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. Author manuscript; available in PMC: 2011 Mar 8.
Published in final edited form as: Clin Gastroenterol Hepatol. 2009 Nov;7(11 Suppl):S40–S43. doi: 10.1016/j.cgh.2009.07.040

Ras Activity in Acinar Cells Links Chronic Pancreatitis and Pancreatic Cancer

CRAIG D LOGSDON *,‡, BAOAN JI *
PMCID: PMC3050544  NIHMSID: NIHMS268542  PMID: 19896097

Abstract

The relationship between chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) is unclear. CP is a risk factor for PDAC, CP is found within the vicinity of PDAC, and both share many similar genetic alterations. However, it has been long thought that PDAC arises only from duct cells. However, we have recently found that excessive activity within the Ras signaling pathway can lead to acinar cell death or metaplasia and is associated with the development of fibrosis resembling CP and the development of PDAC from acinar cells through the full complement of preneoplastic (pancreatic intraepithelial neoplasia) lesions. Therefore, it is time to reevaluate the relationship between CP and PDAC. We proposed a new model in which Ras activity is the direct link between these 2 diseases. Here we will briefly review the shared properties between CP and PDAC and describe the new model.

The nature of the relationship between chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) has always been controversial. Largely this is because PDAC was thought to originate in duct cells, whereas CP clearly develops in acinar cells. However, recently it has become clear that acinar cells can also be a source of PDAC. Furthermore, we have recently found that excessive activity within the Ras signaling pathway can lead to acinar cell death or metaplasia and is associated with the development of fibrosis resembling CP. Therefore, it is time to reevaluate the relationship between these 2 diseases. We have recently proposed a new model in which Ras activity is a direct link between these 2 diseases.1,2 Here we will briefly review the shared properties between CP and PDAC and describe the new model. A more comprehensive coverage of the same issues will be available later.2

Previously Observed Relationships Between Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma

Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma Share a Prominent Stroma

Both CP and PDAC develop an extensive fibrotic response often referred to as desmoplasia that leads to similar histopathologic features. Both diseases possess extensive fibrotic stroma infiltrated with a variety of leukocytes, acinar cell atrophy, and distorted and blocked ducts.3,4 The only important histologic difference between CP and PDAC is the presence of carcinoma in PDAC. However, cancer cells typically make up only a small fraction (~10%) of the volume of the tumors.5,6 Furthermore, focal areas of fibrosis lacking cancer that resemble CP are inevitably present surrounding PDAC, such that PDAC always occurs in the presence of CP. Also, precursors to PDAC are often observed within areas of CP. These observations suggest strong linkage between the diseases but do not clearly indicate the relationship between these diseases.

Chronic Pancreatitis Is a Risk Factor for Pancreatic Ductal Adenocarcinoma

CP is a major risk factor for PDAC.7–10 Although the vast majority of CP patients do not progress to PDAC, the cumulative risk of pancreatic cancer in subjects with CP was reported to be 4% after 20 years, with a standardized incidence ratio of 14.10 This is at least 10-fold greater risk than for those without CP. For patients with a rare form of CP, hereditary pancreatitis, the risk is even greater at 53 times the normal and a cumulative lifetime risk of 40%, which is the highest of any known genetically associated risk factor.11 However, the mutations associated with hereditary CP are not observed in PDAC from patients without hereditary CP.12 Furthermore, the vast majority of patients with CP do not progress to PDAC. Therefore, significant barriers must exist between the mechanisms responsible for CP and the development of PDAC.

Both Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma Possess Preneoplastic Lesions

Pathologic studies have suggested 2 important precursors to PDAC, pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms.13,14 PanINs are present in nearly all patients with CP.15–17 It has also been observed that chromosomal instability and genomic damage are present in pancreatic duct cells from patients with CP, similar to what is observed in PDAC.18 The specific mechanisms responsible for the genetic instability observed in CP are unclear. Nonetheless, these observations provide a potential explanation for the relationship between CP and PDAC.

Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma Possess K-Ras Mutations

In PDAC, mutations in the proto-oncogene K-Ras are found in nearly all cases.19 For this reason, this mutation has been extensively explored as a potential diagnostic marker.20–23 Unfortunately for use of K-Ras mutations as a diagnostic aid, K-Ras mutations have also been observed in ~30% of samples from patients with CP, although highly variable levels have been reported.24 –27 This is likely due to differences in sampling, DNA extraction, or polymerase chain reaction methods. Nonetheless, it is clear that K-Ras mutations are very often found in CP. Furthermore, CP generally contains early PanINs that often possess mutations in K-Ras.28 –31 Therefore, K-Ras mutations are not specific for invasive PDAC, and their presence in normal individuals32 suggests that they can precede CP. This is particularly interesting in light of the observation that elevated levels of K-Ras activity in acinar cells generate CP in a mouse model.33 Taken together, the data indicate that the qualitative presence of K-Ras mutations is not an accurate predictor of pancreatic cancer, because this mutation can clearly precede other required alterations.

New Evidence for the Role of Ras Activity in Chronic Pancreatitis and Cancer Development

Ras Activity in Acinar Cells Generates Both Fibrosis and Cancer

Mutations in K-Ras are nearly universal in PDAC. Therefore, a number of models based on expression of mutant K-Ras have been developed. Several studies have shown that when mutant K-Ras expression is directed by promoters active during pancreatic development such as PDX1,34,35 p48,34 nestin,36 or elastase,37 it results in development of PanINs that progress to invasive PDAC. On the other hand, adult mice were reported to be refractory to adult acinar cell37 or duct cell38 expression of mutant K-Ras and did not develop PanINs or PDAC.37 However, if mice with adult acinar cell expression of mutant K-Ras were challenged with an inflammatory stimulus, then they developed the full spectrum of PanINs and invasive PDAC.37 These observations have been interpreted to suggest that during adulthood, PDAC is initiated by a combination of genetic (eg, somatic K-Ras mutations) and non-genetic (eg, tissue damage) events.37 However, another interpretation of this observation is that low levels of mutant K-Ras expression are not sufficient to meet a threshold of pathologic Ras pathway signaling, but that when further activated by exogenous stimulants, such a threshold can be met.

Evidence for the existence of a threshold of Ras pathway activity in pancreatic pathology comes from studies expressing higher than endogenous levels of mutant K-Ras. Although the expression of endogenous levels of mutant K-Ras results in only a minor change in K-Ras activity within the targeted cells,35 higher levels of expression generate Ras pathway activity that mimics what is observed in PDAC.1 In this model, elevated, but not endogenous, mutant K-Ras expression in adult acinar cells caused a rapid development of CP with abundant PanINs and intraductal papillary mucinous neoplasms that progressed to invasive and meta-static PDAC. Therefore, this model confirms the potential of acinar cells to form PDAC as previously reported37 and suggests that at least in mouse models, elevated levels of Ras activity are necessary and sufficient to cause both CP and PDAC. It is important to note that in this model increased activity of Ras was the cause, rather than the result, of CP.

These data suggest that the activity level of the K-Ras pathway, rather than the presence of mutations, is the biologically relevant parameter. Currently nothing is known about the activity level of K-Ras in CP. However, it is known that K-Ras is activated by several stimuli including CCK treatments,39 expression of cyclooxygenase-2,40 and expression of transforming growth factor–α,41 and each of these has been shown to induce CP-like fibrosis when examined in animal models.40,42,43 Furthermore, the addition of CCK44 or transforming growth factor–α45 to animals with endogenous levels of mutant K-Ras expression has been found to accelerate tumor development. Therefore, these data suggest the possibility that increases of Ras activity in pancreatic acinar cells brought about by various etiologic stimulations might mediate fibrosis and inflammation.

A Model for Ras Activity as a Common Cause of Inflammation in Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma

With our current understanding of the influence of inflammation on tumorigenesis, we can describe a model that explains many of the known links between CP and PDAC (Figure 1). The initial event common to CP and PDAC is inflammation. The causes of pancreatic inflammation in CP can be the effects of ethanol, bile, blockage of ducts, hereditary alterations of trypsinogen, or a variety of other etiologies.4 Most of these stimuli are known to activate the Ras pathway, and our recent data indicate that high levels of Ras activity are sufficient for initiating an inflammatory response. Therefore, we suggest that elevated levels of Ras pathway activity are the key event in both diseases. If these stimuli are sufficiently strong, acinar cells are lost, and pancreatic stellate cells are recruited and activated, resulting in the formation of focal histologic CP. Multiple repetitions of this cycle lead to full-blown clinical CP. During this initiation period, increases in Ras activity likely occur primarily through the extrinsic pathway without K-Ras mutations. However, the chronic inflammatory microenvironment found in CP increases genetic instability18 and cell proliferation,17 thus greatly accelerating the rate of gene mutations and therefore the probability of K-Ras mutations. Thus, longer durations of CP are more highly correlated with mutations of K-Ras. If K-Ras becomes mutated, then this feeds into the Ras pathway activity, and if, in combination, the intrinsic and extrinsic pathways of Ras activation reach a sufficient level of activity, it results in the development of early PanINs and increases the likelihood of developing PDAC.23 However, the development of PDAC requires further genetic events beyond Ras mutation, which partially explains why most CP does not lead to PDAC. Alternatively, spontaneous preexisting mutations in K-Ras, or other molecules impinging on the K-Ras signaling pathway, might increase responses to extrinsic factors, leading to higher levels of Ras signaling pathway activity and the resulting inflammation. Thus, K-Ras mutations might predispose to pancreatitis.

Figure 1.

Figure 1

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Ras activity levels control the development of pancreatic diseases. For the initiation of pathologies, Ras activity levels must be elevated beyond a threshold. This level of activity can be achieved by high levels of extrinsic Ras activators (extrinsic pathway), by intrinsic alterations of Ras activity including activating mutations of K-Ras (intrinsic pathway), or by a combination of these 2 pathways. Pathologic levels of Ras activity cause acinar cells to undergo acinarductal metaplasia (ADM) and to form PanINs. High levels of Ras activity also lead to the generation of inflammation resembling CP. Inflammation induced genetic instability, and increased proliferation likely increases the probability of genetic alterations including mutations in K-Ras and loss of tumor suppressors (TS), which are required for the development of PDAC. (Modified from Ji et al1).

Genetic instability mediated by increased inflammation also increases the rate of other spontaneous genetic alterations, including silencing of p16 and other genetic and epigenetic changes that bring about the progression to advanced PanINs and eventually invasive carcinoma.46 Thus, CP-generated inflammation explains it as a risk factor for PDAC. Increased genetic instability explains the presence of many early genetic mutations found in CP and low-grade PanINs that are shared with PDAC. The common histology between CP and PDAC is explained by the inflammatory influences of both CP and PDAC on the surrounding stromal cells. The shared microenvironment explains the commonality in gene expression observed between CP and PDAC. Further understanding of these processes will be necessary for prevention of this cancer and might guide the development of new therapies.

This model for the relationship between CP and PDAC does not change greatly on the basis of the cell of origin of PDAC. However, if the cell of origin of PDAC is metaplastic acinar cells, then both CP and PDAC originate in the same cell type, and these 2 diseases are likely consequences of the same mechanisms, with CP forming a direct precursor stage to PDAC. In this case, there would be a continuum of gene expression changes in the same cell lineage directly linking these 2 diseases.

Summary

Pancreatic cancer and CP share many features. On the basis of new evidence from genetic mouse models, a new explanation for this has arisen. In this model, pancreatic cancer and CP might have many features in common because both are part of a spectrum of alterations that occurs in pancreatic acinar cells. The activity of the Ras signaling pathway appears to be the key mechanism controlling these changes. Activation of this pathway, either by genetic mutations or by alterations in the levels of signaling molecules in the microenvironment, can trigger alterations in acinar cells, leading to their death or metaplasia in a background of fibrosis and inflammation. This concept fits with most previous observations made in humans and in mouse models on these 2 diseases and provides new hypotheses for further testing.

Acknowledgments

Funding

This research was supported by NIH DK052067, 5R21DK068414, M.D. Anderson Support Core grant CA16672, M.D. Anderson Pancreatic Specialized Programs of Research Excellence (SPORE) grant P20 CA101936, and by the Lockton Endowment.

Abbreviations used in this paper

CP

chronic pancreatitis

PanIN

pancreatic intraepithelial neoplasia

PDAC

pancreatic ductal adenocarcinoma

Footnotes

Conflicts of interest

The authors disclose no conflicts.

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