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Brennan A.J.,Peter MacCallum Cancer Center
Nature Nanotechnology | Year: 2017

Perforin is a key protein of the vertebrate immune system. Secreted by cytotoxic lymphocytes as soluble monomers, perforin can self-assemble into oligomeric pores of 10–20 nm inner diameter in the membranes of virus-infected and cancerous cells. These large pores facilitate the entry of pro-apoptopic granzymes, thereby rapidly killing the target cell. To elucidate the pathways of perforin pore assembly, we carried out real-time atomic force microscopy and electron microscopy studies. Our experiments reveal that the pore assembly proceeds via a membrane-bound prepore intermediate state, typically consisting of up to approximately eight loosely but irreversibly assembled monomeric subunits. These short oligomers convert to more closely packed membrane nanopore assemblies, which can subsequently recruit additional prepore oligomers to grow the pore size. © 2017 Nature Publishing Group

Vesely M.D.,University of Washington | Kershaw M.H.,Peter MacCallum Cancer Center | Kershaw M.H.,University of Melbourne | Kershaw M.H.,Monash University | And 3 more authors.
Annual Review of Immunology | Year: 2011

The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer. © 2011 by Annual Reviews. All rights reserved.

Kelleher F.C.,St Vincents University Hospital | Kelleher F.C.,Peter MacCallum Cancer Center
Carcinogenesis | Year: 2011

Objective: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. Method. PubMed search (2000-2010) and literature based references. Results: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. Conclusions: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer. © The Author 2010. Published by Oxford University Press. All rights reserved.

Prince H.M.,Peter MacCallum Cancer Center
Future oncology (London, England) | Year: 2013

Cutaneous T-cell lymphomas are relatively rare lymphomas and the most common form is mycosis fungoides. Its rare leukemic variant is Sezary syndrome. Advanced-stage disease is typically treated with bexarotene (a retinoid), IFN-α or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors that modify the epigenome are an attractive addition to the armamentarium. Based on two large Phase II studies, the US FDA approved intravenous romidepsin for patients with relapsed/refractory cutaneous T-cell lymphomas. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side-effect profile.

Campbell B.A.,Peter MacCallum Cancer Center
Current Hematologic Malignancy Reports | Year: 2013

The role of radiation therapy (RT) in the treatment of Stage I-II diffuse large B cell lymphoma (DLBCL) is controversial: consolidation RT improves local control, but does this translate into an overall survival benefit? The paucity of randomized clinical trials means that the debate surrounding the benefit of consolidation RT remains unresolved. To date, the published literature demonstrates that consolidation RT has dual advantages in patients stage I-II DLBCL: (1) to improve local control and progression-free survival, and (2) to spare additional cycles of chemotherapy in patient with favourable-risk disease. Critics of consolidation RT are often influenced by the profile of late toxicities that are associated with outdated RT techniques. In the current era of molecular-based targeted therapy and functional imaging, prospective randomized studies are required to answer this research question and to investigate risk-adapted treatment strategies for patients with stage I-II DLBCL. © 2013 Springer Science+Business Media New York.

Kinnane N.A.,Peter MacCallum Cancer Center
Supportive Care in Cancer | Year: 2012

Background: Although information seeking is encouraged by health care professionals as a positive coping strategy evidence suggests information needs of those affected by cancer are not always fully met. In response to the need for novel models of information provision and educational support for people affected by cancer, a hospital-based cancer information and support centre (CISC) was introduced into a tertiary cancer hospital. Professional support is provided by a cancer support nurse (CSN) with the clinical experience of working with cancer patients, whilst peer support is provided by volunteers. Materials and methods: A survey was developed to ascertain the perceptions and experiences of consumers (users) of a hospital-based CISC. The aim was to understand what information and support patients and families consider important and helpful in order to develop the service to reflect the needs of its users. During a 12-month period 111 surveys were distributed to users of the centre. Results: Sixty-nine surveys were returned (62.1%). Nearly all visits were motivated by the need to access (58/84.0%) information, indicating an unmet or changing need. The CSN initiated referrals to support services, both internal and community based, for 21 (53.9%) participants with whom there was contact. Contact with the CISC volunteers also resulted in internal or community-based referrals for 15 (32.6%) of participants. Of note, half of the participants (35/50.7%) reported seeking additional information from the internet as a consequence of having visited the CISC and/or having contact with the CSN or volunteer, in contrast to the six (8.7%) who had reported internet use for information prior to their first visit. Participants indicated a desire for the service to provide additional support to enhance self-care capacity and to do so alongside other people affected by cancer. Conclusions: Our study results support the capacity of a hospital-based CISC to provide a highly valued service that can broaden information options and meet changing information and support needs of people affected by cancer in an ongoing capacity. An experienced, qualified CSN in this setting is ideally positioned to screen for unmet information and support needs and deliver tailored education to support both inpatient and ambulatory care services. Information prescriptions have the potential to provide a 'directed information seeking approach' to those who visit a CISC. Through the use of information technology there is scope to develop information and support that expands beyond pamphlets and booklets. © 2011 Springer-Verlag.

Stagg J.,Peter MacCallum Cancer Center | Smyth M.J.,Peter MacCallum Cancer Center
Oncogene | Year: 2010

Adenosine triphosphate (ATP) is actively released in the extracellular environment in response to tissue damage and cellular stress. Through the activation of P2X and P2Y receptors, extracellular ATP enhances tissue repair, promotes the recruitment of immune phagocytes and dendritic cells, and acts as a co-activator of NLR family, pyrin domain-containing 3 (NLRP3) inflammasomes. The conversion of extracellular ATP to adenosine, in contrast, essentially through the enzymatic activity of the ecto-nucleotidases CD39 and CD73, acts as a negative-feedback mechanism to prevent excessive immune responses. Here we review the effects of extracellular ATP and adenosine on tumorigenesis. First, we summarize the functions of extracellular ATP and adenosine in the context of tumor immunity. Second, we present an overview of the immunosuppressive and pro-angiogenic effects of extracellular adenosine. Third, we present experimental evidence that extracellular ATP and adenosine receptors are expressed by tumor cells and enhance tumor growth. Finally, we discuss recent studies, including our own work, which suggest that therapeutic approaches that promote ATP-mediated activation of inflammasomes, or inhibit the accumulation of tumor-derived extracellular adenosine, may constitute effective new means to induce anticancer activity. © 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10.

Harvey K.F.,Peter MacCallum Cancer Center | Harvey K.F.,University of Melbourne | Zhang X.,Peter MacCallum Cancer Center | Zhang X.,University of Melbourne | And 2 more authors.
Nature Reviews Cancer | Year: 2013

The Hippo pathway controls organ size in diverse species, whereas pathway deregulation can induce tumours in model organisms and occurs in a broad range of human carcinomas, including lung, colorectal, ovarian and liver cancer. Despite this, somatic or germline mutations in Hippo pathway genes are uncommon, with only the upstream pathway gene neurofibromin 2 (NF2) recognized as a bona fide tumour suppressor gene. In this Review, we appraise the evidence for the Hippo pathway as a cancer signalling network, and discuss cancer-relevant biological functions, potential mechanisms by which Hippo pathway activity is altered in cancer and emerging therapeutic strategies. © 2013 Macmillan Publishers Limited. All rights reserved.

Cytotoxic lymphocytes serve a key role in immune homeostasis by eliminating virus-infected and transformed target cells through the perforin-dependent delivery of proapoptotic granzymes. However, the mechanism of granzyme entry into cells remains unresolved. Using biochemical approaches combined with time-lapse microscopy of human primary cytotoxic lymphocytes engaging their respective targets, we defined the time course of perforin pore formation in the context of the physiological immune synapse. We show that, on recognition of targets, calcium influx into the lymphocyte led to perforin exocytosis and target cell permeabilization in as little as 30 seconds. Within the synaptic cleft, target cell permeabilization by perforin resulted in the rapid diffusion of extracellular milieu-derived granzymes. Repair of these pores was initiated within 20 seconds and was completed within 80 seconds, thus limiting granzyme diffusion. Remarkably, even such a short time frame was sufficient for the delivery of lethal amounts of granzymes into the target cell. Rapid initiation of apoptosis was evident from caspase-dependent target cell rounding within 2 minutes of perforin permeabilization. This study defines the final sequence of events controlling cytotoxic lymphocyte immune defense, in which perforin pores assemble on the target cell plasma membrane, ensuring efficient delivery of lethal granzymes.

Thomas D.M.,Peter MacCallum Cancer Center
Journal of Pathology | Year: 2011

Next-generation sequencing technologies are having an enormous impact on mapping mutations in cancer. However, it is unclear to what extent mutations in genes are shared between cancer types, and to what extent these are unique to different cancers. While the mapping of mutations is almost saturated in common cancer types, the study of rare tumours offers surprising insights into pathways that are deranged in cancer. The paper by Amary et al. in this issue of the Journal of Pathology illustrates the value of studying uncommon cancer types. The authors report on a startlingly high incidence of IDH1/2 mutations in cartilaginous tumours. This finding not only represent a major step forward in mapping the molecular pathogenesis of these tumours, but provides further evidence of the intriguing roles of metabolic pathways in carcinogenesis. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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