Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions.

BACKGROUND & AIMS Rb1 encodes a cell-cycle regulator that is functionally disrupted in most human cancers. Pancreatic ductal adenocarcinomas (PDACs) have a high frequency of mutations in KRAS and INK4A/CDKN2A that might allow cells to bypass the regulatory actions of retinoblastoma (RB). To determine the role of loss of RB function in PDAC progression, we investigated the effects of Rb disruption during pancreatic malignant transformation initiated by oncogenic Kras. METHODS We generated mice with pancreas-specific disruption of Rb, in the absence or presence of oncogenic Kras, to examine the role of RB in pancreatic carcinogenesis. RESULTS In the presence of oncogenic Kras, loss of Rb from the pancreatic epithelium accelerated formation of pancreatic intraepithelial neoplasia (PanIN), increased the frequency of cystic neoplasms, and promoted rapid progression toward PDAC. Early stage cancers were characterized by acute pancreatic inflammation, associated with up-regulation of proinflammatory cytokines within the pancreas. Despite the presence of markers associated with oncogene-induced senescence, low-grade PanIN were highly proliferative and expressed high levels of p53. Pancreatic cancer cell lines derived from these mice expressed high levels of cytokines, and transcriptional activity of p53 was impaired. CONCLUSIONS Rb encodes a tumor suppressor that attenuates progression of oncogenic Kras-induced carcinogenesis in the pancreas by mediating the senescence response and promoting activity of the tumor suppressor p53.

[1]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[2]  A. Ashworth,et al.  LKB1 Haploinsufficiency Cooperates With Kras to Promote Pancreatic Cancer Through Suppression of p21-Dependent Growth Arrest , 2010, Gastroenterology.

[3]  Michael R. Green,et al.  Role for IGFBP7 in Senescence Induction by BRAF , 2010, Cell.

[4]  K. Wiman,et al.  The p53 tumor suppressor: a master regulator of diverse cellular processes and therapeutic target in cancer. , 2010, Biochemical and biophysical research communications.

[5]  M. Korc,et al.  Kinase signaling pathways as targets for intervention in pancreatic cancer , 2010, Cancer biology & therapy.

[6]  Michael Ruogu Zhang,et al.  Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence , 2022 .

[7]  Jean Y. J. Wang,et al.  Targeting the RB-pathway in Cancer Therapy , 2010, Clinical Cancer Research.

[8]  D. Meek.  Tumour suppression by p53: a role for the DNA damage response? , 2009, Nature Reviews Cancer.

[9]  D. Ginsberg,et al.  p53 and E2f: partners in life and death , 2009, Nature Reviews Cancer.

[10]  Huamin Wang,et al.  Ras activity levels control the development of pancreatic diseases. , 2009, Gastroenterology.

[11]  M. Korc,et al.  Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. , 2009, Biochemical and biophysical research communications.

[12]  J. Bartholomew,et al.  Caveolin-1 regulates the antagonistic pleiotropic properties of cellular senescence through a novel Mdm2/p53-mediated pathway. , 2009, Cancer research.

[13]  M. Korc,et al.  Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia. , 2009, Cancer research.

[14]  Judith Campisi,et al.  Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor , 2008, PLoS biology.

[15]  M. Korc,et al.  14-3-3σ Modulates Pancreatic Cancer Cell Survival and Invasiveness , 2008, Clinical Cancer Research.

[16]  J. Sage,et al.  Cellular mechanisms of tumour suppression by the retinoblastoma gene , 2008, Nature Reviews Cancer.

[17]  Michael R. Green,et al.  Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7 , 2008, Cell.

[18]  K. Lim,et al.  Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. , 2007, Genes & development.

[19]  M. Korc,et al.  The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia , 2007, Proceedings of the National Academy of Sciences.

[20]  M. Barbacid,et al.  Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. , 2007, Cancer cell.

[21]  R. Hruban,et al.  Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. , 2007, Cancer cell.

[22]  Akiko Takahashi,et al.  Irreversibility of cellular senescence: dual roles of p16INK4a/Rb-pathway in cell cycle control , 2007, Cell Division.

[23]  Gerald C. Chu,et al.  Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. , 2006, Genes & development.

[24]  H. Ohge,et al.  Re: "Intraductal papillary-mucinous neoplasms and mucinous cystic neoplasms of the pancreas differentiated by ovarian-type stroma". , 2006, Surgery.

[25]  M. Serrano,et al.  The power and the promise of oncogene-induced senescence markers , 2006, Nature Reviews Cancer.

[26]  Ralph Weissleder,et al.  Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[27]  R. Hruban,et al.  Molecular pathogenesis of pancreatic cancer. , 2006, Annual review of genomics and human genetics.

[28]  Jonathan P. Williams,et al.  The Retinoblastoma Protein Is Required for Ras-Induced Oncogenic Transformation , 2006, Molecular and Cellular Biology.

[29]  M. Barbacid,et al.  Tumour biology: Senescence in premalignant tumours , 2005, Nature.

[30]  R. Hruban,et al.  Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. , 2005, Cancer cell.

[31]  M. Farnell,et al.  Pancreatic mucinous cystic neoplasm defined by ovarian stroma: demographics, clinical features, and prevalence of cancer. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[32]  Zigang Dong,et al.  Post-translational modification of p53 in tumorigenesis , 2004, Nature Reviews Cancer.

[33]  R. DePinho,et al.  Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. , 2003, Genes & development.

[34]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[35]  M. Oren,et al.  Decision making by p53: life, death and cancer , 2003, Cell Death and Differentiation.

[36]  J. Neoptolemos,et al.  Expression of the Chemokines MCP-1/JE and Cytokine-Induced Neutrophil Chemoattractant in Early Acute Pancreatitis , 2002, Pancreas.

[37]  D. Melton,et al.  Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. , 2002, Development.

[38]  R H Hruban,et al.  Pancreatic Intraepithelial Neoplasia: A New Nomenclature and Classification System for Pancreatic Duct Lesions , 2001, The American journal of surgical pathology.

[39]  A. Berns,et al.  Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. , 2000, Genes & development.

[40]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[41]  N. Dyson.  The regulation of E2F by pRB-family proteins. , 1998, Genes & development.

[42]  J. Kleeff,et al.  Up-regulation of Transforming Growth Factor (TGF)-β Receptors by TGF-β1 in COLO-357 Cells* , 1998, The Journal of Biological Chemistry.

[43]  S. Gansauge,et al.  Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. , 1997, Cancer research.

[44]  S. Lowe,et al.  Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a , 1997, Cell.

[45]  J. R. Smith,et al.  Evidence for a p53‐independent pathway for upregulation of SDI1/CIP1/WAF1/P21 RNA in human cells , 1994, Molecular carcinogenesis.

[46]  D. Givol,et al.  Induction of WAF1/CIP1 by a p53-independent pathway. , 1994, Cancer research.

[47]  B. Cronstein,et al.  Neutrophil chemotaxis in response to TGF-beta isoforms (TGF-beta 1, TGF-beta 2, TGF-beta 3) is mediated by fibronectin. , 1994, Journal of immunology.

[48]  Yi-Song Wang,et al.  WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. , 1994, Cancer research.

[49]  Y. Qian,et al.  The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle , 1991, Cell.

[50]  M. Korc,et al.  Effects of dietary manganese deficiency on rat pancreatic amylase mRNA levels. , 1990, The Journal of nutrition.

[51]  Wen-Hwa Lee,et al.  The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity , 1987, Nature.

[52]  W. Rutter,et al.  Isolation of full-length putative rat lysophospholipase cDNA using improved methods for mRNA isolation and cDNA cloning. , 1987, Biochemistry.

[53]  Stephen H. Friend,et al.  A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma , 1986, Nature.

[54]  Gerald C. Chu,et al.  Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic KRas Citation , 2009 .

[55]  R. Hruban,et al.  Pancreatic cancer in mice and man: the Penn Workshop 2004. , 2006, Cancer research.

[56]  R. Weinberg,et al.  The role of RB in cell cycle control. , 1995, Progress in cell cycle research.

[57]  N. Jamieson,et al.  ASIC — LIVER , PANCREAS , AND BILIARY RACT KB 1 Haploinsufficiency Cooperates With Kras to Promote Pancreatic ancer Through Suppression of p 21-Dependent Growth Arrest , 2022 .