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A Case of Mistaken Identity? Nonductal Origins of Pancreatic “Ductal” Cancers

2007; Cell Press; Volume: 11; Issue: 3 Linguagem: Inglês

10.1016/j.ccr.2007.02.020

1878-3686

L. Charles Murtaugh, Steven D. Leach,

Pancreatitis Pathology and Treatment

In this issue of Cancer Cell, Guerra and colleagues provide important new insights regarding the ability of specific pancreatic cell types to generate invasive pancreatic cancer. First, they demonstrate that classical pancreatic "ductal" neoplasia can be induced by activation of oncogenic Kras in nonductal exocrine cells. Second, they show that, while Kras activation in immature acinar and centroacinar cells is readily able to induce ductal neoplasia, Kras-mediated tumorigenesis in mature exocrine pancreas requires the induction of chronic epithelial injury. The results shed new light on the "cell of origin" of pancreatic ductal cancer and demonstrate that chronic pancreatitis provides a permissive environment for Kras-induced pancreatic neoplasia. In this issue of Cancer Cell, Guerra and colleagues provide important new insights regarding the ability of specific pancreatic cell types to generate invasive pancreatic cancer. First, they demonstrate that classical pancreatic "ductal" neoplasia can be induced by activation of oncogenic Kras in nonductal exocrine cells. Second, they show that, while Kras activation in immature acinar and centroacinar cells is readily able to induce ductal neoplasia, Kras-mediated tumorigenesis in mature exocrine pancreas requires the induction of chronic epithelial injury. The results shed new light on the "cell of origin" of pancreatic ductal cancer and demonstrate that chronic pancreatitis provides a permissive environment for Kras-induced pancreatic neoplasia. Among the many problems of cancer research, "cell-of-origin" questions may occasionally be viewed as trivial or semantic. Yet tumors are not born equal: for example, pancreatic ductal adenocarcinomas (PDACs) nearly always arise from precursors that sustain activating KRAS mutations, while such mutations are almost never seen in less common pancreatic cancers such as islet cell carcinomas. Some of these differences may reflect the internal wiring of the initiating cell types, such that KRAS activation favors transformation in one cell but not another. Deciphering these interactions between epigenetic determinants of cell identity and genetic changes leading to tumor formation might identify new targets for cancer treatment and prevention. In this issue of Cancer Cell, Guerra et al., 2007Guerra C. Schuhmacher A.J. Cañamero M. Grippo P.J. Verdaguer L. Pérez-Gallego L. Dubus P. Sandgren E.P. Barbacid M. Cancer Cell. 2007; (this issue)PubMed Google Scholar make an important and surprising advance in clarifying the adult cell of origin for PDAC. What are the possible cellular compartments in which PDAC-producing KRAS mutations might occur? PDAC is often assumed to arise from preexisting duct cells, based on the fact that the two known pancreatic cancer precursor lesions—pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN)—both exhibit features of ductal differentiation. This hypothesis has been surprisingly difficult to prove: direct targeting of oncogenic Kras to mature ductal cells, using the Cytokeratin 19 promoter, fails to induce neoplasia (Brembeck et al., 2003Brembeck F.H. Schreiber F.S. Deramaudt T.B. Craig L. Rhoades B. Swain G. Grippo P. Stoffers D.A. Silberg D.G. Rustgi A.K. Cancer Res. 2003; 63: 2005-2009PubMed Google Scholar). In contrast, similar transgenic studies reveal that acinar cells, which comprise the most abundant cell type in mature pancreas, are susceptible to transformation by a variety of oncogenes (including Kras) and give rise to tumors that often contain ductal elements (Hruban et al., 2006Hruban R.H. Adsay N.V. Albores-Saavedra J. Anver M.R. Biankin A.V. Boivin G.P. Furth E.E. Furukawa T. Klein A. Klimstra D.S. et al.Cancer Res. 2006; 66: 95-106Crossref PubMed Scopus (293) Google Scholar). In addition to acini and ducts, of course, the pancreas is also comprised of endocrine islets, as well as several less common cell types, including centroacinar cells and clear ("Helle Zelle") cells. Centroacinar cells have recently been implicated as the apparent source of ductal tumors induced by pancreas-specific Pten deletion (Stanger et al., 2005Stanger B.Z. Stiles B. Lauwers G.Y. Bardeesy N. Mendoza M. Wang Y. Greenwood A. Cheng K.H. McLaughlin M. Brown D. et al.Cancer Cell. 2005; 8: 185-195Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar), and chemical carcinogenesis studies in rat and hamster have suggested that hyperplastic lesions leading to ductal tumors may be initiated among a variety of nonductal cell types (Bockman et al., 2003Bockman D.E. Guo J. Buchler P. Muller M.W. Bergmann F. Friess H. Lab. Invest. 2003; 83: 853-859Crossref PubMed Scopus (73) Google Scholar, Pour et al., 2003Pour P.M. Pandey K.K. Batra S.K. Mol. Cancer. 2003; 2: 13Crossref PubMed Scopus (52) Google Scholar). Although all of these studies have provided fascinating insights into cellular plasticity in the setting of neoplastic transformation, it has been difficult to reconcile their conclusions, or extrapolate to the human form of the disease. Chemical carcinogenesis can, in principle, affect multiple pancreatic cell types, making it almost impossible to establish a lineage relationship between normal cells, precancerous lesions, and invasive tumors. Transgenic constructs are likely to produce nonphysiological levels of oncogene expression, and use of heterologous cell type-specific promoters essentially limits the ability of a tumor to change its cellular phenotype. Perhaps for this reason, most of these models have failed to recapitulate the PanIN/PDAC progression seen in humans (Hruban et al., 2006Hruban R.H. Adsay N.V. Albores-Saavedra J. Anver M.R. Biankin A.V. Boivin G.P. Furth E.E. Furukawa T. Klein A. Klimstra D.S. et al.Cancer Res. 2006; 66: 95-106Crossref PubMed Scopus (293) Google Scholar). A recent breakthrough in PDAC modeling came with the development of conditionally activatable Kras alleles in the mouse (Aguirre et al., 2003Aguirre A.J. Bardeesy N. Sinha M. Lopez L. Tuveson D.A. Horner J. Redston M.S. DePinho R.A. Genes Dev. 2003; 17: 3112-3126Crossref PubMed Scopus (747) Google Scholar, Hingorani et al., 2003Hingorani S.R. Petricoin E.F. Maitra A. Rajapakse V. King C. Jacobetz M.A. Ross S. Conrads T.P. Veenstra T.D. Hitt B.A. et al.Cancer Cell. 2003; 4: 437-450Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar). These alleles are silent in the majority of cells, yet can be heritably activated by Cre-loxP recombination, mimicking the somatic KRAS point mutations that initiate PDAC formation in human pancreas. When this system is used to activate Kras throughout the developing pancreas, adult mice develop a PanIN/PDAC progression that is almost indistinguishable from its human counterpart (Hruban et al., 2006Hruban R.H. Adsay N.V. Albores-Saavedra J. Anver M.R. Biankin A.V. Boivin G.P. Furth E.E. Furukawa T. Klein A. Klimstra D.S. et al.Cancer Res. 2006; 66: 95-106Crossref PubMed Scopus (293) Google Scholar). Because the initial applications of this system relied on pan-pancreatic Kras activation, they could not address the cell-of-origin question, and it is into this breach that Guerra et al., 2007Guerra C. Schuhmacher A.J. Cañamero M. Grippo P.J. Verdaguer L. Pérez-Gallego L. Dubus P. Sandgren E.P. Barbacid M. Cancer Cell. 2007; (this issue)PubMed Google Scholar now step. These authors have developed a tetracycline-regulated system in which Cre recombinase is conditionally expressed under control of the acinar-specific Elastase promoter. Using this system, they demonstrate the formation of classic PanINs, and eventual invasive PDAC, following Cre-mediated activation of a conditional KrasG12V allele in nonductal exocrine cells. Unfortunately, this system does not fully resolve the cell-of-origin question for PDAC, as the authors observe Cre-loxP recombination in centroacinar as well as acinar cells. Centroacinar cells lie at the junction between acinar cells and adjacent ductal epithelium, and as noted above have previously been proposed as a potential source for ductal neoplasia (Stanger et al., 2005Stanger B.Z. Stiles B. Lauwers G.Y. Bardeesy N. Mendoza M. Wang Y. Greenwood A. Cheng K.H. McLaughlin M. Brown D. et al.Cancer Cell. 2005; 8: 185-195Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar). In addition, centroacinar cells have been suggested to represent a stem- or progenitor-like population for the adult pancreas, particularly following injury. Although the resting pancreas is a relatively quiescent organ, with little evidence for dedicated stem cells, experimental injury elicits the transient appearance and proliferation of progenitor-like cells, variously termed "tubular complexes" or "acinar-ductal metaplasia" (Bockman, 1997Bockman D.E. Microsc. Res. Tech. 1997; 37: 509-519Crossref PubMed Scopus (48) Google Scholar). The origin of these cells is no better understood than that of PDAC (indeed, experimental PDAC models are often associated with similar metaplastic structures): do they arise from dedifferentiation of acinar cells, or from the expansion of centroacinar or duct cells? This question bears on another provocative finding of Guerra et al., 2007Guerra C. Schuhmacher A.J. Cañamero M. Grippo P.J. Verdaguer L. Pérez-Gallego L. Dubus P. Sandgren E.P. Barbacid M. Cancer Cell. 2007; (this issue)PubMed Google Scholar, that experimental pancreatitis dramatically sensitizes mice to KrasG12V-driven PanIN/PDAC formation. Human patients suffering from chronic pancreatitis, especially its hereditary form, are at increased risk for pancreatic cancer (Lowenfels et al., 1997Lowenfels A.B. Maisonneuve P. DiMagno E.P. Elitsur Y. Gates Jr., L.K. Perrault J. Whitcomb D.C. J. Natl. Cancer Inst. 1997; 89: 442-446Crossref PubMed Scopus (773) Google Scholar), and this mouse model may allow us to establish exactly why this is the case, and what can be done about it. Indeed, although chronic inflammatory conditions in numerous tissues are associated with increased cancer risk, untangling causes, effects, and mechanisms has proven very difficult in humans. Genetically tractable model systems for inflammation-associated cancer make it possible to unravel basic mechanisms and may also provide a preclinical test bed for therapeutics targeting the relevant components of the inflammatory process. Here, the authors create a chronic pancreatitis-like state by long-term treatment with caerulein, an acinar cell secretagogue. Much prior research into caerulein-induced pancreatitis has focused on two important questions: what are the molecular mechanisms determining the severity of injury, and what are the cellular mechanisms of postinjury repair? With regard to the determinants of injury, caerulein treatment induces rapid activation of the NF-κB transcription factor; as in other organ inflammation models, blocking this activation appears to blunt subsequent pancreatitis (Gukovsky et al., 1998Gukovsky I. Gukovskaya A.S. Blinman T.A. Zaninovic V. Pandol S.J. Am. J. Physiol. 1998; 275: G1402-G1414PubMed Google Scholar). As expected, Guerra et al., 2007Guerra C. Schuhmacher A.J. Cañamero M. Grippo P.J. Verdaguer L. Pérez-Gallego L. Dubus P. Sandgren E.P. Barbacid M. Cancer Cell. 2007; (this issue)PubMed Google Scholar observe NF-κB activation in acinar cells of caerulein-treated mice, although this activation occurs to the same extent in wild-type and KrasG12V-expressing pancreata, and little or no NF-κB activation is seen in the actual PanIN lesions or tumors induced by KrasG12V. Thus, while the current results fail to definitively characterize the role of NF-κB in PDAC initiation and progression, this unique system for the study of pancreatitis-associated cancer should provide new opportunities to resolve this important issue. The second question regarding caerulein-induced pancreatitis is also likely to be relevant here: how does injured pancreatic tissue repair itself? Caerulein-induced pancreatitis is one of the experimental insults known to provoke expansion of metaplastic tubular complexes, and one school of thought suggests that metaplastic epithelial cells serve as progenitors to replace lost acinar tissue (Jensen et al., 2005Jensen J.N. Cameron E. Garay M.V. Starkey T.W. Gianani R. Jensen J. Gastroenterology. 2005; 128: 728-741Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). In in vitro culture systems, activation of the Notch and/or EGF receptor pathways causes acinar cells to dedifferentiate and assume a metaplastic phenotype (Miyamoto et al., 2003Miyamoto Y. Maitra A. Ghosh B. Zechner U. Argani P. Iacobuzio-Donahue C.A. Sriuranpong V. Iso T. Meszoely I.M. Wolfe M.S. et al.Cancer Cell. 2003; 3: 565-576Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar), potentially mimicking a process induced by injury in vivo. Alternatively, metaplasia may represent the induced expansion of centroacinar cells (Stanger et al., 2005Stanger B.Z. Stiles B. Lauwers G.Y. Bardeesy N. Mendoza M. Wang Y. Greenwood A. Cheng K.H. McLaughlin M. Brown D. et al.Cancer Cell. 2005; 8: 185-195Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar), and it is important to recognize that acinar cell dedifferentiation and centroacinar expansion are in no way mutually exclusive events (Figure 1). Whatever the source, one might imagine that pancreatitis causes otherwise quiescent adult cells to assume a progenitor-like phenotype, in which they are more susceptible to transformation by oncogenic Kras. It should be emphasized that this possibility is not strictly academic, as it implies that interfering with injury-induced metaplasia might prevent the earliest stages of pancreatic cancer. This work represents the first direct demonstration that cells in adult mouse pancreas are susceptible to transformation by activated Kras, and the first model for pancreatitis-associated tumor promotion. Further work, using Cre lines with stricter specificity for duct, centroacinar, or acinar cells, will be required to more definitively resolve the cell-of-origin problem for PDAC, and it may yet turn out that the precise cell of origin matters less than the context in which that cell finds itself—i.e., whether Kras mutations occur in the context of inflammation and/or regenerative metaplasia. Nonetheless, the results of Guerra et al., 2007Guerra C. Schuhmacher A.J. Cañamero M. Grippo P.J. Verdaguer L. Pérez-Gallego L. Dubus P. Sandgren E.P. Barbacid M. Cancer Cell. 2007; (this issue)PubMed Google Scholar represent a major advance in the field of pancreatic cancer modeling and provide an important foundation for future studies of pancreatic cancer initiation and progression. This work was supported by NIH grants DK61215 and DK56211 (to S.D.L.) and by Lustgarten Foundation grant RFP06-059 and Searle Scholars Program grant 06-B-116 (to L.C.M.). S.D.L. is also supported by the Paul K. Neumann Professorship at Johns Hopkins University. Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult MiceGuerra et al.Cancer CellMarch 13, 2007In BriefPancreatic ductal adenocarcinoma (PDA), one of the deadliest human cancers, often involves somatic activation of K-Ras oncogenes. We report that selective expression of an endogenous K-RasG12V oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells. Surprisingly, adult mice become refractory to K-RasG12V-induced PanINs and PDA. Full-Text PDF Open Archive