Abstract
Introduction
Chemoresistance is the main cause of disease progression and mortality among patients diagnosed from pancreatic adenocarcinoma. Nowadays, most patients are diagnosed with advanced disease, and chemotherapy becomes the corner stone of care, looking for clinical benefit and improvement in survival. However, response rates are low, and disease outcome is very short, needing for new drugs that overcome resistance.
Background
Till date, one of the better known mechanisms of drug resistance in cancer is related to ATP-binding cassette (ABC) transporters, highly expressed in solid tumors and, moreover, in cancer stem cells. These cancer stem cells are thought to be responsible for tumor maintenance, progression, and relapse of the disease due, in part, to an exhibition of multiple resistance mechanisms to chemotherapy and radiation.
Purpose
In order to remove this cancer stem cell population within the tumors, it is imperative to look for new molecular pathways involved in pancreatic carcinogenesis and stemness. In this study, we suggest a potential role of hedgehog-GLI pathway in pancreatic cancer chemoresistance, based on ABC transporters’ overexpression.
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References
Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev. 2003;55(1):3–29.
Kuo MT. Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal. 2009;11(1):99–133.
Gottesman MM, Ling V. The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett. 2006;580(4):998–1009.
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996;183(4):1797–806.
Allen JD, van Loevezijn A, Lakhai JM, van der Valk M, van Tellingen O, Reid G, et al. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol Cancer Ther. 2002;1(6):417–25.
Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics. 2008;9(1):105–27.
Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275–84.
Lee CJ, Dosch J, Simeone DM. Pancreatic cancer stem cells. J Clin Oncol. 2008;26(17):2806–12.
Simeone DM. Pancreatic cancer stem cells: implications for the treatment of pancreatic cancer. Clin Cancer Res. 2008;14(18):5646–8.
Kuo MT, Liu Z, Wei Y, Lin-Lee YC, Tatebe S, Mills GB, et al. Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-kappaB signaling. Oncogene. 2002;21(13):1945–54.
Barancik M, Bohacova V, Sedlak J, Sulova Z, Breier A. LY294, 002, a specific inhibitor of PI3K/Akt kinase pathway, antagonizes P-glycoprotein-mediated multidrug resistance. Eur J Pharm Sci. 2006;29(5):426–34.
Wolpin BM, Hezel AF, Abrams T, Blaszkowsky LS, Meyerhardt JA, Chan JA, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27(2):193–8.
Lim JC, Kania KD, Wijesuriya H, Chawla S, Sethi JK, Pulaski L, et al. Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells. J Neurochem. 2008;106(4):1855–65.
Bhattacharya S, Das A, Mallya K, Ahmad I. Maintenance of retinal stem cells by Abcg2 is regulated by notch signaling. J Cell Sci. 2007;120(Pt 15):2652–62.
Scotto KW. Transcriptional regulation of ABC drug transporters. Oncogene. 2003;22(47):7496–511.
Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernandez-Zapico ME, et al. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 2009;23(1):24–36.
Fernandez-Zapico ME. Primers on molecular pathways GLI: more than just hedgehog? Pancreatology. 2008;8(3):227–9.
Dean M. Cancer stem cells: redefining the paradigm of cancer treatment strategies. Mol Interv. 2006;6(3):140–8.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71–96.
Burris 3rd HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403–13.
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960–6.
Sultana A, Smith CT, Cunningham D, Starling N, Neoptolemos JP, Ghaneh P. Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol. 2007;25(18):2607–15.
Chen YJ, Sims-Mourtada J, Izzo J, Chao KS. Targeting the hedgehog pathway to mitigate treatment resistance. Cell Cycle. 2007;6(15):1826–30.
Sims-Mourtada J, Izzo JG, Apisarnthanarax S, Wu TT, Malhotra U, Luthra R, et al. Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res. 2006;12(21):6565–72.
Sims-Mourtada J, Izzo JG, Ajani J, Chao KS. Sonic hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene. 2007;26(38):5674–9.
Lou H, Dean M. Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene. 2007;26(9):1357–60.
Barginear MF, Leung M, Budman DR. The hedgehog pathway as a therapeutic target for treatment of breast cancer. Breast Cancer Res Treat. 2009;116(2):239–46.
Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68(3):918–26.
Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–61.
Santisteban M, Reiman JM, Asiedu MK, Behrens MD, Nassar A, Kalli KR, et al. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 2009;69(7):2887–95.
Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009;69(6):2400–7.
Bissell MJ, Labarge MA. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell. 2005;7(1):17–23.
Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455(7211):406–10.
Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425(6960):851–6.
Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, et al. Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2007;104(12):5103–8.
Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, et al. Widespread requirement for hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425(6960):846–51.
Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007;67(5):2187–96.
Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1(3):313–23.
Mueller MT, Hermann PC, Witthauer J, Rubio-Viqueira B, Leicht SF, Huber S, Ellwart JW, Mustafa M, Bartenstein P, D'Haese JG, et al. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology. 2009;137:1102–13.
Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res. 2004;10(20):6956–61.
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Santisteban, M. ABC Transporters as Molecular Effectors of Pancreatic Oncogenic Pathways: The Hedgehog-GLI Model. J Gastrointest Canc 41, 153–158 (2010). https://doi.org/10.1007/s12029-010-9144-1
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DOI: https://doi.org/10.1007/s12029-010-9144-1