Sir Peter MacCallum Department of Oncology - Research Publications
Now showing items 1-12 of 226
Physiological expression of the PI3K-activating mutation Pik3ca(H1047R) combines with Apc loss to promote development of invasive intestinal adenocarcinomas in mice
PIK3CA, the gene encoding the p110 alpha catalytic subunit of PI3K (phosphoinositide 3-kinase), is mutated in approximately 20% of sporadic CRCs (colorectal cancers), but the role of these mutations in the pathogenesis of CRC remains unclear. In the present study we used a novel mouse model to investigate the role of the Pik3ca(H1047R) mutation, the most common PIK3CA mutation in CRC, during the development and progression of intestinal cancer. Our results demonstrate that Pik3ca(H1047R), when expressed at physiological levels, is insufficient to initiate intestinal tumorigenesis; however, in the context of Apc (adenomatous polyposis coli) loss, which is observed in 80% of CRCs and by itself results in benign intestinal adenomas, the Pik3ca(H1047R) mutation promotes the development of highly aggressive and invasive adenocarcinomas in both the small and large intestines. The results of the present study show that an activating Pik3ca mutation can act in tandem with Apc loss to drive the progression of gastrointestinal cancer and thus this disease may be susceptible to therapeutic targeting using PI3K pathway inhibitors.
Patterns of chemotherapy treatment for women with invasive epithelial ovarian cancer - A population-based study
Objective. Ovarian cancer five-year survival is poor at <40%. In the absence of effective screening or new treatments, ensuring all women receive optimal treatment is one avenue to improve survival. There is little population-based information regarding the primary chemotherapy treatment that women with epithelial ovarian cancer receive. This information is essential to identify potential gaps in care.Methods. Cancer registries identified all women diagnosed with invasive epithelial ovarian cancer in Australia in 2005 (n = 1192). Histopathology, chemotherapy and comorbidity information was abstracted from medical records. Multivariable logistic regression was used to identify factors associated with chemotherapy commencement, regimen, and completion.Results. Women > 70 years (p < 0.0001), those with high-grade, stage IA/IB cancers (vs. stages IC-IV, p = 0.003) and those with mucinous cancers (p = 0.0002) were less likely to start chemotherapy. Most treated women received platinum-based drugs (97%), but only 68% received combination carboplatin-paclitaxel and only half completed six cycles without treatment modification/delay. Approximately 19% received single-agent carboplatin: mostly those aged > 70 (p<0.0001) and/or with co-morbidities (p<0.0001). Age was the strongest predictor of completing six cycles of combination therapy.Conclusions. For specific patient groups, particularly older women, there is notable variation from standard treatment. Understanding how treatment variations affect survival and determining optimal regimens for these groups are research priorities.
Genomic Aberrations of BRCA1-Mutated Fallopian Tube Carcinomas
(ELSEVIER SCIENCE INC, 2014-06-27)
Intraepithelial carcinomas of the fallopian tube are putative precursors to high-grade serous carcinomas of the ovary and peritoneum. Molecular characterization of these early precursors is limited but could be the key to identifying tumor biomarkers for early detection. This study presents a genome-wide copy number analysis of occult fallopian tube carcinomas identified through risk-reducing prophylactic oophorectomy from three women with germline BRCA1 mutations, demonstrating that extensive genomic aberrations are already established at this early stage. We found no indication of a difference in the Level of genomic aberration observed in fallopian tube carcinomas compared with high-grade serous ovarian carcinomas. These findings suggest that spread to the peritoneal cavity may require no or very little further tumor evolution, which raises the question of what is the real window of opportunity to detect high-grade serous peritoneal carcinoma arising from the fallopian tube before it spreads. Nonetheless, the similarity of the genomic aberrations to those observed in high-grade serous ovarian carcinomas suggests that genetic biomarkers identified in late-stage disease may be relevant for early detection.
Combined Anti-CD40 and Anti-IL-23 Monoclonal Antibody Therapy Effectively Suppresses Tumor Growth and Metastases
(AMER ASSOC CANCER RESEARCH, 2014-05-27)
Tumor-induced immunosuppression remains one of the major obstacles to many potentially effective cancer therapies and vaccines. Host interleukin (IL)-23 suppresses the immune response during tumor initiation, growth, and metastases, and neutralization of IL-23 causes IL-12-dependent antitumor effects. Here, we report that combining agonistic anti-CD40 monoclonal antibodies (mAb) to drive IL-12 production and anti-IL-23 mAbs to counter the tumor promoting effects of IL-23 has greater antitumor activity than either agent alone. This increased antitumor efficacy was observed in several experimental and spontaneous lung metastases models as well as in models of de novo carcinogenesis. The combination effects were dependent on host IL-12, perforin, IFN-gamma, natural killer, and/or T cells and independent of host B cells and IFN-alpha beta sensitivity. Interestingly, in the experimental lung metastases tumor models, we observed that intracellular IL-23 production was specifically restricted to MHC-II(hi)CD11c(+)CD11b(+) cells. Furthermore, an increase in proportion of these IL-23-producing cells was detected only in tumor models where IL-23 neutralization was therapeutic. Overall, these data suggest the clinical potential of using anti-CD40 (push) and anti-IL-23 mAbs (pull) to tip the IL-12/23 balance in established tumors.
Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis
(COMPANY OF BIOLOGISTS LTD, 2014-03-27)
The VEGFC/VEGFR3 signaling pathway is essential for lymphangiogenesis (the formation of lymphatic vessels from preexisting vasculature) during embryonic development, tissue regeneration and tumor progression. The recently identified secreted protein CCBE1 is indispensible for lymphangiogenesis during development. The role of CCBE1 orthologs is highly conserved in zebrafish, mice and humans with mutations in CCBE1 causing generalized lymphatic dysplasia and lymphedema (Hennekam syndrome). To date, the mechanism by which CCBE1 acts remains unknown. Here, we find that ccbe1 genetically interacts with both vegfc and vegfr3 in zebrafish. In the embryo, phenotypes driven by increased Vegfc are suppressed in the absence of Ccbe1, and Vegfc-driven sprouting is enhanced by local Ccbe1 overexpression. Moreover, Vegfc- and Vegfr3-dependent Erk signaling is impaired in the absence of Ccbe1. Finally, CCBE1 is capable of upregulating the levels of fully processed, mature VEGFC in vitro and the overexpression of mature VEGFC rescues ccbe1 loss-of-function phenotypes in zebrafish. Taken together, these data identify Ccbe1 as a crucial component of the Vegfc/Vegfr3 pathway in the embryo.
Scribble regulates an EMT polarity pathway through modulation of MAPK-ERK signaling to mediate junction formation
(COMPANY OF BIOLOGISTS LTD, 2013-09-27)
The crucial role the Crumbs and Par polarity complexes play in tight junction integrity has long been established, however very few studies have investigated the role of the Scribble polarity module. Here, we use MCF10A cells, which fail to form tight junctions and express very little endogenous Crumbs3, to show that inducing expression of the polarity protein Scribble is sufficient to promote tight junction formation. We show this occurs through an epithelial-to-mesenchymal (EMT) pathway that involves Scribble suppressing ERK phosphorylation, leading to downregulation of the EMT inducer ZEB. Inhibition of ZEB relieves the repression on Crumbs3, resulting in increased expression of this crucial tight junction regulator. The combined effect of this Scribble-mediated pathway is the upregulation of a number of junctional proteins and the formation of functional tight junctions. These data suggests a novel role for Scribble in positively regulating tight junction assembly through transcriptional regulation of an EMT signaling program.
The Role of the Apoptotic Machinery in Tumor Suppression
(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2012-11-27)
Multicellular organisms have evolved processes to prevent abnormal proliferation or inappropriate tissue infiltration of cells, and these tumor suppressive mechanisms serve to prevent tissue hyperplasia, tumor development, and metastatic spread of tumors. These include potentially reversible processes such as cell cycle arrest and cellular senescence, as well as apoptotic cell death, which in contrast eliminates dangerous cells that may initiate tumor development. Tumor suppressive processes are organized as complex, extensive signaling networks, controlled by central "nodes." These "nodes" are prominent tumor suppressors, such as P53 or PTEN, whose loss is responsible for the development of the majority of human cancers. In this review we discuss the processes by which some of these prominent tumor suppressors trigger apoptotic cell death and how this process protects us from cancer development.
Targeting Oncogenic Drivers and the Immune System in Melanoma
(AMER SOC CLINICAL ONCOLOGY, 2013-02-27)
Melanoma is one of the most common cancers in Western countries but has defied the trend of reductions in age-adjusted mortality observed in most other cancers in recent years. Biologically, melanoma is characterized by a high propensity to metastasize at low tumor volumes necessitating the need for effective drug therapies to support efforts in prevention and early detection for reducing mortality. Efforts to study the clinical biology of melanoma have led to a new understanding of the disease, with genomic studies identifying several targetable oncogenes, in particular the protein kinases BRAF and KIT. Biologic studies have also identified a variety of immunologic targets, including the programmed death 1 (PD-1) and cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitory molecules expressed on T lymphocytes. After several decades of clinical trials that failed to demonstrate improvement in overall survival in patients with advanced melanoma, small molecule inhibitors of BRAF or MEK and inhibition of CTLA-4 can improve survival in patients with advanced disease. These early clinical studies have provided a great opportunity to improve mortality in melanoma with the significant potential of combinations of signaling inhibitors or signaling inhibitors combined with immunologic agents, particularly when used in the adjuvant setting, and to transform the care of patients with this most challenging of cancers. J Clin Oncol 31:499-506.
NLRP3 Suppresses NK Cell-Mediated Responses to Carcinogen-Induced Tumors and Metastases
(AMER ASSOC CANCER RESEARCH, 2012-11-27)
The NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response upon infectious insults or tissue injury and damage. However, the role of the NLRP3 inflammasome in natural killer (NK) cell-mediated control of tumor immunity is poorly understood. Here, we show in a model of chemical-induced carcinogenesis and a series of experimental and spontaneous metastases models that mice lacking NLRP3 display significantly reduced tumor burden than control wild-type (WT) mice. The suppression of spontaneous and experimental tumor metastases and methylcholanthrene (MCA)-induced sarcomas in mice deficient for NLRP3 was NK cell and IFN-gamma-dependent. Focusing on the amenable B16F10 experimental lung metastases model, we determined that expression of NLRP3 in bone marrow-derived cells was necessary for optimal tumor metastasis. Tumor-driven expansion of CD11b(+)Gr-1(intermediate) (Gr-1(int)) myeloid cells within the lung tumor microenvironment of NLRP3(-/-) mice was coincident with increased lung infiltrating activated NK cells and an enhanced antimetastatic response. The CD11b(+)Gr-1(int) myeloid cells displayed a unique cell surface phenotype and were characterized by their elevated production of CCL5 and CXCL9 chemokines. Adoptive transfer of this population into WT mice enhanced NK cell numbers in, and suppression of, B16F10 lung metastases. Together, these data suggested that NLRP3 is an important suppressor of NK cell-mediated control of carcinogenesis and metastases and identify CD11b(+)Gr-1(int) myeloid cells that promote NK cell antimetastatic function. Cancer Res; 72(22); 5721-32.
The interaction between murine melanoma and the immune system reveals that prolonged responses predispose for autoimmunity
(LANDES BIOSCIENCE, 2013-02-27)
An assessment of antitumor immunity versus autoimmunity as provoked by the specific depletion of FOXP3(+) Tregs is now possible with the development of Foxp3-diphtheria toxin receptor-like transgenic mouse models. We have used the poorly immunogenic B16F10 melanoma model to characterize a very heterogeneous antitumor effect of the immune response induced by Treg depletion. Depletion and neutralization studies demonstrated the importance of host T cells and interferon gamma (IFN gamma) in mediating the antitumor response developing in Treg-depleted mice. Such a response correlated with increased proliferation of granzyme B-and IFN.-producing T cells in the tumor. Furthermore, enhanced antitumor immunity modulated the expression of MHC Class I molecules by B16F10 melanoma cells in Treg-depleted mice. Since Foxp3(+) Treg depletion induced a significantly heterogeneous antitumor response, for the first time we were able to assess antitumor immunity and autoimmunity across different groups of responding mice. Strikingly, the duration of the tumor-immune system interaction provoked in individual Treg-depleted mice positively correlated with their propensity to develop vitiligo. A rapid complete tumor rejection was not associated with the development of autoimmunity, however, a proportion of mice that suppressed, but did not effectively clear, B16F10 melanoma did develop vitiligo. The significant implication is that approaches that combine with Treg depletion to rapidly reject tumors may also diminish autoimmune toxicities.
Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma
(LANDES BIOSCIENCE, 2012-11-27)
Recent evidence demonstrates that the efficacy of conventional anticancer therapies including chemotherapy requires a functional immune system. Here, we addressed the possibility that the antitumor effect of a selective Smoothened antagonist and Hedgehog (Hh) pathway inhibitor (LDE225), a promising anticancer drug, might at least partially depend on the immune system. To this aim, we used tumor cell lines derived from a murine model of radiation-induced osteosarcoma. In vitro treatment of osteosarcoma cells with LDE225 resulted in a decreased ability of tumor cells to proliferate, but had no effect on their viability. Flow cytometry analysis demonstrated that LDE225-treatment did not detectably modulate the immunogenicity of tumor cells. Moreover, LDE225 did not display any pro-apoptotic properties on osteosarcoma cells, highlighting that its antitumor profile mainly derives from a cytostatic effect. Furthermore, calreticulin exposure, a key feature of immunogenic cell death, was not provoked by LDE225, neither alone nor combined with recognized immunogenic drugs. Finally, the oral administration of LDE225 to osteosarcoma-bearing mice did significantly delay the tumor growth even in an immunocompromised setting. These data suggest that inhibiting Hh signaling can control osteosarcoma cell proliferation but does not modulate the immunogenic profile of these cells.
The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity
(NATURE PUBLISHING GROUP, 2014)
Apoptosis of pancreatic beta cells is a feature of type 2 diabetes and its prevention may have therapeutic benefit. High glucose concentrations induce apoptosis of islet cells, and this requires the proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins Bim and Puma. We studied the stress pathways induced by glucotoxicity in beta cells that result in apoptosis. High concentrations of glucose or ribose increased expression of the transcription factor CHOP (C/EBP homologous protein) but not endoplasmic reticulum (ER) chaperones, indicating activation of proapoptotic ER stress signaling. Inhibition of ER stress prevented ribose-induced upregulation of Chop and Puma mRNA, and partially protected islets from glucotoxicity. Loss of Bim or Puma partially protected islets from the canonical ER stressor thapsigargin. The antioxidant N-acetyl-cysteine also partially protected islets from glucotoxicity. Islets deficient in both Bim and Puma, but not Bim or Puma alone, were significantly protected from killing induced by the mitochondrial reactive oxygen species donor rotenone. Our data demonstrate that high concentrations of glucose induce ER and oxidative stress, which causes cell death mediated by Bim and Puma. We observed significantly higher Bim and Puma mRNA in islets of human donors with type 2 diabetes. This indicates that inhibition of Bim and Puma, or their inducers, may prevent beta-cell destruction in type 2 diabetes.