Abstract
The identity of the cell of origin for pancreatic ductal adenocarcinoma (PDAC) has long been debated. PDAC has a ductal morphology, but there is no formal proof that it originates from the ductal compartment. Targeting Kras expression to adult acinar or endocrine lineages induces the formation of tumors reminiscent of human PDAC, but only in the presence of concomitant inflammation. Apart from cells of the Pdx1-positive lineage in the adult pancreas, which can be transformed (albeit with low frequency), the cells susceptible to acquiring or retaining oncogenic mutations remain elusive. Hypothetically, a subset of cells that renew the adult organ physiologically or regenerate it upon severe tissue damage would be more susceptible to oncogenic transformation than mature, differentiated cells. Such a compartment could consist of putative pancreatic stem cells, progenitor cells, facultative stem cells or transdifferentiated bone marrow cells. An integrated approach combining techniques from stem cell and cancer biology will be necessary to define and map these cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jemal, A., Siegel, R., Xu, J. & Ward, E. Cancer statistics. CA Cancer J. Clin. 60, 277–300 (2010).
Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).
Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).
Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).
Habbe, N. et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl Acad. Sci. USA 105, 18913–18918 (2008).
Morris, J. P. T., Cano, D. A., Sekine, S., Wang, S. C. & Hebrok, M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Invest. 120, 508–520 (2010).
Furuyama, K. et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat. Genet. 43, 34–41 (2011).
Kopp, J. L. et al. Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138, 653–665 (2011).
Perez-Caro, M. et al. Cancer induction by restriction of oncogene expression to the stem cell compartment. EMBO J. 28, 8–20 (2009).
Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).
Dor, Y., Brown, J., Martinez, O. I. & Melton, D. A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–46 (2004).
Fukuda, A. et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19, 441–455 (2011).
Fuchs, E. The tortoise and the hair: slow-cycling cells in the stem cell race. Cell 137, 811–819 (2009).
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).
Zulewski, H. et al. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50, 521–533 (2001).
Seaberg, R. M. et al. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat. Biotechnol. 22, 1115–1124 (2004).
Smukler, S. R. et al. The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell 8, 281–293 (2011).
Rovira, M. et al. Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc. Natl Acad. Sci. USA 107, 75–80 (2010).
Stanger, B. Z., Tanaka, A. J. & Melton, D. A. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 445, 886–891 (2007).
Strobel, O. et al. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology 133, 1999–2009 (2007).
Desai, B. M. et al. Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration. J. Clin. Invest. 117, 971–977 (2007).
Yanger, K. & Stanger, B. Z. Facultative stem cells in liver and pancreas: fact and fancy. Dev. Dyn. 240, 521–529 (2011).
Thorel, F. et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149–1154 (2010).
Theise, N. D. et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 31, 235–240 (2000).
Krause, D. S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).
Ianus, A., Holz, G. G., Theise, N. D. & Hussain, M. A. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J. Clin. Invest. 111, 843–850 (2003).
Lechner, A. et al. No evidence for significant transdifferentiation of bone marrow into pancreatic beta-cells in vivo. Diabetes 53, 616–623 (2004).
Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004).
Milyavsky, M. et al. A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell 7, 186–197 (2010).
Collado, M., Blasco, M. A. & Serrano, M. Cellular senescence in cancer and aging. Cell 130, 223–233 (2007).
Sharpless, N. E. & DePinho, R. A. Telomeres, stem cells, senescence, and cancer. J. Clin. Invest. 113, 160–168 (2004).
Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010).
Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004).
Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002).
Morton, J. P. et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl Acad. Sci. USA 107, 246–251 (2010).
Pinho, A. V., Rooman, I. & Real, F. X. p53-dependent regulation of growth, epithelial–mesenchymal transition and stemness in normal pancreatic epithelial cells. Cell Cycle 10, 1312–1321 (2011).
Goggins, M. et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 56, 5360–5364 (1996).
Foudi, A. et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat. Biotechnol. 27, 84–90 (2009).
Orford, K. W. & Scadden, D. T. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat. Rev. Genet. 9, 115–128 (2008).
Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010).
Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010).
Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010).
Steck, P. A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet. 15, 356–362 (1997).
Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186–2189 (2001).
Penninger, J. M. & Woodgett, J. Stem cells. PTEN–coupling tumor suppression to stem cells? Science 294, 2116–2118 (2001).
Stanger, B. Z. et al. Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell 8, 185–195 (2005).
Means, A. L. et al. Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology 124, 1020–1036 (2003).
Wagner, M., Luhrs, H., Kloppel, G., Adler, G. & Schmid, R. M. Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice. Gastroenterology 115, 1254–1262 (1998).
Miyatsuka, T. et al. Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation. Genes Dev. 20, 1435–1440 (2006).
Strobel, O. et al. Beta cell transdifferentiation does not contribute to preneoplastic/metaplastic ductal lesions of the pancreas by genetic lineage tracing in vivo. Proc. Natl Acad. Sci. USA 104, 4419–4424 (2007).
Hill, R. et al. PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res. 70, 7114–7124 (2010).
Xu, X., Ehdaie, B., Ohara, N., Yoshino, T. & Deng, C. X. Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice. Oncogene 29, 674–686 (2010).
Jiao, Y. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331, 1199–1203 (2011).
Sato, N. et al. STK11/LKB1 Peutz–Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am. J. Pathol. 159, 2017–2022 (2001).
Hezel, A. F. et al. Pancreatic LKB1 deletion leads to acinar polarity defects and cystic neoplasms. Mol. Cell Biol. 28, 2414–2425 (2008).
Morton, J. P. et al. LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology 139, 586–597 (2010).
Su, G. H. et al. Germline and somatic mutations of the STK11/LKB1 Peutz–Jeghers gene in pancreatic and biliary cancers. Am. J. Pathol. 154, 1835–1840 (1999).
Lee, S. K. et al. Metformin sensitizes insulin signaling through AMPK-mediated PTEN down-regulation in preadipocyte 3T3-L1 cells. J. Cell Biochem. 112, 1259–1267 (2011).
Khasawneh, J. et al. Inflammation and mitochondrial fatty acid beta-oxidation link obesity to early tumor promotion. Proc. Natl Acad. Sci. USA 106, 3354–3359 (2009).
Author information
Authors and Affiliations
Contributions
B. Kong, C. W. Michalski, M. Erkan, H. Friess and J. Kleeff reviewed the literature and drafted the manuscript. All authors approved the final version of the paper.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Kong, B., Michalski, C., Erkan, M. et al. From tissue turnover to the cell of origin for pancreatic cancer. Nat Rev Gastroenterol Hepatol 8, 467–472 (2011). https://doi.org/10.1038/nrgastro.2011.114
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrgastro.2011.114
This article is cited by
-
Heavy Metals in Soils and Road Dust in Akure City, Southwest Nigeria: Pollution, Sources, and Ecological and Health Risks
Exposure and Health (2022)
-
Histone acetyltransferase 1 promotes gemcitabine resistance by regulating the PVT1/EZH2 complex in pancreatic cancer
Cell Death & Disease (2021)
-
Cells of origin of pancreatic neoplasms
Surgery Today (2018)
-
Lipid-modified G4-decoy oligonucleotide anchored to nanoparticles: delivery and bioactivity in pancreatic cancer cells
Scientific Reports (2016)
-
A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels
Scientific Reports (2015)