K-ras oncogene subtype mutations are associated with survival but not expression of p53, p16INK4A, p21WAF-1, cyclin D1, erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma

Kawesha, Anthony; Ghaneh, Paula; Andrén‐Sandberg, Åke; Ögraed, Dagfinn; Skar, Robert; Dawiskiba, Sigmund; Evans, James D.; Campbell, Fiona; Lemoine, Nicholas R.; Neoptolemos, John P.

doi:10.1002/1097-0215(20001120)89:6<469::aid-ijc1>3.0.co;2-l

Cited by 137 publications

(112 citation statements)

References 37 publications

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“…Moreover, in this paper, a combination of node-negativity and lack of perineural or duodenal invasion constituted a significant prognostic marker (Nitecki et al, 1995). Finally, Kawesha et al (2000) demonstrated that significant prognostic factors in pancreatic cancer patients were TNM stage of disease and lymph node involvement. In addition, preoperative estimation of tumour size and lymph node involvement is difficult.…”

Section: Discussionmentioning

confidence: 57%

Nuclear and cytoplasmic expression of survivin in 67 surgically resected pancreatic cancer patients

et al. 2005

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Pancreatic cancer is one of the most aggressive gastrointestinal cancer with less than 10% long-term survivors. The apoptotic pathway deregulation is a postulated mechanism of carcinogenesis of this tumour. The present study investigated the prognostic role of apoptosis and apoptosis-involved proteins in a series of surgically resected pancreatic cancer patients. All patients affected by pancreatic adenocarcinoma and treated with surgical resection from 1988 to 2003 were considered for the study. Patients' clinical data and pathological tumour features were recorded. Survivin and Cox-2 expression were evaluated by immunohistochemical staining. Apoptotic cells were identified using the TUNEL method. Tumour specimen of 67 resected patients was included in the study. By univariate analysis, survival was influenced by Survivin overexpression. The nuclear Survivin overexpression was associated with better prognosis (P ¼ 0.0009), while its cytoplasmic overexpression resulted a negative prognostic factor (P ¼ 0.0127). Also, the apoptotic index was a statistically significant prognostic factor in a univariate model (P ¼ 0.0142). By a multivariate Cox regression analysis, both the nuclear (P ¼ 0.002) and cytoplasmic (P ¼ 0.040) Survivin overexpression maintained the prognostic statistical value. This is the first study reporting a statistical significant prognostic relevance of nuclear and cytoplasmic Survivin overexpression in pancreatic cancer. In particular, patients with high nuclear Survivin staining showed a longer survival, whereas patients with high cytoplasmic Survivin staining had a shorter overall survival.

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Section: Discussionmentioning

confidence: 57%

Nuclear and cytoplasmic expression of survivin in 67 surgically resected pancreatic cancer patients

et al. 2005

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“…These results indicated that E1A of AxdA (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) and dl 1101 with the partial deletion of the p300 binding site showed reduced binding capacity to p300, and a weaker inhibitory effect on VEGF expression in the hypoxic condition as compared to wild E1A binding to p300.…”

Section: Western Blotting and Immunoprecipitation Of E1a P300 Proteinmentioning

confidence: 92%

“…These are the activation of KRAS oncogene (more than 80% of cases), and mutational inactivation of the tumor suppressor genes, TP53 (50-70% of patients), MTS1 (more than 80% of patients), and SMAD4 (55% of patients). [4][5][6][7] These genetic alterations are candidate targets for the development of novel therapeutic approaches including virus-mediated gene therapy. 8,9 Cancer gene therapy can be directed at different components of the tumor biology.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region

et al. 2005

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An adenovirus (Adv) retaining normal E1A but lacking the 55 kDa E1B protein replicates preferentially in TP53-deficient cancer cells including pancreatic cancer cell lines, resulting in the oncolysis of the tumor. When tumor cells are exposed to hypoxia, hypoxia-inducible factor-1a (HIF-1a) is stabilized and activated to promote the transcription of several genes such as vascular endothelial growth factor (VEGF), but in the presence of E1A hypoxia-induced VEGF m-RNA synthesis is inhibited by E1A binding to p300. In this study, we demonstrated that the cancer cells infected with a mutant Adv in which the p300 binding site in E1A was partially deleted induced a higher expression level of VEGF as compared to those of Adv with normal E1A. An immunoprecipitation study for E1A confirmed that mutant E1A had a reduced binding capacity for p300. Although the expressions of HIF-1a m-RNA were almost the same in both cancer cells infected with the mutant Adv and those with the wild Adv, the amount of HIF-1a protein in cancer cells infected with the wild E1A Adv was lower than in those infected with the mutant E1A type Adv. In vivo, in contrast to the angiogenesis treated with mutant E1A, wild-E1A inhibited tumor angiogenesis significantly. These results suggested that E1A suppressed the production of VEGF and inhibited tumor angiogenesis by binding with p300, resulting in the inhibition of the HIF1a-mediated transcription of genes through binding to HRE. This study demonstrates, for the first time, the effect of an oncolytic replication-competent Adv in inhibiting tumor angiogenesis.

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“…For pancreatic cancer, K-ras mutations have been reported as a negative prognostic factor after surgery and adjuvant chemoradiation (16) or surgery alone (17). In addition to oncogenic mutations in K-ras, signaling through Ras proteins can be stimulated by epidermal growth factor receptor (EGFR) ligand overexpression and EGFR activation (18,19), and HER-2/neu overexpression (20).…”

Section: Introductionmentioning

confidence: 99%

Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras

et al. 2005

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Activating K-ras mutations are found in f90% of pancreatic carcinomas and may contribute to the poor prognosis of these tumors. Because radiotherapy is frequently used in pancreatic cancer treatment, we assessed the contribution of oncogenic K-ras signaling to pancreatic cancer radiosensitivity. Seven human pancreatic carcinoma lines with activated K-ras and two cell lines with wild-type ras were used to examine clonogenic cell survival after Ras inhibition. Ras inhibition was accomplished by small interfering RNA (siRNA) knockdown of K-ras expression and by blocking Ras processing using a panel of prenyltransferase inhibitors of differing specificity for the two prenyltransferases that modify K-Ras. K-ras knockdown by siRNA or inhibition of prenyltransferase activity resulted in radiation sensitization in vitro and in vivo in tumors with oncogenic K-ras mutations. Inhibition of farnesyltransferase alone was sufficient to radiosensitize most K-ras mutant tumors, although K-Ras prenylation was not blocked. These results show that inhibition of activated K-Ras can promote radiation killing of pancreatic carcinoma in a superadditive manner. The finding that farnesyltransferase inhibition alone radiosensitizes tumors with K-ras mutations implies that a farnesyltransferase inhibitor-sensitive protein other than K-Ras may contribute to survival in the context of mutant K-ras. Farnesyltransferase inhibitors could therefore be of use as sensitizers for pancreatic carcinoma radiotherapy. (Cancer Res 2005; 65(18): 8433-41)

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K-ras oncogene subtype mutations are associated with survival but not expression of p53, p16INK4A, p21WAF-1, cyclin D1, erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma

Cited by 137 publications

References 37 publications

Nuclear and cytoplasmic expression of survivin in 67 surgically resected pancreatic cancer patients

Nuclear and cytoplasmic expression of survivin in 67 surgically resected pancreatic cancer patients

Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region

Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras

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