Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult Mice

Guerra, Carmen; Schuhmacher, Alberto J.; Cañamero, Marta; Grippo, Paul J.; Verdaguer, Lena; Pérez-Gallego, Lucía; Dubus, Pierre; Sandgren, Eric P.; Barbacid, Mariano

doi:10.1016/j.ccr.2007.01.012

Cited by 1,051 publications

(1,061 citation statements)

References 41 publications

Supporting

Mentioning

984

Contrasting

Unclassified

Order By: Relevance

“…Immature acinar cells are more susceptible to the transforming effects of K-ras activation than mature acinar cells in vivo (45). Providing new insights into the identity of the immature acinar cells targeted during cancer development (45) is an important issue to understand the nature of pancreatic cancer precursors.…”

Section: Discussionmentioning

confidence: 99%

Murine Embryonic Stem Cell–Derived Pancreatic Acinar Cells Recapitulate Features of Early Pancreatic Differentiation

et al. 2008

View full text Add to dashboard Cite

Background & Aims-Acinar cells constitute 90% of the pancreas epithelium, are polarized, and secrete digestive enzymes. These cells play a crucial role in pancreatitis and pancreatic cancer. However, there are no models to study normal acinar cell differentiation in vitro. The aim of this work was to generate and characterize purified populations of pancreatic acinar cells from embryonic stem cells (ES).

show abstract

Section: Discussionmentioning

confidence: 99%

Murine Embryonic Stem Cell–Derived Pancreatic Acinar Cells Recapitulate Features of Early Pancreatic Differentiation

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Members of the RAS family are the most frequently mutated dominant oncogenes in human cancer, and activated oncogenic components of the RAS-RAF signalling pathway, in turn, induce the production of tumour-promoting inflammatory chemokines and cytokines [11][12][13] . Another oncogene, MYC, encodes a transcription factor that is over expressed in many human tumours; deregulated expression of this gene initiates and maintains key aspects of the tumour phenotype.…”

mentioning

confidence: 99%

“…This interplay is likely to occur in pancreatic carcinoma, in which both pancreatitis and mutations in the gene encoding K-RAS are frequently found. In a relevant mouse model, adult mice are resistant to mutated Kras-induced pancreatic carcinogenesis 11 . Both mild chronic pancreatitis (possibly mirroring the clinical epidemiology) and mutated Kras are required to induce pancreatic intra-epithelial neoplasia and invasive ductal carcinoma 11 .…”

mentioning

confidence: 99%

“…In a relevant mouse model, adult mice are resistant to mutated Kras-induced pancreatic carcinogenesis 11 . Both mild chronic pancreatitis (possibly mirroring the clinical epidemiology) and mutated Kras are required to induce pancreatic intra-epithelial neoplasia and invasive ductal carcinoma 11 . Thus, although the RAS-RAF pathway 12,13 can drive tumour-promoting inflammation to a certain extent, an extrinsic inflammatory condition (pancreatitis) is needed to drive carcinogenesis in mice and presumably in humans.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cancer-related inflammation

Mantovani

Allavena

Sica

et al. 2008

Nature

9,558

112

7,817

View full text Add to dashboard Cite

Links between cancer and inflammation were first made in the nineteenth century, on the basis of observations that tumours often arose at sites of chronic inflammation and that inflammatory cells were present in biopsied samples from tumours 1 . The idea that these processes are connected was out of favour for more than a century, but there has been a recent resurgence in interest. Several lines of evidence 1-4 (Box 1) -based on a range of findings, from epidemiological studies of patients to molecular studies of genetically modified mice -have led to a general acceptance that inflammation and cancer are linked.Epidemiological studies have shown that chronic inflammation predisposes individuals to various types of cancer. It is estimated that underlying infections and inflammatory responses are linked to 15-20% of all deaths from cancer worldwide 1 . There are many triggers of chronic inflammation that increase the risk of developing cancer. Such triggers include microbial infections (for example, infection with Helicobacter pylori is associated with gastric cancer and gastric mucosal lymphoma), autoimmune diseases (for example, inflammatory bowel disease is associated with colon cancer) and inflammatory conditions of unknown origin (for example, prostatitis is associated with prostate cancer). Accordingly, treatment with non-steroidal anti-inflammatory agents decreases the incidence of, and the mortality that results from, several tumour types [5][6][7] .The hallmarks of cancer-related inflammation include the presence of inflammatory cells and inflammatory mediators (for example, chemokines, cytokines and prostaglandins) in tumour tissues, tissue remodelling and angiogenesis similar to that seen in chronic inflammatory responses, and tissue repair. These signs of 'smouldering' inflammation 2 are also present in tumours for which a firm causal relationship to inflammation has not been established (for example, breast tumours). Indeed, inflammatory cells and mediators are present in the microenvironment of most, if not all, tumours, irrespective of the trigger for development.Studies of genetically modified mice, adoptive-transfer experiments in mice, and analyses of human tumours have allowed researchers to begin to unravel the molecular pathways that link inflammation and cancer. Here we review current knowledge of the molecular and cellular pathways that link inflammation and cancer, and we describe how these pathways suppress effective antitumour immunity during tumour progression. We also discuss how cancer-related inflammation affects many aspects of malignancy, including the proliferation and survival of malignant cells, angiogenesis (which is required for the survival of cells within tumours of a certain size), tumour metastasis, and tumour response to chemotherapeutic drugs and hormones.Advances in understanding the genetic pathways involved in cancer have led to the development of a range of therapies that target malignant cells. Understanding the pathways involved in cancer-related inflammation could ...

show abstract

“…1 Recently, epidemiological and experimental data have demonstrated a close connection between chronic pancreatitis and pancreatic cancer. 2,3 However, the mechanisms involved are still far from defined.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

et al. 2016

View full text Add to dashboard Cite

Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Aca and PP2Acb isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-kB (NF-kB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Aca overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-kB pathway in vitro. LPS and MCM induced IKK and IkB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKa attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-kB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-kB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-kB pathway-dependent PP2Ac repression.

show abstract

Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult Mice

Cited by 1,051 publications

References 41 publications

Murine Embryonic Stem Cell–Derived Pancreatic Acinar Cells Recapitulate Features of Early Pancreatic Differentiation

Murine Embryonic Stem Cell–Derived Pancreatic Acinar Cells Recapitulate Features of Early Pancreatic Differentiation

Cancer-related inflammation

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

Contact Info

Product

Resources

About