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Port Glasgow, United Kingdom

Lunardi S.,University of Oxford | Jamieson N.B.,Royal Infirmary | Lim S.Y.,University of Oxford | Griffiths K.L.,University of Oxford | And 13 more authors.
Oncotarget | Year: 2014

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines and growth factors. IP-10/ CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 was elevated in human PDAC specimens, and positively correlated with high stroma content. Furthermore, gene expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, high IP-10 expression levels correlated with decreased median overall survival. Finally, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with PDAC. Our findings suggest that, in pancreatic cancer, CXCR3+ Tregs can be recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects. Source

Willder J.M.,University of Glasgow | Heng S.J.,University of Glasgow | McCall P.,University of Glasgow | Adams C.E.,University of Glasgow | And 8 more authors.
British Journal of Cancer | Year: 2013

Background:Prostate cancer cell growth is dependent upon androgen receptor (AR) activation, which is regulated by specific kinases. The aim of the current study is to establish if AR phosphorylation by Cdk1 or ERK1/2 is of prognostic significance.Methods:Scansite 2.0 was utilised to predict which AR sites are phosphorylated by Cdk1 and ERK1/2. Immunohistochemistry for these sites was then performed on 90 hormone-naive prostate cancer specimens. The interaction between Cdk1/ERK1/2 and AR phosphorylation was investigated in vitro using LNCaP cells.Results:Phosphorylation of AR at serine 515 (pAR S515) and PSA at diagnosis were independently associated with decreased time to biochemical relapse. Cdk1 and pCdk1 161, but not ERK1/2, correlated with pAR S515. High expression of pAR S515 in patients with a PSA at diagnosis of ≤20 ng ml-1 was associated with shorter time to biochemical relapse (P=0.019). This translated into a reduction in disease-specific survival (10-year survival, 38.1% vs 100%, P<0.001). In vitro studies demonstrated that treatment with Roscovitine (a Cdk inhibitor) caused a reduction in pCdk1 161 expression, pAR S515 expression and cellular proliferation.Conclusion:In prostate cancer patients with PSA at diagnosis of ≤20 ng ml-1, phosphorylation of AR at serine 515 by Cdk1 may be an independent prognostic marker. © 2013 Cancer Research UK. All rights reserved. Source

Phesse T.J.,University of Cardiff | Phesse T.J.,Ludwig Institute for Cancer Research | Phesse T.J.,Walter and Eliza Hall Institute of Medical Research | Phesse T.J.,University of Melbourne | And 11 more authors.
Cell Death and Differentiation | Year: 2014

Recent studies have suggested that C-MYC may be an excellent therapeutic cancer target and a number of new agents targeting C-MYC are in preclinical development. Given most therapeutic regimes would combine C-MYC inhibition with genotoxic damage, it is important to assess the importance of C-MYC function for DNA damage signalling in vivo. In this study, we have conditionally deleted the c-Myc gene in the adult murine intestine and investigated the apoptotic response of intestinal enterocytes to DNA damage. Remarkably, c-Myc deletion completely abrogated the immediate wave of apoptosis following both ionizing irradiation and cisplatin treatment, recapitulating the phenotype of p53 deficiency in the intestine. Consistent with this, c-Myc-deficient intestinal enterocytes did not upregulate p53. Mechanistically, this was linked to an upregulation of the E3 Ubiquitin ligase Mdm2, which targets p53 for degradation in c-Myc-deficient intestinal enterocytes. Further, low level overexpression of c-Myc, which does not impact on basal levels of apoptosis, elicited sustained apoptosis in response to DNA damage, suggesting c-Myc activity acts as a crucial cell survival rheostat following DNA damage. We also identify the importance of MYC during DNA damage-induced apoptosis in several other tissues, including the thymus and spleen, using systemic deletion of c-Myc throughout the adult mouse. Together, we have elucidated for the first time in vivo an essential role for endogenous c-Myc in signalling DNA damage-induced apoptosis through the control of the p53 tumour suppressor protein. © 2014 Macmillan Publishers Limited All rights reserved. Source

Pommier R.M.,French Institute of Health and Medical Research | Pommier R.M.,French National Center for Scientific Research | Pommier R.M.,University of Lyon | Pommier R.M.,Center Leon Berard | And 62 more authors.
Cancer Research | Year: 2015

The transcription accessory factor TIF1g/TRIM33/RFG7/PTC7/Ectodermin functions as a tumor suppressor that promotes development and cellular differentiation. However, its precise function in cancer has been elusive. In the present study, we report that TIF1g inactivation causes cells to accumulate chromosomal defects, a hallmark of cancer, due to attenuations in the spindle assembly checkpoint and the post-mitotic checkpoint. TIF1g deficiency also caused a loss of contact growth inhibition and increased anchorage-independent growth in vitro and in vivo. Clinically, reduced TIF1g expression in human tumors correlated with an increased rate of genomic rearrangements. Overall, our work indicates that TIF1g exerts its tumor-suppressive functions in part by promoting chromosomal stability. © 2015 American Association for Cancer Research. Source

Cole A.M.,Beatson Institute of Cancer Research | Myant K.,Beatson Institute of Cancer Research | Ridgway R.A.,Beatson Institute of Cancer Research | Athineos D.,Beatson Institute of Cancer Research | And 9 more authors.
Cancer Research | Year: 2010

Inactivation of the Apc gene is recognized as the key early event in the development of sporadic colorectal cancer (CRC), where its loss leads to constitutive activation of β-catenin/T-cell factor 4 signaling and hence transcription of Wnt target genes such as c-Myc. Our and other previous studies have shown that although cyclin D1 is required for adenoma formation, it is not immediately upregulated following Apc loss within the intestine, suggesting that proliferation following acute Apc loss may be dependent on another D-type cyclin. In this study, we investigated the expression and functional relevance of cyclin D2 following Apc loss in the intestinal epithelium. Cyclin D2 is upregulated immediately following Apc loss, which corresponded with a significant increase in cyclin-dependent kinase 4 (CDK4) and hyperphosphorylated Rb levels. Deficiency of cyclin D2 resulted in a reduction in enterocyte proliferation and crypt size within Apc-deficient intestinal epithelium. Moreover, cyclin D2 dramatically reduced tumor growth and development in ApcMin/+ mice. Importantly, cyclin D2 knockout did not affect proliferation of normal enterocytes, and furthermore, CDK4/6 inhibition also suppressed the proliferation of adenomatous cells and not normal cells from ApcMin/+ mice. Taken together, these results indicate that cyclin D - CDK4/6 complexes are required for the efficient proliferation of cells with deregulated Wnt signaling, and inhibiting this complex may be an effective chemopreventative strategy in CRC. ©2010 AACR. Source

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