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Cancers, Volume 8, Issue 3 (March 2016)

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Open AccessArticle
Proteomics Analysis Reveals Novel RASSF2 Interaction Partners
Received: 14 January 2016 / Revised: 18 February 2016 / Accepted: 9 March 2016 / Published: 16 March 2016
Cited by 4 | Viewed by 2105 | PDF Full-text (1865 KB) | HTML Full-text | XML Full-text
Abstract
RASSF2 is a tumor suppressor that shares homology with other Ras-association domain (RASSF) family members. It is a powerful pro-apoptotic K-Ras effector that is frequently inactivated in many human tumors. The exact mechanism by which RASSF2 functions is not clearly defined, but it [...] Read more.
RASSF2 is a tumor suppressor that shares homology with other Ras-association domain (RASSF) family members. It is a powerful pro-apoptotic K-Ras effector that is frequently inactivated in many human tumors. The exact mechanism by which RASSF2 functions is not clearly defined, but it likely acts as a scaffolding protein, modulating the activity of other pro-apoptotic effectors, thereby regulating and integrating tumor suppressor pathways. However, only a limited number of RASSF2 interacting partners have been identified to date. We used a proteomics based approach to identify additional RASSF2 interactions, and thereby gain a better insight into the mechanism of action of RASSF2. We identified several proteins, including C1QBP, Vimentin, Protein phosphatase 1G and Ribonuclease inhibitor that function in diverse biological processes, including protein post-translational modifications, epithelial-mesenchymal transition, cell migration and redox homeostasis, which have not previously been reported to interact with RASSF2. We independently validated two of these novel interactions, C1QBP and Vimentin and found that the interaction with C1QBP was enhanced by K-Ras whereas, interestingly, the Vimentin interaction was reduced by K-Ras. Additionally, RASSF2/K-Ras regulated the acetylation of Vimentin. Our data thus reveal novel mechanisms by which RASSF2 may exert its functions, several of which may be Ras-regulated. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)
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Open AccessFeature PaperReview
Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy
Received: 8 January 2016 / Revised: 7 March 2016 / Accepted: 10 March 2016 / Published: 15 March 2016
Cited by 57 | Viewed by 9795 | PDF Full-text (874 KB) | HTML Full-text | XML Full-text
Abstract
This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy––a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities [...] Read more.
This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy––a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4+ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8+ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4+ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors. Full article
(This article belongs to the Special Issue Cancer Immunotherapies)
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Open AccessReview
Mechanisms of Nuclear Export in Cancer and Resistance to Chemotherapy
Received: 30 January 2016 / Revised: 3 March 2016 / Accepted: 8 March 2016 / Published: 14 March 2016
Cited by 13 | Viewed by 3587 | PDF Full-text (1663 KB) | HTML Full-text | XML Full-text
Abstract
Tumour suppressor proteins, such as p53, BRCA1, and ABC, play key roles in preventing the development of a malignant phenotype, but those that function as transcriptional regulators need to enter the nucleus in order to function. The export of proteins between the nucleus [...] Read more.
Tumour suppressor proteins, such as p53, BRCA1, and ABC, play key roles in preventing the development of a malignant phenotype, but those that function as transcriptional regulators need to enter the nucleus in order to function. The export of proteins between the nucleus and cytoplasm is complex. It occurs through nuclear pores and exported proteins need a nuclear export signal (NES) to bind to nuclear exportin proteins, including CRM1 (Chromosomal Region Maintenance protein 1), and the energy for this process is provided by the RanGTP/RanGDP gradient. Due to the loss of DNA repair and cell cycle checkpoints, drug resistance is a major problem in cancer treatment, and often an initially successful treatment will fail due to the development of resistance. An important mechanism underlying resistance is nuclear export, and a number of strategies that can prevent nuclear export may reverse resistance. Examples include inhibitors of CRM1, antibodies to the nuclear export signal, and alteration of nuclear pore structure. Each of these are considered in this review. Full article
(This article belongs to the Special Issue Small GTPases in Cancer)
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Open AccessReview
Melanoma Cancer Stem Cells: Markers and Functions
Received: 22 January 2016 / Revised: 2 March 2016 / Accepted: 4 March 2016 / Published: 11 March 2016
Cited by 10 | Viewed by 4447 | PDF Full-text (181 KB) | HTML Full-text | XML Full-text
Abstract
The discovery of cancer stem cells (CSCs) in human solid tumors has allowed a better understanding of the biology and neoplastic transformation of normal melanocytes, and the possible mechanisms by which melanoma cells acquire tumorigenicity. In this review I summarize the literature findings [...] Read more.
The discovery of cancer stem cells (CSCs) in human solid tumors has allowed a better understanding of the biology and neoplastic transformation of normal melanocytes, and the possible mechanisms by which melanoma cells acquire tumorigenicity. In this review I summarize the literature findings on the potential biomarkers of melanoma CSCs, their presence in the melanoma cell populations, the interaction with the immune system (with both T and NK cells) and the role of melanoma CSCs in the clinics. Given the extraordinary progress in the therapy of melanoma caused by immune checkpoint antibodies blockade, I discuss how these antibodies can work by the activation of melanoma infiltrating T cells specifically recognizing neo-antigens expressed even by melanoma CSCs. This is the mechanism that can induce a regression of the metastatic melanomas. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Tumor Microenvironment)
Open AccessArticle
Antioxidant Capacities of Hot Water Extracts and Endopolysaccharides of Selected Chinese Medicinal Fruits
Received: 22 December 2015 / Revised: 26 February 2016 / Accepted: 2 March 2016 / Published: 9 March 2016
Cited by 5 | Viewed by 1999 | PDF Full-text (976 KB) | HTML Full-text | XML Full-text
Abstract
Fruits are a rich source of antioxidants and traditional Chinese fruits have been studied for their chemopreventive and chemotherapeutic properties against cancers and other diseases. The total phenol and flavonoid contents of eleven Chinese fruits extracts were determined. Total phenolic and flavonoid contents [...] Read more.
Fruits are a rich source of antioxidants and traditional Chinese fruits have been studied for their chemopreventive and chemotherapeutic properties against cancers and other diseases. The total phenol and flavonoid contents of eleven Chinese fruits extracts were determined. Total phenolic and flavonoid contents were estimated by both the Folin-Ciocalteau and aluminium chloride methods. The antioxidant activities were evaluated by four assays: a biological assay using Saccharomyces cerevisiae, DPPH radical scavenging activity, chelating ability for ferrous ions and ferric reducing antioxidant power (FRAP). The phenols and flavonoids contents of the hot water extracts were in the range of 17.7 to 94.7 mg/g and 12.3 to 295.4 mg/g, whereas the endopolysaccharides lie in the range of 4.5 to 77.4 mg/g and 22.7 to 230.0 mg/g. Significant amounts of phenols and flavonoids were present in the majority of the fruit extracts and showed strong antioxidant activities. The antioxidant properties of the fruit extracts of Crataegus pinnatifida, Illicium verum, Ligustrum lucidum, Momordica grosvenori and Psoralea corylifolia as determined by the DPPH and FRAP methods, were significant compared to other fruit extracts. In the present study, we found that significant amounts of phenolic and flavonoid compounds were present in these fruit extracts and may contribute to in vitro antioxidant activities. Full article
(This article belongs to the Special Issue Antioxidants in Cancer)
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Open AccessReview
South Asian Medicinal Compounds as Modulators of Resistance to Chemotherapy and Radiotherapy
Received: 18 January 2016 / Revised: 5 February 2016 / Accepted: 29 February 2016 / Published: 5 March 2016
Cited by 4 | Viewed by 2400 | PDF Full-text (1765 KB) | HTML Full-text | XML Full-text
Abstract
Cancer is a hyperproliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis and metastasis. During the last 30 years, extensive research has revealed much about the biology of cancer. Chemotherapy and radiotherapy are the mainstays of cancer treatment, particularly for patients [...] Read more.
Cancer is a hyperproliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis and metastasis. During the last 30 years, extensive research has revealed much about the biology of cancer. Chemotherapy and radiotherapy are the mainstays of cancer treatment, particularly for patients who do not respond to surgical resection. However, cancer treatment with drugs or radiation is seriously limited by chemoresistance and radioresistance. Various approaches and strategies are employed to overcome resistance to chemotherapy and radiation treatment. Many plant-derived phytochemicals have been investigated for their chemo- and radio-sensitizing properties. The peoples of South Asian countries such as India, Pakistan, Sri Lanka, Nepal, Bangladesh and Bhutan have a large number of medicinal plants from which they produce various pharmacologically potent secondary metabolites. The medicinal properties of these compounds have been extensively investigated and many of them have been found to sensitize cancer cells to chemo- and radio-therapy. This review focuses on the role of South Asian medicinal compounds in chemo- and radio-sensitizing properties in drug- and radio-resistant cancer cells. Also discussed is the role of South Asian medicinal plants in protecting normal cells from radiation, which may be useful during radiotherapy of tumors to spare surrounding normal cells. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessArticle
Differentially Expressed MicroRNAs in Meningiomas Grades I and II Suggest Shared Biomarkers with Malignant Tumors
Received: 25 January 2016 / Revised: 19 February 2016 / Accepted: 24 February 2016 / Published: 3 March 2016
Cited by 2 | Viewed by 2034 | PDF Full-text (2904 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Meningiomas represent the most common primary tumors of the central nervous system, but few microRNA (miRNA) profiling studies have been reported so far. Deep sequencing of small RNA libraries generated from two human meningioma biopsies WHO grades I (benign) and II (atypical) were [...] Read more.
Meningiomas represent the most common primary tumors of the central nervous system, but few microRNA (miRNA) profiling studies have been reported so far. Deep sequencing of small RNA libraries generated from two human meningioma biopsies WHO grades I (benign) and II (atypical) were compared to excess dura controls. Nineteen differentially expressed miRNAs were validated by RT-qPCR using tumor RNA from 15 patients and 5 meninges controls. Tumor suppressor miR-218 and miR-34a were upregulated relative to normal controls, however, miR-143, miR-193b, miR-451 and oncogenic miR-21 were all downregulated. From 10 selected putative mRNA targets tested by RT-qPCR only four were differentially expressed relative to normal controls. PTEN and E-cadherin (CDH1) were upregulated, but RUNX1T1 was downregulated. Proliferation biomarker p63 was upregulated with nuclear localization, but not detected in most normal arachnoid tissues. Immunoreactivity of E-cadherin was detected in the outermost layer of normal arachnoids, but was expressed throughout the tumors. Nuclear Cyclin D1 expression was positive in all studied meningiomas, while its expression in arachnoid was limited to a few trabecular cells. Meningiomas of grades I and II appear to share biomarkers with malignant tumors, but with some additional tumor suppressor biomarkers expression. Validation in more patients is of importance. Full article
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Open AccessReview
Melanoma and the Unfolded Protein Response
Received: 23 June 2015 / Revised: 3 February 2016 / Accepted: 18 February 2016 / Published: 27 February 2016
Cited by 17 | Viewed by 2785 | PDF Full-text (1129 KB) | HTML Full-text | XML Full-text
Abstract
The UPR (unfolded protein response) has been identified as a key factor in the progression and metastasis of cancers, notably melanoma. Several mediators of the UPR are upregulated in cancers, e.g., high levels of GRP78 (glucose-regulator protein 78 kDa) correlate with progression and [...] Read more.
The UPR (unfolded protein response) has been identified as a key factor in the progression and metastasis of cancers, notably melanoma. Several mediators of the UPR are upregulated in cancers, e.g., high levels of GRP78 (glucose-regulator protein 78 kDa) correlate with progression and poor outcome in melanoma patients. The proliferative burden of cancer induces stress and activates several cellular stress responses. The UPR is a tightly orchestrated stress response that is activated upon the accumulation of unfolded proteins within the ER (endoplasmic reticulum). The UPR is designed to mediate two conflicting outcomtes, recovery and apoptosis. As a result, the UPR initiates a widespread signaling cascade to return the cell to homeostasis and failing to achieve cellular recovery, initiates UPR-induced apoptosis. There is evidence that ER stress and subsequently the UPR promote tumourigenesis and metastasis. The complete role of the UPR has yet to be defined. Understanding how the UPR allows for adaption to stress and thereby assists in cancer progression is important in defining an archetype of melanoma pathology. In addition, elucidation of the mechanisms of the UPR may lead to development of effective treatments of metastatic melanoma. Full article
(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)
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Open AccessArticle
Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells
Received: 28 January 2016 / Revised: 20 February 2016 / Accepted: 22 February 2016 / Published: 26 February 2016
Cited by 22 | Viewed by 3186 | PDF Full-text (1981 KB) | HTML Full-text | XML Full-text
Abstract
The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and [...] Read more.
The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p < 0.05) proliferation in HCT-116 cells and elevated (p < 0.05) apoptosis in both HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer. Full article
(This article belongs to the Special Issue Antioxidants in Cancer)
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Open AccessReview
Targeted Therapy in Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (LA-R/M HNSCC)
Received: 27 November 2015 / Revised: 16 February 2016 / Accepted: 16 February 2016 / Published: 26 February 2016
Cited by 23 | Viewed by 2776 | PDF Full-text (1745 KB) | HTML Full-text | XML Full-text
Abstract
Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemoradiotherapy is an alternative for patients with locally advanced disease. In recurrent/metastatic disease and after progression to platin-based regimens, no standard treatments other [...] Read more.
Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemoradiotherapy is an alternative for patients with locally advanced disease. In recurrent/metastatic disease and after progression to platin-based regimens, no standard treatments other than best supportive care are currently available. Most SCCHN tumours overexpress the epidermal growth factor receptor (EGFR). This receptor is a tyrosine-kinase membrane receptor that has been implicated in angiogenesis, tumour progression and resistance to different cancer treatments. In this review, we analysed the different drugs and pathways under development to treat SCCHN, especially recurrent/metastatic disease. Until now, the EGFR signalling pathway has been considered the most important target with respect to new drugs; however, new drugs, such as immunotherapies, are currently under study. As new treatments for SCCHN are developed, the influence of therapies with respect to overall survival, progression free survival and quality of life in patients with this disease is changing. Full article
(This article belongs to the Special Issue Head and Neck Cancer)
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Open AccessReview
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
Received: 8 December 2015 / Revised: 17 February 2016 / Accepted: 22 February 2016 / Published: 25 February 2016
Cited by 8 | Viewed by 4471 | PDF Full-text (2589 KB) | HTML Full-text | XML Full-text
Abstract
Most radiation biologists/radiation oncologists have long accepted the concept that the biologic effects of radiation principally involve damage to deoxyribonucleic acid (DNA), which is the critical target, as described in “Radiobiology for the Radiologist”, by E.J. Hall and A.J. Giaccia [1]. Although the [...] Read more.
Most radiation biologists/radiation oncologists have long accepted the concept that the biologic effects of radiation principally involve damage to deoxyribonucleic acid (DNA), which is the critical target, as described in “Radiobiology for the Radiologist”, by E.J. Hall and A.J. Giaccia [1]. Although the concepts of direct and indirect effects of radiation are fully applicable to low-LET (linear energy transfer) radioresistant tumor cells/normal tissues such as osteosarcoma cells and chondrocytes, it is believed that radiation-associated damage to DNA does not play a major role in the mechanism of cell death in low-LET radiosensitive tumors/normal tissues such as malignant lymphoma cells and lymphocytes. Hall and Giaccia describe lymphocytes as very radiosensitive, based largely on apoptosis subsequent to irradiation. As described in this review, apoptosis of lymphocytes and lymphoma cells is actually induced by the “hydrogen peroxide (H2O2) effect”, which I propose in this review article for the first time. The mechanism of lymphocyte death via the H2O2 effect represents an ideal model to develop the enhancement method of radiosensitivity for radiation therapy of malignant neoplasms. In terms of imitating the high radiosensitivity of lymphocytes, osteosarcoma cells (representative of low-LET radioresistant cells) might be the ideal model for indicating the conversion of cells from radioresistant to radiosensitive utilizing the H2O2 effect. External beam radiation such as X-rays and high-energy electrons for use in modern radiotherapy are generally produced using a linear accelerator. We theorized that when tumors are irradiated in the presence of H2O2, the activities of anti-oxidative enzymes such as peroxidases and catalase are blocked and oxygen molecules are produced at the same time via the H2O2 effect, resulting in oxidative damage to low-LET radioresistant tumor cells, thereby rendering them highly sensitive to irradiation. In this review, this potential paradigm shift in modern radiation biology/radiation oncology is discussed in detail in terms of overcoming drug/radiation resistance in radiation therapy and/or anti-cancer chemotherapy. Full article
(This article belongs to the Special Issue Drug/Radiation Resistance in Cancer Therapy)
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Open AccessFeature PaperArticle
Aberrant Promoter Methylation of the Tumour Suppressor RASSF10 and Its Growth Inhibitory Function in Breast Cancer
Received: 8 December 2015 / Revised: 3 February 2016 / Accepted: 19 February 2016 / Published: 25 February 2016
Cited by 8 | Viewed by 1842 | PDF Full-text (2069 KB) | HTML Full-text | XML Full-text
Abstract
Breast cancer is the most common cancer in women, with 1.7 million new cases each year. As early diagnosis and prognosis are crucial factors in cancer treatment, we investigated potential DNA methylation biomarkers of the tumour suppressor family Ras-association domain family (RASSF). Promoter [...] Read more.
Breast cancer is the most common cancer in women, with 1.7 million new cases each year. As early diagnosis and prognosis are crucial factors in cancer treatment, we investigated potential DNA methylation biomarkers of the tumour suppressor family Ras-association domain family (RASSF). Promoter hypermethylation of tumour suppressors leads to their inactivation and thereby promotes cancer development and progression. In this study we analysed the tumour suppressors RASSF1A and RASSF10. Our study shows that RASSF10 is expressed in normal breast but inactivated by methylation in breast cancer. We observed a significant inactivating promoter methylation of RASSF10 in primary breast tumours. RASSF10 is inactivated in 63% of primary breast cancer samples but only 4% of normal control breast tissue is methylated (p < 0.005). RASSF1A also shows high promoter methylation levels in breast cancer of 56% vs. 8% of normal tissue (p < 0.005). Interestingly more than 80% of breast cancer samples harboured a hypermethylation of RASSF10 and/or RASSF1A promoter. Matching samples exhibited a strong tumour specific promoter methylation of RASSF10 in comparison to the normal control breast tissue. Demethylation treatment of breast cancer cell lines MCF7 and T47D reversed RASSF10 promoter hypermethylation and re-established RASSF10 expression. In addition, we could show the growth inhibitory potential of RASSF10 in breast cancer cell lines MCF7 and T47D upon exogenous expression of RASSF10 by colony formation. We could further show, that RASSF10 induced apoptotic changes in MCF7 and T47D cells, which was verified by a significant increase in the apoptotic sub G1 fraction by 50% using flow cytometry for MCF7 cells. In summary, our study shows the breast tumour specific inactivation of RASSF10 and RASSF1A due to DNA methylation of their CpG island promoters. Furthermore RASSF10 was characterised by the ability to block growth of breast cancer cell lines by apoptosis induction. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)
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