Ras Activity Levels Control the Development of Pancreatic Diseases

Ji, Baoan; Tsou, L.; Wang, Huamin; Gaiser, Sebastian; Chang, David Z.; Daniluk, Jarosław; Bi, Yan; Grote, Tobias; Longnecker, Daniel S.; Logsdon, Craig D.

doi:10.1053/j.gastro.2009.05.052

Cited by 180 publications

(187 citation statements)

References 38 publications

Supporting

Mentioning

174

Contrasting

Order By: Relevance

“…Similarly, physiological levels of oncogenic K-Ras expressed in adult pancreatic cells were without pathologic effect (9,10). In contrast, high levels of Ras activity very efficiently caused severe inflammation and a rapid progression to cancer (10). Therefore, it seems clear that activating Ras mutations simply do not by themselves induce sufficient Ras activity to pose a large risk for development of disease.…”

Section: Introductionmentioning

confidence: 99%

“…Ras mutations have also been reported to initiate hematopoietic malignancies in a dosedependent manner (8). Similarly, physiological levels of oncogenic K-Ras expressed in adult pancreatic cells were without pathologic effect (9,10). In contrast, high levels of Ras activity very efficiently caused severe inflammation and a rapid progression to cancer (10).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

et al. 2012

Self Cite

View full text Add to dashboard Cite

Genetic mutations that give rise to active mutant forms of Ras are oncogenic and found in several types of tumor. However, such mutations are not clear biomarkers for disease, since they are frequently detected in healthy individuals. Instead, it has become clear that elevated levels of Ras activity are critical for Ras-induced tumorigenesis. However, the mechanisms underlying the production of pathological levels of Ras activity are unclear. Here, we show that in the presence of oncogenic Ras, inflammatory stimuli initiate a positive feedback loop involving NF-κB that further amplifies Ras activity to pathological levels. Stimulation of Ras signaling by typical inflammatory stimuli was transient and had no long-term sequelae in wild-type mice. In contrast, these stimuli generated prolonged Ras signaling and led to chronic inflammation and precancerous pancreatic lesions (PanINs) in mice expressing physiological levels of oncogenic K-Ras. These effects of inflammatory stimuli were disrupted by deletion of inhibitor of NF-κB kinase 2 (IKK2) or inhibition of Cox-2. Likewise, expression of active IKK2 or Cox-2 or treatment with LPS generated chronic inflammation and PanINs only in mice expressing oncogenic K-Ras. The data support the hypothesis that in the presence of oncogenic Ras, inflammatory stimuli trigger an NF-κB-mediated positive feedback mechanism involving Cox-2 that amplifies Ras activity to pathological levels. Because a large proportion of the adult human population possesses Ras mutations in tissues including colon, pancreas, and lung, disruption of this positive feedback loop may be an important strategy for cancer prevention.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…Research has shown that the K-ras gene mutation rate in pancreatic cancer is approximately 90% (19). It has been found that a point mutation of codon 12 of the K-ras gene is an early event in pancreatic cancer (20). The clinical significance of the K-ras gene mutation for effective diagnosis of early pancreatic cancer may exceed imaging and cytology examination (21).…”

Section: Discussionmentioning

confidence: 99%

Induction of CTLs by DCs pulsed with K-ras mutant peptide on the surface of nanoparticles in the treatment of pancreatic cancer

Wang¹

2011

Oncol Rep

View full text Add to dashboard Cite

Abstract. the aim of this study was to investigate the role of specific cytotoxic T lymphocytes (CTLs) activated by dendritic cells (DCs) presenting cationic nanoparticles with the K-ras (12-Val) mutant peptide in the killing of different pancreatic cancer cell lines in vivo and in vitro. Peripheral blood DCs were induced by rhGM-CSF and IL-4 and cultured. DCs were sensitized by whole antigen of PANC-1 with expression of K-ras mutant, K-ras mutant peptide (K-ras+peptide) and cationic nanoparticles with K-ras mutant peptide (K-ras+peptide-CNP), respectively. Cell surface markers were measured by flow cytometry. Lymphocyte proliferation was detected by the 3 H-tdr test, and IL-12 and IFN-γ secretion was detected by ELISA. 125 I-UdR was used to measure the killing effect of CTLs. The antitumor activity of CTLs in tumor-bearing nude mouse models prepared with PANC-1 and SW1990 cells was evaluated. Results showed that, compared with K-ras+peptide, low concentrations of K-ras+peptide-CNP were effectively presented by DCs (P<0.05). CTLs induced by DCs pulsed with whole tumor antigen had a significantly greater killing effect (P<0.05) on PANC-1 and SW1990 pancreatic cancer cells compared with K-ras+peptide-and K-ras+peptide-CNP-induced CTLs. CTLs induced by DCs pulsed with K-ras+peptide and K-ras+peptide-CNP had a specific killing effect (P<0.05) on PANC-1 cells and no effect (P>0.05) on SW1990 cells. In conclusion, cationic nanoparticles with the K-ras (12-Val) mutant peptide can be effectively presented by DCs at a low concentration. CTLs induced by K-ras+peptide-CNP had specific killing activity for the pancreatic cancer cell line with the K-ras mutant and significantly inhibited tumor growth and increased the survival time of tumor-bearing nude mice. Although this study confirmed that whole cell antigen induced a good antitumor immune response, the possibility of immune tolerance and autoimmunity which has been previously proven contribute to the difficulty in the application of this DC vaccine.

show abstract

“…KC mice express endogenous levels of oncogenic Kras, and the tumor suppressor p53 has a tendency to be mutated or lost in the later stages of tumor development (Hingorani et al, 2003). In contrast, mice engineered to express high levels of oncogenic Kras in pancreatic cells or LGL model), rapidly lose p16 (Ji et al, 2009). These observations are consistent with those seen in patients, whereby pancreatic adenocarcinoma does not occur without the accumulation of multiple genetic alterations, potentially over the course of many years (Yachida et al, 2010).…”

Section: Krasmentioning

confidence: 99%

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

2015

Frontiers Research Topics

View full text Add to dashboard Cite

Purpose of the review: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer.Recent findings: Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer.Summary: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.

show abstract

Ras Activity Levels Control the Development of Pancreatic Diseases

Cited by 180 publications

References 38 publications

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

Induction of CTLs by DCs pulsed with K-ras mutant peptide on the surface of nanoparticles in the treatment of pancreatic cancer

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

Contact Info

Product

Resources

About