Hypoxic microenvironments frequently exist in many solid tumours with oxygen levels fluctuating temporally and spatially from normoxia to hypoxia. The response to hypoxia in human cells is mainly regulated by hypoxia-inducible factors (HIFs), a family of transcription factors which orchestrate signalling events leading to angiogenesis and tumorigenesis. Several events conspire together to lead to the stabilization of HIF-α, commonly expressed in many cancer cell types. These events can result from low oxygen tensions occurring within the expanding tumour mass to produce hypoxic microenvironments or from mutations whereby the HIFs cause changes in expression of genes involved in several cellular functions. Hypoxia-mediated HIF-α regulation has gained significant prominence in tumour biology over recent years, and the hypoxic microenvironments have been shown to facilitate and trigger major molecular and immunological processes necessary to drive the progression of tumours to malignancy. More recently, it has been realized that the hypoxic microenvironments also play significant roles in shielding tumour cells from immune attack by promoting immune suppression. In addition, the hypoxic microenvironment promotes many other oncogenic events, such as the metabolic reconfiguration of tumour cells, neovascularization, epithelial to mesenchymal transition (EMT), and cancer stem cell renewal and accumulation. This article reviews the molecular mechanisms underlying tumour hypoxia and their pro-tumour contributions, such as immune suppression, development of nascent and more permeable tumour vasculature, selective cancer stem cell renewal, accumulation, mobilization and promotion of EMT leading to tumour cell metastasis.
SUMMARYIsocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II–III glioma and secondary glioblastoma (GBM). A causal role for IDH1R132H in gliomagenesis has been proposed, but functional validation in vivo has not been demonstrated. In this study, we assessed the role of IDH1R132H in glioma development in the context of clinically relevant cooperating genetic alterations in vitro and in vivo. Immortal astrocytes expressing IDH1R132H exhibited elevated (R)-2-hydroxyglutarate levels, reduced NADPH, increased proliferation, and anchorage-independent growth. Although not sufficient on its own, IDH1R132H cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo. These tumors resembled pro-neural human mutant IDH1 GBM genetically, histologically, and functionally. Our findings support the hypothesis that IDH1R132H promotes glioma development. This model enhances our understanding of the biology of IDH1R132H-driven gliomas and facilitates testing of therapeutic strategies designed to combat this deadly disease.
Mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) were recently found in ~80% of WHO grade II–III gliomas and secondary glioblastomas. These mutations reduce the enzyme’s ability to convert isocitrate to α-ketoglutarate and, instead, confer a novel gain-of-function resulting in the conversion of α-ketoglutarate to 2-hydroxglutarate (2-HG). However, IDH mutations exist in a heterozygous state such that a functional wild type allele is retained. Recent data suggest that the ability of mutant IDH1, but not mutant IDH2, to produce 2-HG is dependent on the activity of the retained wild type allele. In this study, we aimed to further our understanding of the interaction and function of wild type and mutant IDH heterodimers utilizing Bimolecular Fluorescence Complementation (BiFC). Dimerization of wild type and mutant IDH monomers conjugated to the N- and C-terminus of Venus protein, respectively, is directly proportional to the amount of fluorescence emitted and can be used as an approach to visualize and assess IDH dimerization. Thus, we utilized this method to visualize IDH homo- and heterodimers and to examine their cellular physiology based on subcellular localization, NADPH production, and 2-HG levels. Our results demonstrate that wild type and mutant IDH1 or IDH2 heterodimers display similar physiological characteristics to that of mutant IDH1 or IDH2 homodimers with the exception of their ability to generate NADPH. IDH1 heterodimers consistently generate NADPH whereas IDH2 heterodimers do not. However, the presence of mutant IDH1 or IDH2 in homo- or heterodimer configurations consistently generates equivalent levels of 2-HG. Our data suggest that the wild type protein is not required for the generation of 2-HG.
Type 1 diabetes mellitus formerly called juvenile diabetes, is an organ specific T-cell mediated autoimmune disease characterized by the progressive loss of function of the insulin producing beta–cells of the islets of Langerhans. Cytotoxic T lymphocyte-associated antigen 4 gene (CTLA-4) has been proposed as a candidate gene for conferring susceptibility to autoimmunity. Association of CTLA-4 gene polymorphism is well established in autoimmune endocrinopathies across world population. The present study was conducted to investigate the association of CTLA-4 exon 1 49A/G polymorphism with TIDM in Madurai, a city in Southern India. Fifty three clinically proven T1DM patients and 53 control subjects with no history of autoimmune disease were recruited for the study. Genomic DNA was extracted from peripheral blood. CTLA-4 exon 1 49 A/G polymorphism was assessed using PCR-RFLP methods. Our findings revealed a significant association of CTLA-4 exon 1 49 A/G polymorphism with T1DM in Madurai population.
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Hypoxic microenvironments frequently exist within many solid tumors with oxygen levels fluctuating temporally and spatially from normoxia to hypoxia. The response to hypoxia in human cells is mainly regulated by hypoxia-inducible factors or HIFs, a family of transcription factors which orchestrate signalling events promoting cancer stem cells, leading to angiogenesis and increased tumorigenesis. Several events conspire together to stabilize HIF-αs to become constitutively expressed in many cancer cell types, regardless of oxygen levels. Prolyl hydroxylases (PHDs) play a crucial role in HIF regulation by hydroxylating HIF proline residues to target these proteins for proteasomal degradation. Hypoxic microenvironments existing within tumors and cytosolic accumulation of mitochondrial metabolites such as succinate or increased ROS production are known to suppress PHD function, resulting in HIF stabilisation and transcriptional activation in the nucleus thereby triggering various pro-oncogenic signalling pathways. Abnormal HIF-αα regulation has gained significant prominence in tumor biology over recent years and the hypoxic microenvironments have been shown to facilitate and trigger major molecular and immunological processes necessary as a driver promoting greater tumor malignancy. More recently, it has been realized that these hypoxic microenvironments also play significant roles in shielding tumour cells from immune attack by promoting immune suppression. We address many of these functions and their relationship to cancer stem cells and their metastastic properties. We also show that overexpressing prolyl hydroxylase reduces HIF expression and malignancy of cancer cells as well as affecting the levels of reactive oxygen species and respiratory chain function in these cells. Citation Format: Beatrice Philip, Koichi Ito, Rafael Moreno-Sanchez, Stephen J. Ralph. Prolyl hydroxylase and the regulation of reactive oxygen species (ROS) levels in cancer cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B87. doi:10.1158/1538-7445.CHTME14-B87
Galectin-1 has been shown as a major protein secreted by the majority of cancer types. It plays important roles in the tumor microenvironment protecting against immune cell attack, from reactive oxygen species production and promotes metastasis. Galectin-1 binds at high levels to the surfaces of human endothelial cell lines and binding is inhibited by pre-treatment with inhibitory disaccharides. Galectin blockade in this manner can be used to inhibit growth of primary cancers in murine models. We have shown galectin-1 is highly expressed within hypoxic domains of primary human melanoma, associated with cancer stem cell markers, but is widely expressed at high levels in metastases from the same patients. Using siRNA knockdown or binding inhibitors, galectin-1 expression is shown to be critical for protecting endothelial cells in tumor angiogenesis and for promoting tumor metastasis. More recently, it has been shown that galectin blockade using small drug molecules significantly enhanced the permeability and access of other chemotherapies inside tumors by promoting vascular leakiness, increasing cytotoxic efficacy and immune cell killing in-situ detected by TUNEL assays inside tumors. Galectin-1 blockade or siRNA knockdown also significantly inhibits metastases to the lung in the 4T1 murine breast cancer model. When used in combination as a triple therapy with whole cancer cell vaccines subjected to IFN and expressing CD80 together with anti-CTLA4 Ig treatment, galectin-1 blockade produced synergistic enhancements increasing CD8+ CTL anticancer responses to inhibit cancer growth in a range of different mouse tumor models including the CT26 colon and 4T-1 breast cancers. These results together with flow cytometric analysis showed that the melanoma stem cell markers, CD271 and ABCB5 co-localized with bound galectin-1 in hypoxic regions of melanomas, suggesting that galectin-1 may play a role in cancer stem cell function, promoting their mobilization and metastasis. Published References: 1. Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment. Ito K, Stannard K, Gabutero E, Clark AM, Neo SY, Onturk S, Blanchard H, Ralph SJ. Cancer Metastasis Rev. 2012 Dec;31(3-4):763-78. 2. Inhibiting galectin-1 reduces murine lung metastasis with increased CD4(+) and CD8 (+) T cells and reduced cancer cell adherence. Ito K, Ralph SJ. Clin Exp Metastasis. 2012 Aug;29(6):561-72. 3. Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress. Ito K, Scott SA, Cutler S, Dong LF, Neuzil J, Blanchard H, Ralph SJ. Angiogenesis. 2011 Sep;14(3):293-307. 4. Galectin inhibitory disaccharides promote tumour immunity in a breast cancer model. Stannard KA, Collins PM, Ito K, Sullivan EM, Scott SA, Gabutero E, Darren Grice I, Low P, Nilsson UJ, Leffler H, Blanchard H, Ralph SJ. Cancer Lett. 2010 Dec 28;299(2):95-110. Citation Format: Koichi Ito, Selda Onturk, Katie Powell, Beatrice Philip, James Wilmott, Richard Scolyer, Peter Hersey, Stephen J. Ralph. Galectin-1 expressed in human melanoma is bound to cancer stem cells: A driver for metastatic progression and target for antimetastatic cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B8.
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