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Khew-Goodall Y.,Center for Cancer Biology | Goodall G.J.,Center for Cancer Biology
Nature Cell Biology | Year: 2012

Cancer-associated fibroblasts contribute to malignancy by expressing secreted pro-tumorigenic molecules. The microRNA miR-320 is now shown to be a crucial component of a PTEN-controlled tumour-suppressive axis in stromal fibroblasts. Loss of PTEN and miR-320 induces an oncogenic secretome that reprogrammes the tumour microenvironment to promote invasion and angiogenesis. © 2012 Macmillan Publishers Limited. All rights reserved.


Denton D.,Center for Cancer Biology | Denton D.,University of Adelaide | Nicolson S.,Center for Cancer Biology | Kumar S.,Center for Cancer Biology | Kumar S.,University of Adelaide
Cell Death and Differentiation | Year: 2012

Autophagy (the process of self-digestion by a cell through the action of enzymes originating within the lysosome of the same cell) is a catabolic process that is generally used by the cell as a mechanism for quality control and survival under nutrient stress conditions. As autophagy is often induced under conditions of stress that could also lead to cell death, there has been a propagation of the idea that autophagy can act as a cell death mechanism. Although there is growing evidence of cell death by autophagy, this type of cell death, often called autophagic cell death, remains poorly defined and somewhat controversial. Merely the presence of autophagic markers in a cell undergoing death does not necessarily equate to autophagic cell death. Nevertheless, studies involving genetic manipulation of autophagy in physiological settings provide evidence for a direct role of autophagy in specific scenarios. This article endeavours to summarise these physiological studies where autophagy has a clear role in mediating the death process and discusses the potential significance of cell death by autophagy. © 2012 Macmillan Publishers Limited All rights reserved.


Pham D.H.,University of Adelaide | Pham D.H.,Center for Cancer Biology | Pham D.H.,University of South Australia
Oncogene | Year: 2014

Sphingosine kinase 1 (SK1) is a lipid kinase that catalyses the formation of sphingosine-1-phosphate (S1P). Considerable evidence has implicated elevated cellular SK1 in tumour development, progression and disease severity. In particular, SK1 has been shown to enhance cell survival and proliferation and induce neoplastic transformation. Although S1P has been found to have both cell-surface G-protein-coupled receptors and intracellular targets, the specific downstream pathways mediating oncogenic signalling by SK1 remain poorly defined. Here, using a gene expression array approach, we have demonstrated a novel mechanism whereby SK1 regulates cell survival, proliferation and neoplastic transformation through enhancing expression of transferrin receptor 1 (TFR1). We showed that elevated levels of SK1 enhanced total as well as cell-surface TFR1 expression, resulting in increased transferrin uptake into cells. Notably, we also found that SK1 activation and localization to the plasma membrane, which are critical for its oncogenic effects, are necessary for regulation of TFR1 expression specifically through engagement of the S1P G-protein coupled receptor, S1P2. Furthermore, we showed that blocking TFR1 function with a neutralizing antibody inhibits SK1-induced cell proliferation, survival and neoplastic transformation of NIH3T3 fibroblasts. Similar effects were observed following antagonism of S1P2. Together these findings suggest that TFR1 has an important role in SK1-mediated oncogenesis.


Pitson S.M.,Center for Cancer Biology | Pitson S.M.,University of Adelaide
Trends in Biochemical Sciences | Year: 2011

Bioactive sphingolipids, including ceramide, sphingosine and sphingosine 1-phosphate are important regulators of many cellular processes, including cell survival, proliferation, differentiation, migration and immune responses. Although the levels of these bioactive sphingolipids are regulated by complex pathways subject to spatial and temporal control, the sphingosine kinases have emerged as critical central regulators of this system and, as a consequence, they have received substantial recent attention as potential therapeutic targets for cancer and a range of other conditions. Deciphering the molecular mechanisms that regulate both the activity and subcellular localization of these enzymes is vital for understanding the control of bioactive sphingolipid generation and action, and has clear implications for therapeutic strategies targeting these enzymes. © 2010 Elsevier Ltd.


Neilsen C.T.,Center for Cancer Biology | Neilsen C.T.,University of Adelaide | Goodall G.J.,Center for Cancer Biology | Goodall G.J.,University of Adelaide | And 2 more authors.
Trends in Genetics | Year: 2012

The development of deep sequencing has enabled the identification of novel microRNAs (miRNAs), leading to a growing appreciation for the fact that individual miRNAs can be heterogeneous in length and/or sequence. These variants, termed isomiRs, can be expressed in a cell-specific manner, and numerous recent studies suggest that at least some isomiRs may affect target selection, miRNA stability, or loading into the RNA-induced silencing complex (RISC). Reports indicating differential functionality for isomiRs are currently confined to several specific variants, and although isomiRs are common, their broader biological significance is yet to be fully resolved. Here we review the growing body of evidence suggesting that isomiRs have functional differences, of which at least some appear biologically relevant, and caution researchers to take miRNA isoforms into consideration in their experiments. © 2012 Elsevier Ltd.


Chereda B.,Center for Cancer Biology | Melo J.V.,University of Adelaide
Annals of Hematology | Year: 2015

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder arising in the haemopoietic stem cell (HSC) compartment. This disease is characterised by a reciprocal t(9;22) chromosomal translocation, resulting in the formation of the Philadelphia (Ph) chromosome containing the BCR-ABL1 gene. As such, diagnosis and monitoring of disease involves detection of BCR-ABL1. It is the BCR-ABL1 protein, in particular its constitutively active tyrosine kinase activity, that forges the pathogenesis of CML. This aberrant kinase signalling activates downstream targets that reprogram the cell to cause uncontrolled proliferation and results in myeloid hyperplasia and ‘indolent’ symptoms of chronic phase (CP) CML. Without successful intervention, the disease will progress into blast crisis (BC), resembling an acute leukaemia. This advanced disease stage takes on an aggressive phenotype and is almost always fatal. The cell biology of CML is also centred on BCR-ABL1. The presence of BCR-ABL1 can explain virtually all the cellular features of the leukaemia (enhanced cell growth, inhibition of apoptosis, altered cell adhesion, growth factor independence, impaired genomic surveillance and differentiation). This article provides an overview of the clinical and cell biology of CML, and highlights key findings and unanswered questions essential for understanding this disease. © 2015, Springer-Verlag Berlin Heidelberg.


Branford S.,Center for Cancer Biology
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Monitoring response to therapy for patients with chronic myeloid leukemia using an effective strategy is fundamental for achieving optimal patient outcomes. It will allow the initiation of timely therapeutic intervention for patients with a suboptimal response or kinase inhibitor therapy failure. Evidence is mounting that reaching molecular targets early in therapy is as important as the initial hematologic and cytogenetic response for the identification of patients who may have a poorer outcome. When the molecular target of a major molecular response is achieved at 18 months, patients reach a safe haven where loss of response is rare. However, this benefit is dependent on continuous drug adherence in most patients. As some patients reach their second decade of successful imatinib therapy, how long will frequent response monitoring be necessary? Assuming that very late relapse will be extremely rare for responding patients remaining on kinase inhibitor therapy, there are reasons for maintaining a regular molecular monitoring frequency, including monitoring adherence assessment and confirming sustained undetectable BCR-ABL1 for those considering a discontinuation trial and for late molecular recurrence in patients who maintain response after treatment discontinuation.


Cortes J.,University of Houston | Goldman J.M.,Imperial College London | Hughes T.,Center for Cancer Biology
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2012

Despite the success with tyrosine kinase inhibitors (TKIs) in most patients with chronic myelogenous leukemia (CML), some patients still experience resistance or intolerance and need alternative therapies. Monitoring response to TKI therapy is a critical component of managing CML, and molecular response seems to be the most important milestone for predicting long-term outcomes. How best to assess response, including how to define treatment failure, and how monitoring should be conducted remain controversial. Strategies for overcoming imatinib resistance include increasing the imatinib dose or switching to a second-generation TKI. Another approach is to use higher doses of imatinib or second-generation TKIs up front to increase the rate of earlier responses, with the hope that this will translate into a reduced risk of resistance. Several investigational therapies are also being evaluated as a means of overcoming TKI resistance, including ponatinib (AP24534), omacetaxine, and bosutinib (SKI-606). Allogeneic hematopoietic stem cell transplantation has also shown efficacy in patients with imatinib-resistant disease. Alternatives to long-term TKI therapy that are currently being explored include discontinuation of treatment and eradication of minimal residual disease with investigational treatment regimens, such as those involving interferon, hydroxychloroquine, BCL6 inhibitors, and the smoothened antagonists LDF225 and BMS-833923. © JNCCN - Journal of the National Comprehensive Cancer Network.


Scheffner M.,University of Konstanz | Kumar S.,Center for Cancer Biology | Kumar S.,University of Adelaide | Kumar S.,University of South Australia
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2014

Members of the HECT family of E3 ubiquitin-protein ligases are characterized by a C-terminal HECT domain that catalyzes the covalent attachment of ubiquitin to substrate proteins and by N-terminal extensions of variable length and domain architecture that determine the substrate spectrum of a respective HECT E3. Since their discovery in 1995, it has become clear that deregulation of distinct HECT E3s plays an eminent role in human disease or disease-related processes including cancer, cardiovascular and neurological disorders, viral infections, and immune response. Thus, a detailed understanding of the structure-function aspects of HECT E3s as well as the identification and characterization of the substrates and regulators of HECT E3s is critical in developing new approaches in the treatment of respective diseases. In this review, we summarize what is currently known about mammalian HECT E3s, with a focus on their biological functions and roles in pathophysiology.This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf. © 2013 Elsevier B.V.


News Article | February 15, 2017
Site: www.eurekalert.org

Scientists at VIB-KU Leuven have identified a new mechanism that impacts tumor growth. The typical lack of oxygen in tumors doesn't only stimulate proliferation, but also offsets the important role of the protein PHD2 as 'cancer cell killer'. A possible solution lies in blocking the enzyme PP2A/B55, which restores the function of PHD2 and consequently slows down cancer growth. The research, led by prof. Massimiliano Mazzone (VIB-KU Leuven), is published in the leading scientific journal Cell Reports. Poor prognosis in cancer is typically correlated with hypoxia, a disturbance in the oxygen supply to the tumor cells. The protein PHD2 is known as a 'hypoxic sensor', as its function is highly dependent on the amount of oxygen. In the VIB-KU Leuven Center for Cancer Biology, Dr. Giusy Di Conza and colleagues, led by prof. Massimiliano Mazzone, focused on the phosphorylation -- the addition of a phosphate group -- of this protein. When phosphorylated, PHD2 is more active, promoting the death of cancer cells in the low-oxygen areas of the tumor. However, tumors tend to overexpress the phosphatase PP2A/B55, an enzyme that removes the phosphate group ('dephosphorylation') from PHD2. As a result, PHD2 is partially inactivated, which offsets the positive effects of this 'cancer cell killer'. Prof. Massimiliano Mazzone (VIB-KU Leuven): "Surprisingly, we found that the phosphorylation status of PHD2 is regulated by pathways such as mTOR, which in tumor and normal cells represents the main sensor of metabolic stresses such as lack of nutrients or growth factors. This means that our findings might be applied not only to cancer but also to other diseases, such inflammatory or metabolic diseases." During the research, prof. Mazzone's lab collaborated closely with several domestic and foreign researchers. In particular, the German ISAS lab (Dortmund) and the Leuven University Hospital played decisive roles, with the latter providing the human cancer samples necessary for the research. In these samples, the researchers discovered high expressions of PP2A/B55 in tumors compared to healthy tissues. Prof. Massimiliano Mazzone (VIB-KU Leuven): "This leads us to the conclusion that PP2A/B55 is a promising potential target for cancer therapy. That is why we started working together with an interested partner to study the potential of specific drugs against PP2A/B55. The ultimate goal is to design molecules that block the function of this phosphatase, thereby fighting cancer in a targeted way." On top of new cancer treatment perspectives, these findings may also lead to new biomarkers: the phosphorylation status of PHD2 might be instrumental to understanding a tumor's transformation process and, consequently, to select the appropriate treatment. Prof. Massimiliano Mazzone (VIB-KU Leuven): "To fully understand all the ins and outs of these processes, we also need to take a closer look at the tumor microenvironment and the immune system. After all, they strongly impact tumor growth. As we speak, we are defining the role of PP2A/B55 in both the tumor microenviro

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