The genetic classification of pancreatic neoplasia

Matthaei, Hanno; Semaan, Alexander; Hruban, Ralph H.

doi:10.1007/s00535-015-1037-4

Cited by 6 publications

(6 citation statements)

References 149 publications

(184 reference statements)

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“…PDACs are the most commonly occurring form of PanC (90%), with mutated KRAS expressed in ≥95% of cases. Other frequently mutated genes present in ≥50% of PanC types are p16/CDKN2A , TP53 , and SMAD4 …”

Section: Introductionmentioning

confidence: 99%

“…Other frequently mutated genes present in ≥50% of PanC types are p16/CDKN2A, TP53, and SMAD4. 7 Other than genetic alterations, in recent years, cancer stem cells (CSCs) have been identified to play a major role in cancer progression and recurrence in pancreatic as well as other cancers. 8,9 PanC-CSCs were first identified in 2007 by Li et al,8 in established human PanC xenografts of NOD/SCID mice.…”

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confidence: 99%

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Bitter melon juice exerts its efficacy against pancreatic cancer via targeting both bulk and cancer stem cells

Dhar

Deep

Kumar

et al. 2018

Molecular Carcinogenesis

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Pancreatic cancer (PanC) is one of the deadliest malignancies worldwide and frontline treatment with gemcitabine becomes eventually ineffective due to increasing PanC resistance, suggesting additional approaches are needed to manage PanC. Recently, we have shown the efficacy of bitter melon juice (BMJ) against PanC cells, including those resistant to gemcitabine. Since cancer stem cells (CSCs) are actively involved in PanC initiation, progression, relapse and drug-resistance, here we assessed BMJ ability in targeting pancreatic cancer-associated cancer stem cells (PanC-CSCs). We found BMJ efficacy against CD44+/CD24+/EpCAMhigh enriched PanC-CSCs in spheroid assays; BMJ also increased the sensitivity of gemcitabine-resistant PanC-CSCs. Exogenous addition of BMJ to PanC-CSC generated spheroids (not pre-exposed to BMJ) also significantly reduced spheroid number and size. Mechanistically, BMJ effects were associated with a decrease in the expression of genes and proteins involved in PanC-CSC renewal and proliferation. Specifically, immunofluorescence staining showed that BMJ decreases protein expression/nuclear localization of CSC-associated transcription factors SOX2, OCT4 and NANOG, and CSC marker CD44. Immunohistochemical analysis of MiaPaCa2 xenografts from BMJ treated animals also showed a significant decrease in the levels of CSC-associated transcription factors. Together, these results show BMJ potential in targeting PanC-CSC pool and associated regulatory pathways, suggesting the need for further investigation of its efficacy against PanC growth and progression including gemcitabine-resistant PanC.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Bitter melon juice exerts its efficacy against pancreatic cancer via targeting both bulk and cancer stem cells

Dhar

Deep

Kumar

et al. 2018

Molecular Carcinogenesis

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“…The majority (ca 95%) are classified as ductal adenocarcinomas, and of the others, the majority are neuroendocrine in origin. Tumours are associated most strongly with k-RAS mutations in almost all patients 2 . Mutated P53 and mutations in several other oncogenes such as CDKN2 are frequently observed 1 .…”

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confidence: 99%

A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

Ohnmacht

Marchetti

Gunaratnam

et al. 2015

Sci Rep

110

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We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41.

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“…In mouse models, activating mutations of Kras seem essential for initiating the development of PanINs, and indeed, 90% of human PDACs have activating KRAS mutations, as do most of even the lowest grade of PanIN. 128,129 As noted, 128 targeting oncogenic Kras to various pancreatic cell types in GEMMs has shown the malignant potential of duct, endocrine and acinar cells; however, is this a reflection of the human situation? In humans, KRAS mutations are typically followed by loss of CDKN2/p16, while loss of TP53 and SMAD4 is usually only found in high-grade PanIN.…”

Section: Pancreasmentioning

confidence: 99%

The cellular origins of cancer with particular reference to the gastrointestinal tract

Alison

2020

Int J Experimental Path

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Summary Stem cells or their closely related committed progenitor cells are the likely founder cells of most neoplasms. In the continually renewing and hierarchically organized epithelia of the oesophagus, stomach and intestine, homeostatic stem cells are located at the beginning of the cell flux, in the basal layer of the oesophagus, the isthmic region of gastric oxyntic glands and at the bottom of gastric pyloric‐antral glands and colonic crypts. The introduction of mutant oncogenes such as KrasG12D or loss of Tp53 or Apc to specific cell types expressing the likes of Lgr5 and Mist1 can be readily accomplished in genetically engineered mouse models to initiate tumorigenesis. Other origins of cancer are discussed including ‘reserve’ stem cells that may be activated by damage or through disruption of morphogen gradients along the crypt axis. In the liver and pancreas, with little cell turnover and no obvious stem cell markers, the importance of regenerative hyperplasia associated with chronic inflammation to tumour initiation is vividly apparent, though inflammatory conditions in the renewing populations are also permissive for tumour induction. In the liver, hepatocytes, biliary epithelial cells and hepatic progenitor cells are embryologically related, and all can give rise to hepatocellular carcinoma and cholangiocarcinoma. In the exocrine pancreas, both acinar and ductal cells can give rise to pancreatic ductal adenocarcinoma (PDAC), although the preceding preneoplastic states are quite different: acinar‐ductal metaplasia gives rise to pancreatic intraepithelial neoplasia culminating in PDAC, while ducts give rise to PDAC via. mucinous cell metaplasia that may have a polyclonal origin.

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The genetic classification of pancreatic neoplasia

Cited by 6 publications

References 149 publications

Bitter melon juice exerts its efficacy against pancreatic cancer via targeting both bulk and cancer stem cells

Bitter melon juice exerts its efficacy against pancreatic cancer via targeting both bulk and cancer stem cells

A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

The cellular origins of cancer with particular reference to the gastrointestinal tract

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