Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence.

Rienk Offringa

Rienk Offringa

Rienk Offringa

+ -1 Evaluators

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.

Giovanni Neri

Giovanni Neri

Giovanni Neri

Eugenio Sangiorgi

Eugenio Sangiorgi

Eugenio Sangiorgi

+ 0 Evaluators

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.

Domenico Grieco

Domenico Grieco

Domenico Grieco

+ -1 Evaluators

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.