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Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence.
Cancer Cell. 2011 Jun 14; 19(6):728-39
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20 Jun 2011
New Finding, Technical Advance
DOI: 10.3410/f.11370957.12382055
Apart from further illustrating the role of inflammation in oncogenesis, this paper strongly advocates the use of conditional – rather than constitutive – genetically engineered mouse models for cancer research. It is of key importance that the genetic hits are delivered at the adult stage.
Most primary...Continue reading
Most primary...Continue reading
Apart from further illustrating the role of inflammation in oncogenesis, this paper strongly advocates the use of conditional – rather than constitutive – genetically engineered mouse models for cancer research. It is of key importance that the genetic hits are delivered at the adult stage.
Most primary pancreatic ductal adenocarcinomas (PDACs) in humans feature mutations in four or more genes/pathways (e.g. K-ras, CDKN2A, SMAD4, p53 {1,2}). In contrast, two genetic hits (e.g. in K-ras and p53) suffice to trigger full pancreatic oncogenesis in commonly used genetic mouse models for pancreatic cancer. This raises the question of whether the use of such mouse models for drug screening would result in reliable information concerning treatment of the human disease. Initial work by Barbacid and coworkers {3} showed that this discrepancy between human disease and mouse models is mainly due to the timing of the genetic hits: a mutation in K-ras was sufficient to trigger pancreatic neoplasia in neonatal mice but failed to induce lesions in adult mice (a setting more relevant as a model for sporadic oncogenesis in humans!). Their most recent paper demonstrates that this resistance to transformation still persists after two genetic hits: K-ras mutation in combination with inactivation of either CDKN2A or p53. Their work furthermore shows that chronic inflammation can overcome this blockade and predicts that inclusion of additional conditional genetic mutations in their model (although technically demanding) would have the same effect. In view of the supplementary finding that transient episodes of inflammation suffice to enable oncogenesis, it is tempting to speculate that the tumors developing in, for instance, K-ras.G12VxTrp53.lox mice have accumulated hits in additional genes, in particular Ink4a/Arf and SMAD4.
Most primary pancreatic ductal adenocarcinomas (PDACs) in humans feature mutations in four or more genes/pathways (e.g. K-ras, CDKN2A, SMAD4, p53 {1,2}). In contrast, two genetic hits (e.g. in K-ras and p53) suffice to trigger full pancreatic oncogenesis in commonly used genetic mouse models for pancreatic cancer. This raises the question of whether the use of such mouse models for drug screening would result in reliable information concerning treatment of the human disease. Initial work by Barbacid and coworkers {3} showed that this discrepancy between human disease and mouse models is mainly due to the timing of the genetic hits: a mutation in K-ras was sufficient to trigger pancreatic neoplasia in neonatal mice but failed to induce lesions in adult mice (a setting more relevant as a model for sporadic oncogenesis in humans!). Their most recent paper demonstrates that this resistance to transformation still persists after two genetic hits: K-ras mutation in combination with inactivation of either CDKN2A or p53. Their work furthermore shows that chronic inflammation can overcome this blockade and predicts that inclusion of additional conditional genetic mutations in their model (although technically demanding) would have the same effect. In view of the supplementary finding that transient episodes of inflammation suffice to enable oncogenesis, it is tempting to speculate that the tumors developing in, for instance, K-ras.G12VxTrp53.lox mice have accumulated hits in additional genes, in particular Ink4a/Arf and SMAD4.
References
1.
Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
Science 2008 Sep 26; 5897(321):1801-6
PMID: 18772397
2.
Distant metastasis occurs late during the genetic evolution of pancreatic cancer.
Nature 2010 Oct 28; 7319(467):1114-7
PMID: 20981102
3.
Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
Cancer Cell 2007 Mar; 3(11):291-302
PMID: 17349585
Disclosures
None declared
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Offringa R: F1000Prime Recommendation of [Guerra C et al., Cancer Cell 2011, 19(6):728-39]. In F1000Prime, 20 Jun 2011; DOI: 10.3410/f.11370957.12382055. F1000Prime.com/11370957#eval12382055
28 Jun 2011
New Finding
DOI: 10.3410/f.11370957.12603055
In a previous work {1}, the authors showed that pancreatitis is essential for induction of pancreatic ductal adenocarcinoma (PDAC) mediated by Kras. In this paper, they significantly expand our knowledge on the basic mechanisms of origin of PDAC.
Here, the investigators show that adult acinar cells are...Continue reading
Here, the investigators show that adult acinar cells are...Continue reading
In a previous work {1}, the authors showed that pancreatitis is essential for induction of pancreatic ductal adenocarcinoma (PDAC) mediated by Kras. In this paper, they significantly expand our knowledge on the basic mechanisms of origin of PDAC.
Here, the investigators show that adult acinar cells are resistant to transformation by the loss of p16Ink4a or Trp53, and only the presence of a Kras mutation along with pancreatitis can transform low-grade PanINs (pancreatic intraepithelial neoplasia) into high-grade PanINs and progress to ductal adenocarcinoma. All mouse mutants without Kras develop low-grade PanINs but never progress to adenocarcinoma. The authors convincingly demonstrate that the mechanism responsible for transformation is the pancreatitis-mediated ablation of oncogene-induced senescence and they show this phenomenon both in vivo in mouse and in human biopsies.
This mechanism could be halted by anti-inflammatory drugs. In their experiments, the authors treated mice carrying a Kras mutation and pancreatitis using sulindac, showing a 95% reduction of high-grade PanINs compared to the untreated controls. This suggests a crucial role for inflammation in the progression of low- to high-grade PanINs and ductal adenocarcinoma.
PDAC represents a dramatic disease because it is a lethal cancer in most patients, it is difficult to treat and near impossible to prevent given the pancreas location, and lacks symptoms until the tumour has spread outside the organ.
The discovery that an appropriate anti-inflammatory treatment against chronic pancreatitis could potentially reduce the burden of this deadly tumour is an important one. It represents a potential new avenue for improved screening programs on susceptible populations and in testing whether non-steroidal anti-inflammatory drugs can significantly reduce the incidence of PDACs.
Here, the investigators show that adult acinar cells are resistant to transformation by the loss of p16Ink4a or Trp53, and only the presence of a Kras mutation along with pancreatitis can transform low-grade PanINs (pancreatic intraepithelial neoplasia) into high-grade PanINs and progress to ductal adenocarcinoma. All mouse mutants without Kras develop low-grade PanINs but never progress to adenocarcinoma. The authors convincingly demonstrate that the mechanism responsible for transformation is the pancreatitis-mediated ablation of oncogene-induced senescence and they show this phenomenon both in vivo in mouse and in human biopsies.
This mechanism could be halted by anti-inflammatory drugs. In their experiments, the authors treated mice carrying a Kras mutation and pancreatitis using sulindac, showing a 95% reduction of high-grade PanINs compared to the untreated controls. This suggests a crucial role for inflammation in the progression of low- to high-grade PanINs and ductal adenocarcinoma.
PDAC represents a dramatic disease because it is a lethal cancer in most patients, it is difficult to treat and near impossible to prevent given the pancreas location, and lacks symptoms until the tumour has spread outside the organ.
The discovery that an appropriate anti-inflammatory treatment against chronic pancreatitis could potentially reduce the burden of this deadly tumour is an important one. It represents a potential new avenue for improved screening programs on susceptible populations and in testing whether non-steroidal anti-inflammatory drugs can significantly reduce the incidence of PDACs.
Disclosures
None declared
Neri G and Sangiorgi E: F1000Prime Recommendation of [Guerra C et al., Cancer Cell 2011, 19(6):728-39]. In F1000Prime, 28 Jun 2011; DOI: 10.3410/f.11370957.12603055. F1000Prime.com/11370957#eval12603055
01 Aug 2011
Confirmation, Novel Drug Target
DOI: 10.3410/f.11370957.13494054
This is a very interesting paper that confirms the crucial role for the inflammatory response in cancer progression.
In particular, the authors used a pancreatic cancer mouse model to show how oncogene activation is largely insufficient to promote frank malignancy, unless it is accompanied by inflammation....Continue reading
In particular, the authors used a pancreatic cancer mouse model to show how oncogene activation is largely insufficient to promote frank malignancy, unless it is accompanied by inflammation....Continue reading
This is a very interesting paper that confirms the crucial role for the inflammatory response in cancer progression.
In particular, the authors used a pancreatic cancer mouse model to show how oncogene activation is largely insufficient to promote frank malignancy, unless it is accompanied by inflammation. The barrier to cancer progression that cells implement through a senescence response, in case of oncogene activation, is attenuated in the context of an inflamed tissue. Based on their observations, the authors very wisely provide a strong recommendation to the use of anti-inflammatory drugs even in the case of mild pancreatitis for the purpose of cancer prevention.
In particular, the authors used a pancreatic cancer mouse model to show how oncogene activation is largely insufficient to promote frank malignancy, unless it is accompanied by inflammation. The barrier to cancer progression that cells implement through a senescence response, in case of oncogene activation, is attenuated in the context of an inflamed tissue. Based on their observations, the authors very wisely provide a strong recommendation to the use of anti-inflammatory drugs even in the case of mild pancreatitis for the purpose of cancer prevention.
Disclosures
None declared
Grieco D: F1000Prime Recommendation of [Guerra C et al., Cancer Cell 2011, 19(6):728-39]. In F1000Prime, 01 Aug 2011; DOI: 10.3410/f.11370957.13494054. F1000Prime.com/11370957#eval13494054
F1000Prime Recommendations, Dissents and Comments for [Guerra C et al., Cancer Cell 2011, 19(6):728-39]. In F1000Prime, 24 May 2013; F1000Prime.com/11370957
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Pancreatic acinar cells of adult mice (≥P60) are resistant to transformation by some of the most robust oncogenic insults including expression of K-Ras oncogenes and loss of p16Ink4a/p19Arf or Trp53 tumor suppressors. Yet, these acinar cells yield pancreatic intraepithelial neoplasias (mPanIN) and ductal adenocarcinomas (mPDAC) if exposed to limited bouts of non-acute pancreatitis, providing they harbor K-Ras oncogenes. Pancreatitis contributes to tumor progression by abrogating the senescence barrier characteristic of low-grade mPanINs. Attenuation of pancreatitis-induced inflammation also accelerates tissue repair and thwarts mPanIN expansion. Patients with chronic pancreatitis display senescent PanINs, providing they have received antiinflammatory drugs. These results support the concept that antiinflammatory treatment of people diagnosed with pancreatitis may reduce their risk of developing PDAC.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccr.2011.05.011
PMID: 21665147
