Ovarian and Prostate Cancer Research Trust Laboratory

Guildford, United Kingdom

Ovarian and Prostate Cancer Research Trust Laboratory

Guildford, United Kingdom

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Vinay D.S.,Tulane University | Ryan E.P.,Colorado State University | Pawelec G.,University of Tübingen | Talib W.H.,University of Jordan | And 27 more authors.
Seminars in Cancer Biology | Year: 2015

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, deregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection. © 2015 Elsevier Ltd.


Chen S.S.,Ovarian and Prostate Cancer Research Trust Laboratory | Michael A.,University of Surrey | Butler-Manuel S.A.,Royal Surrey County Hospital
Discovery Medicine | Year: 2013

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies worldwide. The five-year survival rates for stage IIIC and IV patients are 29% and 13%, respectively. Type-2 EOC cells have been found to be associated with this late stage disease. In contrast, women diagnosed in stage 1 disease, which mostly exhibits type-1 cells, have a high 5-year survival rate (90%). Recent progress in understanding the pathogenesis of EOC and inflammatory signaling pathways revealed that type-2 cells frequently express a deleted or mutated TP53 (60-80%), or aberrations in BRCA1 (30-60%) and BRCA2 (15-30%). The deletion or mutation of TP53 results in a dysregulated inflammatory signal network and contributes to an immunosuppressive microenvironment. Thus, to be effective, EOC therapy may be necessary to cover two areas: (1) direct cytotoxic killing of cancer cells; (2) reversion of the immunosuppressive microenvironment. Presently the first strategy is advancing rapidly while the second strategy remains behind. Isolation and characterization of cancer stem cells (CSCs) have helped to confirm the dynamic role of the tumor microenvironment in promoting cancer metastasis and recurrence. Based on widely published in vitro and mouse-model data, some anti-inflammatory phytochemicals appear to exhibit activity in modulating the tumor microenvironment. Specifically, apiegenin, baicalein, curcumin, EGCG, genistein, luteolin, oridonin, quercetin, and wogonin repress NF-kappaB (NF-κB, a proinflammatory transcription factor) and inhibit proinflammatory cytokines such as TNF-α and IL-6. Additionally, most of these phytochemicals have been shown to stabilize p53 protein, sensitize TRAIL (TNF receptor apoptosis-inducing ligand) induced apoptosis, and prevent or delay chemotherapy-resistance. Recent studies further indicate that apigenin, genistein, kaempferol, luteolin, and quercetin potently inhibit VEGF production and suppress ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted. © 2013, Discovery Medicine.


Chen S.,Ovarian and Prostate Cancer Research Trust Laboratory | Cooper M.,University of Surrey | Jones M.,University of Surrey | Madhuri T.K.,Royal Surrey County Hospital | And 4 more authors.
Cell Biology and Toxicology | Year: 2011

The initial response rates of advanced-stage epithelial ovarian cancer to the chemotherapeutic agents carboplatin and paclitaxel are high. However, once drug resistance develops, further chemotherapy is less effective. The objective of this study is to investigate the anti-proliferative activity of the phyto-active chemicals (PACs) oridonin and wogonin in chemo-resistant epithelial ovarian cancer cells. Primary cell cultures from the ascitic fluid of three patients at diagnosis, two patients chemo-resistant to carboplatin and paclitaxel, and one patient treated with letrozole for breast cancer were studied and compared to the ovarian cancer cell lines A2780 and PTX10, by cell viability assay (MTS). Effects on cell cycle modulation and apoptosis were examined by flow cytometry and Western blot analysis (WB). WB was further conducted to investigate protein expressions altered by PACs. The results show that IC50 of the primary cultures ranged from 0.6 to 5.4 μg/ml for oridonin and 0.3-12.7 μg/ml for wogonin. The paclitaxel-resistant cell line PTX10 was more sensitive to each of the PACs than the chemo-sensitive cell line A2780. Of particular interest is that in combination, the two PACs were synergistic in their cytotoxicity to five of six of the primary cultures and to both the cell lines (combination indices of 0.39-0.95). The inhibition is attributable to apoptosis and cell cycle modulation induced by the PACs as demonstrated in A2780 and PTX10. Up-regulation of the functional p53 protein in A2780 and down-regulation of Akt protein in PTX10 have in part contributed to the apoptosis. These findings suggest that oridonin and wogonin may have activity in ovarian cancer following its development of resistance to carboplatin and paclitaxel. © 2010 Springer Science+Business Media B.V.


PubMed | Purdue University, Barbara Ann Karmanos Cancer Institute, Getting to Know Cancer, Tzu Chi University and 23 more.
Type: | Journal: Seminars in cancer biology | Year: 2015

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.


PubMed | Purdue University, University of Rome Tor Vergata, Instituti Of Ricovero E Cura A Carattere Scientifico Instituto Of Ricerche Farmacologiche Mario Negri, United Arab Emirates University and 19 more.
Type: | Journal: Seminars in cancer biology | Year: 2015

Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.


PubMed | CNR Institute of Neuroscience, Purdue University, Baylor College of Medicine, Barbara Ann Karmanos Cancer Institute and 19 more.
Type: | Journal: Seminars in cancer biology | Year: 2015

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through equilibrium and senescence before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.


PubMed | University of Lübeck, University of Rome Tor Vergata, University of Cardiff, Royal Adelaide Hospital and 20 more.
Type: | Journal: Seminars in cancer biology | Year: 2015

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), -catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.


PubMed | Morehouse School of Medicine, CSIR - Central Electrochemical Research Institute, University of Maryland Baltimore County, New York University and 21 more.
Type: | Journal: Seminars in cancer biology | Year: 2015

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.


Chen S.,Ovarian and Prostate Cancer Research Trust Laboratory | Corteling R.,Surrey Research Park | Stevanato L.,Surrey Research Park | Sinden J.,Surrey Research Park
Biochemical and Biophysical Research Communications | Year: 2012

Indoleamine dioxygenase (IDO) is a heme- containing enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine, kynurenine and the downstream quinolinic acid. Though IDO is physiologically important in maintaining tissue integrity, aberrant IDO expression represses T cell function and promotes regulatory T cells (Treg) in cancer. It additionally exacerbates Alzheimer, depression, Huntington and Parkinson diseases via quinolinic acid. Inhibition of IDO has thus been recently proposed as a strategy for treating cancer and neuronal disorders. In the present study, we have developed a cell-based assay to evaluate the suppressive effect of anti-inflammatory phytochemicals on the enzyme. When stimulated by INF-γ, profound high expressions of IDO-1 mRNA as well as the protein were detected in human neural stem cells (hNSC) and verified by real-time retro-transcribed PCR and western blot analysis, respectively. The protein activity was measured by kynurenine concentration and the assay was validated by dose-responsive inhibition of IDO-1 antagonists including 1-methyltryptaphan, indomethacin and acetylsalicylic acid. Among the tested compounds, apigenin, baicalein, chrysin, and wogonin exhibit a potent repressive activity with IC50s comparable to that of indomethacin. The inhibition was further found to be independent of gene expression and protein translation because of the unaltered levels of mRNA and protein expression. Although curcumin displayed a potent inhibitory activity to the enzyme, it appeared to be cytotoxic to hNSCs. Morphological examination of hNSC revealed that baicalein and wogonin at the inhibitory concentrations induced neurite outgrowth. In conclusion, our data shows that certain phytochemicals with 2-phenyl-1-benzopyran-4-one backbone (flavones) attenuate significantly the IDO-1 protein activity without harming hNSCs. The inhibitory activity might have partially contributed to the anti-cancer and neuro-protective property of the compounds. © 2012 Elsevier Inc.


Chen S.S.,Ovarian and Prostate Cancer Research Trust Laboratory
Discovery medicine | Year: 2012

Metastasis is one of the cancer hallmarks described by Hanahan and Weinberg. Emerging evidence shows that it requires interplays between cancer cells and micro-environmental biofactors. Indoleamine 3,5-dioxygenase-1 (IDO-1) produced by cancer, local lymph nodes, and satellite cells have been demonstrated as one of the biofactors. Aberrant IDO-1 activity has partially contributed to immunosuppressive environment by repressing T lymphocyte and natural killer cell activities, and activating regulatory T cells (Treg, CD4+CD25+). Clinical investigations further show a negative correlation between the enzyme activity and prognosis in patients with various cancer types. The findings suggest a possible role of IDO-1 inhibitor in restoring host anti-tumor immunity and attenuating cancer metastasis. Data from preclinical and phase I/II clinical studies with IDO-1 inhibitors support this hypothesis. Polyphenols as antioxidants are shown to exhibit anticancer activities. However, the underlying mechanism has not been entirely characterized. We recently found that certain flavone molecules profoundly inhibit the enzymatic activity of IDO-1 but not mRNA expression in human neuronal stem cells (hNSC) confirmed by cell-based assay and qRT-PCR. To further the investigation, we studied additional anti-cancer phytochemicals including chalcone, flavonol, isoflavone, and diterpene. Here we summarize the results and show that the inhibitory sensitivity depends on the molecular structure in the following order: apigenin > wogonin > chrysin > biacalein ~ genistein > quercetin. Curcumin and isoliquiritigenin (a chalcone) exhibited toxicity to hNSCs. Although oridonin (a diterpene) showed a null toxicity toward hNSCs, it repressed the enzymatic function only marginally in contrast to its potent cytotoxicity in various cancer cell lines. While the mode of action of the enzyme-polyphenol complex awaits to be investigated, the sensitivity of enzyme inhibition was compared to the anti-proliferative activities toward three cancer cell lines. The IC50s obtained from both sets of the experiments indicate that they are in the vicinity of micromolar concentration with the enzyme inhibition slightly more active. These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy.

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