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Pathobiology of pancreatic cancer: implications on therapy

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Pages 219-227 | Received 23 Sep 2015, Accepted 04 Dec 2015, Published online: 11 Jan 2016

References

•• First publication of whole-exome sequencing detecting somatic rearrangements in pancreatic cancer, which were summarized in core signaling pathways.

  • Campbell PJ, Yachida S, Mudie LJ, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467(7319):1109–1113.
  • Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114–1117.
  • Raj D, Aicher A, Heeschen C. Concise reviews: stem cells in pancreatic cancer: from concept to translation. Stem Cells. 2015;33(10):2893–2902.
  • Lonardo E, Hermann PC, Heeschen C. Pancreatic cancer stem cells – update and future perspectives. Mol Oncol. 2010;4(5):431–442.
  • Proctor E, Waghray M, Lee CJ, et al. Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma. Plos One. 2013;8(2):e55820.
  • Lonardo E, Frias-Aldeguer J, Hermann PC, et al. Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle. 2012;11(7):1282–1290.
  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.
  • Lohr M, Kloppel G, Maisonneuve P, et al. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia. 2005;7(1):17–23.
  • Logsdon CD, Ji B. Ras activity in acinar cells links chronic pancreatitis and pancreatic cancer. Clin Gastroenterol Hepatol. 2009;7(11 Suppl):S40–S43.
  • Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11–22.
  • Guerra C, Schuhmacher AJ, Canamero M, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007;11(3):291–302.
  • di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144(6):1220–1229.
  • Hruban RH, Wilentz RE, Kern SE. Genetic progression in the pancreatic ducts. Am J Pathol. 2000;156(6):1821–1825.
  • Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;57(15):3126–3130.
  • Wang Z, Ali S, Banerjee S, et al. Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype. J Cell Physiol. 2013;228(3):556–562.
  • Gil J, Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol. 2006;7(9):667–677.
  • Yachida S, White CM, Naito Y, et al. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin Cancer Res. 2012;18(22):6339–6347.
  • Weissmueller S, Manchado E, Saborowski M, et al. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling. Cell. 2014;157(2):382–394.
  • Fiorini C, Cordani M, Padroni C, et al. Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine. Biochim Biophys Acta. 2015;1853(1):89–100.
  • Hoshino Y, Nishida J, Katsuno Y, et al. Smad4 decreases the population of pancreatic cancer-initiating cells through transcriptional repression of ALDH1A1. Am J Pathol. 2015;185(5):1457–1470.
  • Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399–405.
  • Iacobuzio-Donahue CA. Genetic evolution of pancreatic cancer: lessons learnt from the pancreatic cancer genome sequencing project. Gut. 2012;61(7):1085–1094.
  • Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030–1037.
  • Ben-Porath I, Thomson MW, Carey VJ, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008;40(5):499–507.

•• First identification and isolation of pancreatic cancer stem cells (CSCs).

  • Lu Y, Zhu H, Shan H, et al. Knockdown of Oct4 and Nanog expression inhibits the stemness of pancreatic cancer cells. Cancer Lett. 2013;340(1):113–123.

•• Characterization of pancreatic CSCs and detection of their drug resistance indicating their responsibility regarding tumor relapse.

  • Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1(3):313–323.
  • Li C, Wu JJ, Hynes M, et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 2011;141(6):2218–2227 e2215.
  • Takebe N, Miele L, Harris PJ, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12(8):445–464.
  • Ilmer M, Recio Boiles A, Regel I, et al. RSpo2 enhances canonical Wnt signaling to confer stemness-associated traits to susceptible pancreatic cancer cells. Cancer Res. 2015;75(9):1883–1896.
  • Yen WC, Fischer MM, Axelrod F, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res. 2015;21(9):2084–2095.

• Identification of a ‘don’t eat me’ signal on CSCs. Neutralizing antibodies initiate macrophage-driven phagocytosis of CSCs.

  • Cioffi M, Trabulo S, Hidalgo M, et al. Inhibition of CD47 effectively targets pancreatic cancer stem cells via dual mechanisms. Clin Cancer Res. 2015;21(10):2325–2337.
  • Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–1461.
  • Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–1616.
  • Ozdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25(6):719–734.
  • Rhim AD, Oberstein PE, Thomas DH, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25(6):735–747.
  • Biswas SK, Allavena P, Mantovani A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol. 2013;35(5):585–600.
  • Jinushi M, Chiba S, Yoshiyama H, et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci U S A. 2011;108(30):12425–12430.

• Reprogramming of the stromal compartment results in a better therapeutic outcome of a pancreatic ductal adenocarcinoma mouse model.

  • Sainz B Jr, Martin B, Tatari M, et al. ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res. 2014;74(24):7309–7320.
  • Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73(3):1128–1141.
  • Hamada S, Masamune A, Takikawa T, et al. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem Biophys Res Commun. 2012;421(2):349–354.
  • Sherman MH, Yu RT, Engle DD, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159(1):80–93.
  • Malanchi I, Santamaria-Martinez A, Susanto E, et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature. 2012;481(7379):85–89.
  • Stokes JB, Adair SJ, Slack-Davis JK, et al. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol Cancer Ther. 2011;10(11):2135–2145.
  • Walsh C, Tanjoni I, Uryu S, et al. Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer Biol Ther. 2010;9(10):778–790.
  • Duxbury MS, Ito H, Zinner MJ, et al. Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery. 2004;135(5):555–562.
  • Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell. 2004;118(4):409–418.
  • Cao R, Wang L, Wang H, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298(5595):1039–1043.
  • Taherbhoy AM, Huang OW, Cochran AG. BMI1-RING1B is an autoinhibited RING E3 ubiquitin ligase. Nat Commun. 2015;6:7621.
  • Lee TI, Jenner RG, Boyer LA, et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006;125(2):301–313.
  • van Vlerken LE, Kiefer CM, Morehouse C, et al. EZH2 is required for breast and pancreatic cancer stem cell maintenance and can be used as a functional cancer stem cell reporter. Stem Cells Transl Med. 2013;2(1):43–52.
  • Avan A, Crea F, Paolicchi E, et al. Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells. Mol Cancer Ther. 2012;11(8):1735–1746.
  • Knutson SK, Wigle TJ, Warholic NM, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8(11):890–896.
  • Miyake K, Yoshizumi T, Imura S, et al. Expression of hypoxia-inducible factor-1alpha, histone deacetylase 1, and metastasis-associated protein 1 in pancreatic carcinoma: correlation with poor prognosis with possible regulation. Pancreas. 2008;36(3):e1–e9.
  • Fritsche P, Seidler B, Schuler S, et al. HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA. Gut. 2009;58(10):1399–1409.
  • Nalls D, Tang SN, Rodova M, et al. Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. Plos One. 2011;6(8):e24099.
  • Meidhof S, Brabletz S, Lehmann W, et al. ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat. EMBO Mol Med. 2015;7(6):831–847.
  • Wellner U, Schubert J, Burk UC, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009;11(12):1487–1495.
  • Regel I, Merkl L, Friedrich T, et al. Pan-histone deacetylase inhibitor panobinostat sensitizes gastric cancer cells to anthracyclines via induction of CITED2. Gastroenterology. 2012;143(1):99–109 e110.
  • Deng G, Song GA, Pong E, et al. Promoter methylation inhibits APC gene expression by causing changes in chromatin conformation and interfering with the binding of transcription factor CCAAT-binding factor. Cancer Res. 2004;64(8):2692–2698.
  • Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8(4):286–298.
  • el-Deiry WS, Nelkin BD, Celano P, et al. High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer. Proc Natl Acad Sci U S A. 1991;88(8):3470–3474.

• Treatment of pancreatic cancer cells with demethylating agent induces tumor cell differentiation.

  • Zhang JJ, Zhu Y, Zhu Y, et al. Association of increased DNA methyltransferase expression with carcinogenesis and poor prognosis in pancreatic ductal adenocarcinoma. Clin Transl Oncol. 2012;14(2):116–124.
  • Girault I, Tozlu S, Lidereau R, et al. Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Clin Cancer Res. 2003;9(12):4415–4422.
  • Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21(35):5427–5440.
  • Sun L, Mathews LA, Cabarcas SM, et al. Epigenetic regulation of SOX9 by the NF-kappaB signaling pathway in pancreatic cancer stem cells. Stem Cells. 2013;31(8):1454–1466.
  • Lefebvre B, Belaich S, Longue J, et al. 5′-AZA induces Ngn3 expression and endocrine differentiation in the PANC-1 human ductal cell line. Biochem Biophys Res Commun. 2010;391(1):305–309.

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