Genomic Instability at Both the Base Pair Level and the Chromosomal Level Is Detectable in Earliest PanIN Lesions in Tissues of Chronic Pancreatitis

Baumgart, Mario; Werther, Meike; Bockholt, Anke; Scheurer, Maria; Rüschoff, Josef; Dietmaier, Wolfgang; Ghadimi, B. Michael; Heinmöller, Ernst

doi:10.1097/mpa.0b013e3181dc62f6

Cited by 26 publications

(18 citation statements)

References 62 publications

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“…Mouse genetic lineage tracing studies show that continued severe inflammation and/or underlying mutations in key regulatory genes can cause ADM cells to further increase proliferation and eventually undergo non-normal (neoplastic) changes. The progression from ADM to pancreatic intraepithelial neoplasia (PanIN) has been well established both in mouse models by lineage tracing (first by Habbe, Shi et al (17)) and in humans from pathology specimens (38, 45–47). Mouse models, supported by human histopathological studies, indicate that PanINs are the precursor for full-fledged, invasive PDAC and, accordingly, often already exhibit mutations characteristic of PDAC (48–50).…”

Section: The Process Of Reprogramming and Its Role In Repair Metaplamentioning

confidence: 99%

Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract

2015

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It has long been known that differentiated cells can switch fates, especially in vitro, but only recently has there been a critical mass of publications describing the mechanisms adult, post-mitotic cells use in vivo to reverse their differentiation state. We propose that this sort of cellular reprogramming is a fundamental cellular process akin to apoptosis or mitosis. Because reprogramming can invoke regenerative cells from mature cells, it is critical to the longterm maintenance of tissues like the pancreas, which encounter large insults during adulthood but lack constitutively active adult stem cells to repair the damage. However, even in tissues with adult stem cells, like stomach and intestine, reprogramming may allow mature cells to serve as reserve (“quiescent”) stem cells when normal stem cells are compromised. We propose that the potential downside to reprogramming is that it increases risk for cancers that occur late in adulthood. Mature, long-lived cells may have years of exposure to mutagens. Mutations that affect the physiological function of differentiated, post-mitotic cells may lead to apoptosis, but mutations in genes that govern proliferation might not be selected against. Hence, reprogramming with reentry into the cell cycle might unmask those mutations, causing an irreversible progenitor-like, proliferative state. We review recent evidence showing that reprogramming fuels irreversible metaplastic and precancerous proliferations in stomach and pancreas. Finally, we illustrate how we think reprogrammed differentiated cells are likely candidates as cells of origin for cancers of the intestine.

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Section: The Process Of Reprogramming and Its Role In Repair Metaplamentioning

confidence: 99%

Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract

2015

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“…Mouse models have recapitulated this observation, where Kras activation in combination with point mutation or deletion of one copy of the Trp53 gene is sufficient to induce PDAC with characteristic features of the human disease, including genomic instability and metastatic capacity (Bardeesy et al, 2006a; Hingorani et al, 2005). In particular, progression from preinvasive Pancreatic Intraepithelial Neoplasia lesions (PanINs) to invasive PDACs is associated with loss of heterozygosity (LOH) of Trp53 , highlighting p53’s crucial role as a barrier to invasive pancreatic cancer development (Baumgart et al, 2010; Lüttges et al, 2001). Understanding how p53 acts in this context, and which pathways are dysregulated when it is lost, could provide insight into the molecular mechanisms that enable PDAC progression.…”

Section: Introductionmentioning

confidence: 99%

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

et al. 2017

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SUMMARY The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p5353,54 TAD2 mutant behaves as a “super-tumor suppressor”, with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.

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“…1A). PanIN1A lesions are also seen in patients with chronic pancreatitis and in the elderly, but they are not necessarily pre-malignant [7]. Similarly, PanIN1B lesions are not necessarily pre-malignant and are distinguished from PanIN1A by the presence of papillary structures (Fig.…”

Section: Molecular Pathogenesis Of Pdacmentioning

confidence: 99%

“…In addition, PDAC is associated with increased cyclin D1 expression, aberrant activation of transforming growth factor-beta (TGF- ) pathways in conjunction with increased expression of TGF- isoforms, and a hypoxic microenvironment rich in inflammatory cells and cytokines that promote cancer growth [7]. In addition, there is inappropriate reactivation of developmental pathways, such as Hedgehog (Hh), notch and wnt/ -catenin whose roles have been comprehensively summarized [6, 17, 18].…”

Section: Molecular Pathogenesis Of Pdacmentioning

confidence: 99%

Molecular imaging in pancreatic cancer – A roadmap for therapeutic decisions

Kramer‐Marek¹,

Gore²,

Korc³

2013

Cancer Letters

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Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer characterized by multiple molecular alterations, the presence of an intense stroma, poor perfusion, and resistance to therapy. In addition to standard imaging techniques, experimental imaging strategies, such as those utilizing molecular probes, nanoparticle-based agents, and tagged antibodies are actively being explored experimentally. It is hoped that advances in these technologies will allow for detecting PDAC at an early stage, and could serve to validate experimental therapies, rapidly identify non-responders, and assist in the design of novel therapeutic strategies tailored to the patient’s molecular profile.

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Genomic Instability at Both the Base Pair Level and the Chromosomal Level Is Detectable in Earliest PanIN Lesions in Tissues of Chronic Pancreatitis

Cited by 26 publications

References 62 publications

Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract

Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

Molecular imaging in pancreatic cancer – A roadmap for therapeutic decisions

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