013, 5(4), 1379-1412; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041379 - 01 Nov 2013
Cited by 32 | Viewed by 8221
Abstract
Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the [...] Read more.
Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas. Full article
(This article belongs to the Special Issue Glioblastoma)
676 KiB  
Article
Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells
by Magdalena Milczarek, Michał Chodyński, Beata Filip-Psurska, Agnieszka Martowicz, Małgorzata Krupa, Krzysztof Krajewski, Andrzej Kutner and Joanna Wietrzyk
Cancers 2013, 5(4), 1355-1378; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041355 - 31 Oct 2013
Cited by 23 | Viewed by 7584
Abstract
Diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, were synthesized as advanced intermediates from vitamin D C-22 benzothiazoyl sulfones and side-chain aldehydes using our convergent strategy. Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191) were used as the reference compounds. Among a series of [...] Read more.
Diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, were synthesized as advanced intermediates from vitamin D C-22 benzothiazoyl sulfones and side-chain aldehydes using our convergent strategy. Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191) were used as the reference compounds. Among a series of tested analogs the diastereomeric analog PRI-2202 showed the strongest antiproliferative activity on the human breast cancer cell line MCF-7, whereas the geometric analog PRI-2205 was the weakest. Both analogs were less potent in antiproliferative activity against HL-60 cells compared to the reference compounds. The ability to potentiate antiproliferative effect of cisplatin or doxorubicin against HL-60 cells or that of tamoxifen against the MCF-7 cell line was observed at higher doses of PRI-2202 or PRI-2205 than those of the reference compounds. The proapoptotic activity of tamoxifen, expressed as the diminished mitochondrial membrane potential, as well as the increased phosphatidylserine expression, was partially attenuated by calcitriol, PRI-2191, PRI-2201 and PRI-2205. The treatment of the MCF-7 cells with tamoxifen alone resulted in an increase in VDR expression. Moreover, a further increase in VDR expression was observed when the analogs PRI-2201 or PRI-2205, but not PRI-2191, were used in combination with tamoxifen. This observation could partially explain the potentiation of the antiproliferative effect of tamoxifen by vitamin D analogs. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
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590 KiB  
Review
Oxidative Stress in the Carcinogenicity of Chemical Carcinogens
by Anna Kakehashi, Min Wei, Shoji Fukushima and Hideki Wanibuchi
Cancers 2013, 5(4), 1332-1354; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041332 - 28 Oct 2013
Cited by 39 | Viewed by 9377
Abstract
This review highlights several in vivo studies utilizing non-genotoxic and genotoxic chemical carcinogens, and the mechanisms of their high and low dose carcinogenicities with respect to formation of oxidative stress. Here, we survey the examples and discuss possible mechanisms of hormetic effects with [...] Read more.
This review highlights several in vivo studies utilizing non-genotoxic and genotoxic chemical carcinogens, and the mechanisms of their high and low dose carcinogenicities with respect to formation of oxidative stress. Here, we survey the examples and discuss possible mechanisms of hormetic effects with cytochrome P450 inducers, such as phenobarbital, a-benzene hexachloride and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane. Epigenetic processes differentially can be affected by agents that impinge on oxidative DNA damage, repair, apoptosis, cell proliferation, intracellular communication and cell signaling. Non-genotoxic carcinogens may target nuclear receptors and induce post-translational modifications at the protein level, thereby impacting on the stability or activity of key regulatory proteins, including oncoproteins and tumor suppressor proteins. We further discuss role of oxidative stress focusing on the low dose carcinogenicities of several genotoxic carcinogens such as a hepatocarcinogen contained in seared fish and meat, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, arsenic and its metabolites, and the kidney carcinogen potassium bromate. Full article
(This article belongs to the Special Issue Role of Oxidatively-Induced DNA Damage in Carcinogenesis)
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540 KiB  
Review
MicroRNA in Human Glioma
by Mengfeng Li, Jun Li, Lei Liu, Wei Li, Yi Yang and Jie Yuan
Cancers 2013, 5(4), 1306-1331; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041306 - 23 Oct 2013
Cited by 50 | Viewed by 8010
Abstract
Glioma represents a serious health problem worldwide. Despite advances in surgery, radiotherapy, chemotherapy, and targeting therapy, the disease remains one of the most lethal malignancies in humans, and new approaches to improvement of the efficacy of anti-glioma treatments are urgently needed. Thus, new [...] Read more.
Glioma represents a serious health problem worldwide. Despite advances in surgery, radiotherapy, chemotherapy, and targeting therapy, the disease remains one of the most lethal malignancies in humans, and new approaches to improvement of the efficacy of anti-glioma treatments are urgently needed. Thus, new therapeutic targets and tools should be developed based on a better understanding of the molecular pathogenesis of glioma. In this context, microRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in the development of the malignant phenotype of glioma cells, including cell survival, proliferation, differentiation, tumor angiogenesis, and stem cell generation. This review will discuss the biological functions of miRNAs in human glioma and their implications in improving clinical diagnosis, prediction of prognosis, and anti-glioma therapy. Full article
(This article belongs to the Special Issue Glioblastoma)
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Review
Strategies in Gene Therapy for Glioblastoma
by Aneta Kwiatkowska, Mohan S. Nandhu, Prajna Behera, E. Antonio Chiocca and Mariano S. Viapiano
Cancers 2013, 5(4), 1271-1305; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041271 - 23 Oct 2013
Cited by 74 | Viewed by 12173
Abstract
Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have [...] Read more.
Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy. Full article
(This article belongs to the Special Issue Glioblastoma)
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557 KiB  
Review
Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells
by Satoru Matsuda and Yasuko Kitagishi
Cancers 2013, 5(4), 1261-1270; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041261 - 21 Oct 2013
Cited by 19 | Viewed by 9702
Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
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604 KiB  
Review
Vitamin D Is a Multilevel Repressor of Wnt/b-Catenin Signaling in Cancer Cells
by María Jesús Larriba, José Manuel González-Sancho, Antonio Barbáchano, Núria Niell, Gemma Ferrer-Mayorga and Alberto Muñoz
Cancers 2013, 5(4), 1242-1260; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041242 - 21 Oct 2013
Cited by 116 | Viewed by 12276
Abstract
The Wnt/b-catenin signaling pathway is abnormally activated in most colorectal cancers and in a proportion of other neoplasias. This activation initiates or contributes to carcinogenesis by regulating the expression of a large number of genes in tumor cells. The active vitamin D metabolite [...] Read more.
The Wnt/b-catenin signaling pathway is abnormally activated in most colorectal cancers and in a proportion of other neoplasias. This activation initiates or contributes to carcinogenesis by regulating the expression of a large number of genes in tumor cells. The active vitamin D metabolite 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits Wnt/b-catenin signaling by several mechanisms at different points along the pathway. Additionally, paracrine actions of 1,25(OH)2D3 on stromal cells may also repress this pathway in neighbouring tumor cells. Here we review the molecular basis for the various mechanisms by which 1,25(OH)2D3 antagonizes Wnt/b-catenin signaling, preferentially in human colon carcinoma cells, and the consequences of this inhibition for the phenotype and proliferation rate. The effect of the vitamin D system on Wnt/b-catenin signaling and tumor growth in animal models will also be commented in detail. Finally, we revise existing data on the relation between vitamin D receptor expression and vitamin D status and the expression of Wnt/b-catenin pathway genes and targets in cancer patients. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
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1001 KiB  
Article
Gene Regulatory Scenarios of Primary 1,25-Dihydroxyvitamin D3 Target Genes in a Human Myeloid Leukemia Cell Line
by Jussi Ryynänen, Sabine Seuter, Moray J. Campbell and Carsten Carlberg
Cancers 2013, 5(4), 1221-1241; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041221 - 16 Oct 2013
Cited by 15 | Viewed by 5975
Abstract
Genome- and transcriptome-wide data has significantly increased the amount of available information about primary 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) target genes in cancer cell models, such as human THP-1 myelomonocytic leukemia cells. In this study, we investigated the genes G0S2 [...] Read more.
Genome- and transcriptome-wide data has significantly increased the amount of available information about primary 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) target genes in cancer cell models, such as human THP-1 myelomonocytic leukemia cells. In this study, we investigated the genes G0S2, CDKN1A and MYC as master examples of primary vitamin D receptor (VDR) targets being involved in the control of cellular proliferation. The chromosomal domains of G0S2 and CDKN1A are 140–170 kb in size and contain one and three VDR binding sites, respectively. This is rather compact compared to the MYC locus that is 15 times larger and accommodates four VDR binding sites. All eight VDR binding sites were studied by chromatin immunoprecipitation in THP-1 cells. Interestingly, the site closest to the transcription start site of the down-regulated MYC gene showed 1,25(OH)2D3-dependent reduction of VDR binding and is not associated with open chromatin. Four of the other seven VDR binding regions contain a typical DR3-type VDR binding sequence, three of which are also occupied with VDR in macrophage-like cells. In conclusion, the three examples suggest that each VDR target gene has an individual regulatory scenario. However, some general components of these scenarios may be useful for the development of new therapy regimens. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
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344 KiB  
Review
Detection of Circulating Tumour Cells from Blood of Breast Cancer Patients via RT-qPCR
by Ulrich Andergassen, Alexandra C. Kölbl, Stefan Hutter, Klaus Friese and Udo Jeschke
Cancers 2013, 5(4), 1212-1220; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041212 - 25 Sep 2013
Cited by 16 | Viewed by 7055
Abstract
Breast cancer is still the most frequent cause of cancer-related death in women worldwide. Often death is not caused only by the primary tumour itself, but also by metastatic lesions. Today it is largely accepted, that these remote metastases arise out of cells, [...] Read more.
Breast cancer is still the most frequent cause of cancer-related death in women worldwide. Often death is not caused only by the primary tumour itself, but also by metastatic lesions. Today it is largely accepted, that these remote metastases arise out of cells, which detach from the primary tumour, enter circulation, settle down at secondary sites in the body and are called Circulating Tumour Cells (CTCs). The occurrence of such minimal residual diseases in the blood of breast cancer patients is mostly linked to a worse prognosis for therapy outcome and overall survival. Due to their very low frequency, the detection of CTCs is, still a technical challenge. RT-qPCR as a highly sensitive method could be an approach for CTC-detection from peripheral blood of breast cancer patients. This assumption is based on the fact that CTCs are of epithelial origin and therefore express a different gene panel than surrounding blood cells. For the technical approach it is necessary to identify appropriate marker genes and to correlate their gene expression levels to the number of tumour cells within a sample in an in vitro approach. After that, samples from adjuvant and metastatic patients can be analysed. This approach may lead to new concepts in diagnosis and treatment. Full article
(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)
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Article
Three-Times Daily Ultrafractionated Radiation Therapy, A Novel and Promising Regimen for Glioblastoma Patients
by Patrick Beauchesne
Cancers 2013, 5(4), 1199-1211; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers5041199 - 25 Sep 2013
Cited by 11 | Viewed by 6219
Abstract
Glioblastomas are considered to be one of the most radio resistant tumors. Despite new therapies, the prognosis of this disease remains dismal. Also, the mechanisms of radiation resistance in mammalian cells are more complex than once believed. Experimental studies have indicated that some [...] Read more.
Glioblastomas are considered to be one of the most radio resistant tumors. Despite new therapies, the prognosis of this disease remains dismal. Also, the mechanisms of radiation resistance in mammalian cells are more complex than once believed. Experimental studies have indicated that some human cell lines are sensitive to low radiation doses of <1 Gy. This phenomenon has been termed low-dose hyper-radio-sensitivity (HRS), and is more apparent in radio resistant cell lines, such as glioblastoma cells. Sensitivity may result from the inability of low dose radiation to efficiently induce repair mechanisms, whereas higher doses cause enough damage to trigger repair responses for radio resistance. In vitro studies have demonstrated this phenomenon using various human malignant glioma cell lines: (1) daily repeated irradiation of cells with low doses compared to irradiation using a single biologically equivalent dose resulted in significantly higher cell killing; (2) experiments conducted on glioma xenografts demonstrated that repeated irradiation with low doses was more effective for inhibiting tumor growth than a single dose. In order to confirm and validate these promising studies on HRS, a few phase II trials were developed. For translating the experimental observations into the clinic, ultra fractionation protocols (with three daily doses) were tested in glioblastoma patients. Tolerance and toxicity were the primary endpoints, with overall survival as a secondary endpoint. These protocols were initiated before concomitant radio chemotherapy became the standard of care. For these trials, patients with an unfavorable clinical prognostic factor of newly unresectable GBM were included. When comparing the results of these trials with international literature using multivariate analysis for both progression free survival and overall survival, ultra fractionated irradiation showed superiority over radiotherapy alone. In addition, it was found to be equivalent to treatment using radiotherapy and temozolomide. Therefore, ultra fractionated protocols may prolong survival of glioblastoma patients. In this review, we describe the main experimental data regarding low-dose hypersensitivity as well as the findings of clinical trials that have investigated this new radiotherapy regimen. Full article
(This article belongs to the Special Issue Glioblastoma)
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