The implication of liquid biopsies to predict chemoresistance in pancreatic cancer

Abstract

Pancreatic cancer is one of the most aggressive diseases among solid tumors. Most patients are diagnosed with advanced or metastatic disease and are characterized by poor chemosensitivity. Therefore, earlier diagnosis and novel therapeutic possibilities for pancreatic cancer patients are urgently needed. Liquid biopsy is an emerging technology that allows the noninvasive sampling of tumor material. Nowadays, liquid biopsy has shown promising results as diagnostic, prognostic and predictive biomarkers, but it has not yet been universally adopted into regular use by clinicians. In this review, we describe different components of liquid biopsy, especially circulating tumor cells, circulating tumor DNA and exosomes and their potential clinical utility for pancreatic cancer patients.

Keywords

Pancreatic cancer / liquid biopsy / CTC / ctDNA / exosomes

References

[1] Hezel AF,Stanger BZ,Depinho RA.Genetics and biology of pancreatic ductal adenocarcinoma.Genes Dev2006;20:1218-49

[2] Yao W,Ying H.Recent insights into the biology of pancreatic cancer.EBioMedicine2020;53:102655 PMCID:PMC7118569

[3] Bhutani MS,Roy-Chowdhuri S,Pishvaian MJ.Upfront molecular profiling of pancreatic cancer patients - An idea whose time has come.Pancreatology2020;20:391-3

[4] Siegel RL,Jemal A.Cancer statistics, 2019.CA Cancer J Clin2019;69:7-34

[5] Balsano R,Garajova I.State of the Art for Metastatic Pancreatic Cancer Treatment: Where Are We Now?.Anticancer Res2019;39:3405-12

[6] Verdaguer H,Macarulla T.New horizons in the treatment of metastatic pancreatic cancer: A review of the key biology features and the most recent advances to treat metastatic pancreatic cancer.Target Oncol2018;13:691-704

[7] Mizrahi JD,Valle JW.Pancreatic cancer.Lancet2020;395:2008-20

[8] Conroy T,Ychou M.Groupe Tumeurs Digestives of UnicancerPRODIGE IntergroupFOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.N Engl J Med2011;364:1817-25

[9] Von Hoff DD,Arena FP.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.N Engl J Med2013;369:1691-703 PMCID:PMC4631139

[10] Caparello C,Garajova I.FOLFIRINOX and translational studies: Towards personalized therapy in pancreatic cancer.World J Gastroenterol2016;22:6987-7005 PMCID:PMC4988311

[11] Golan T,Reni M.Maintenance Olaparib for germline BRCA-mutated metastatic pancreatic cancer.N Engl J Med2019;381:317-27 PMCID:PMC6810605

[12] Kamyabi N,Maitra A.Liquid biopsies in pancreatic cancer.Expert Rev Anticancer Ther2019;19:869-78 PMCID:PMC6824837

[13] Petersen GM.Familial pancreatic cancer.Semin Oncol2016;43:548-53 PMCID:PMC5234085

[14] Birnbaum DJ,Finetti P,Mamessier E.Molecular classification as prognostic factor and guide for treatment decision of pancreatic cancer.Biochim Biophys Acta Rev Cancer2018;1869:248-55

[15] Lee JS,Lee YK,Jeffrey SS.Liquid biopsy in pancreatic ductal adenocarcinoma: current status of circulating tumor cells and circulating tumor DNA.Mol Oncol2019;13:1623-50 PMCID:PMC6670020

[16] Biankin AV,Kassahn KS.Australian Pancreatic Cancer Genome InitiativePancreatic cancer genomes reveal aberrations in axon guidance pathway genes.Nature2012;491:399-405 PMCID:PMC3530898

[17] Bailey P,Nones K.Genomic analyses identify molecular subtypes of pancreatic cancer.Nature2016;531:47-52

[18] Genome Atlas Research Network. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma.Cancer Cell2017;32:185-203.e13 PMCID:PMC5964983

[19] Bazzichetto C,Luchini C.From genetic alterations to tumor microenvironment: The Ariadne's string in pancreatic cancer.Cells2020;9:309 PMCID:PMC7072496

[20] Lai E,Ziranu P.New therapeutic targets in pancreatic cancer.Cancer Treat Rev2019;81:101926

[21] Witkiewicz AK,Balaji U.Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets.Nat Commun2015;6:6744 PMCID:PMC4403382

[22] Collisson EA,Chang DK.Molecular subtypes of pancreatic cancer.Nat Rev Gastroenterol Hepatol2019;16:207-20

[23] Moffitt RA,Flate EL.Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.Nat Genet2015;47:1168-78 PMCID:PMC4912058

[24] Waddell N,Patch AM.Whole genomes redefine the mutational landscape of pancreatic cancer.Nature2015;518:495-501 PMCID:PMC4523082

[25] Sinkala M,Martin D.Machine learning and network analyses reveal disease subtypes of pancreatic cancer and their molecular characteristics.Sci Rep2020;10:1212 PMCID:PMC6985164

[26] Erkan M,Kleeff J.The role of hypoxia in pancreatic cancer: a potential therapeutic target?.Expert Rev Gastroenterol Hepatol2016;10:301-16

[27] Perdiguero E, Geissmann F. Cancer immunology. Identifying the infiltrators.Science2014;344:801-2

[28] Ren B,Yang G.Tumor microenvironment participates in metastasis of pancreatic cancer.Mol Cancer2018;17:108 PMCID:PMC6065152

[29] Torres C.Pancreatic cancer subtypes: a roadmap for precision medicine.Ann Med2018;50:277-87 PMCID:PMC6151873

[30] Samandari M,Rice A,Del Rio Hernandez AE.Liquid biopsies for management of pancreatic cancer.Transl Res2018;201:98-127

[31] Alix-Panabières C,Pantel K.Epithelial-mesenchymal plasticity in circulating tumor cells.J Mol Med (Berl)2017;95:133-42

[32] Micalizzi DS,Haber DA.A conduit to metastasis: circulating tumor cell biology.Genes Dev2017;31:1827-40 PMCID:PMC5695084

[33] Dianat-Moghadam H,Eslami-S Z.The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance.Cancers (Basel)2020;12:867 PMCID:PMC7225923

[34] Aceto N,Miyamoto DT.Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis.Cell2014;158:1110-22 PMCID:PMC4149753

[35] Cheung KJ.A collective route to metastasis: Seeding by tumor cell clusters.Science2016;352:167-9

[36] Gilmore AP.Anoikis.Cell Death Differ2005;12 Suppl 2:1473-7

[37] Krog BL.Biomechanics of the circulating tumor cell microenvironment. In: Dong C, Zahir N, Konstantopoulos K, editors. Biomechanics in Oncology. Cham: Springer International Publishing; 2018. pp. 209-33.

[38] Kim YN,Sung JY,Kim H.Anoikis resistance: an essential prerequisite for tumor metastasis.Int J Cell Biol2012;2012:306879 PMCID:PMC3296207

[39] Nicolazzo C,Carpino G,Raimondi C.Molecular characterization of circulating tumor cells to study cancer immunoevasion.Methods Mol Biol2019;1884:247-58

[40] Lin E,Nagrath S.Circulating tumor cells: Diagnostic and therapeutic applications.Annu Rev Biomed Eng2018;20:329-52

[41] Chouaib S,Tittarelli A,Thiery JP.Tumor plasticity interferes with anti-tumor immunity.Crit Rev Immunol2014;34:91-102

[42] Labelle M,Hynes RO.Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis.Cancer Cell2011;20:576-90 PMCID:PMC3487108

[43] Adorno-Cruz V,Liu X.Cancer stem cells: targeting the roots of cancer, seeds of metastasis, and sources of therapy resistance.Cancer Res2015;75:924-9 PMCID:PMC4359955

[44] Poruk KE,Saunders T.Circulating tumor cell phenotype predicts recurrence and survival in pancreatic adenocarcinoma.Ann Surg2016;264:1073-81 PMCID:PMC4936958

[45] Mani SA,Liao MJ.The epithelial-mesenchymal transition generates cells with properties of stem cells.Cell2008;133:704-15 PMCID:PMC2728032

[46] Luo YT,Feng X,Wang YW.The viable circulating tumor cells with cancer stem cells feature, where is the way out?.J Exp Clin Cancer Res2018;37:38 PMCID:PMC5828305

[47] Dasgupta A,Ghajar CM.Circulating and disseminated tumor cells: harbingers or initiators of metastasis?.Mol Oncol2017;11:40-61 PMCID:PMC5423226

[48] Sosa MS,Aguirre-Ghiso JA.Mechanisms of disseminated cancer cell dormancy: an awakening field.Nat Rev Cancer2014;14:611-22 PMCID:PMC4230700

[49] DiPardo BJ,Court CM.Pancreatic cancer circulating tumor cells: applications for personalized oncology.Expert Rev Mol Diagn2018;18:809-20

[50] Arnoletti JP,Reza J.Pancreatic and bile duct cancer circulating tumor cells (CTC) form immune-resistant multi-cell type clusters in the portal venous circulation.Cancer Biol Ther2018;19:887-97 PMCID:PMC6300340

[51] Court CM,Hou S,Tomlinson JS.Improving pancreatic cancer diagnosis using circulating tumor cells: prospects for staging and single-cell analysis.Expert Rev Mol Diagn2015;15:1491-504 PMCID:PMC4893319

[52] Han L,Zhao Q.Prognostic value of circulating tumor cells in patients with pancreatic cancer: a meta-analysis.Tumour Biol2014;35:2473-80

[53] Ren C,Zhang J.Detection of apoptotic circulating tumor cells in advanced pancreatic cancer following 5-fluorouracil chemotherapy.Cancer Biol Ther2011;12:700-6

[54] Wang Y,Hartmann D.Circulating tumor cells in peripheral blood of pancreatic cancer patients and their prognostic role: a systematic review and meta-analysis.HPB (Oxford)2020;22:660-9

[55] Pantel K,Scher HI.Circulating tumor cells in prostate cancer: From discovery to clinical utility.Clin Chem2019;65:87-99

[56] Paoletti C,Dolce EM.Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.Clin Cancer Res2018;24:5860-72

[57] Carter L,Mesquita B.Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer.Nat Med2017;23:114-9

[58] Kilgour E,Brady G.Liquid biopsy-based biomarkers of treatment response and resistance.Cancer Cell2020;37:485-95

[59] Yu KH,Hidalgo M.Pharmacogenomic modeling of circulating tumor and invasive cells for prediction of chemotherapy response and resistance in pancreatic cancer.Clin Cancer Res2014;20:5281-9 PMCID:PMC4346320

[60] Martini V,Fichtner-Feigl S,Kulemann B.Circulating tumor cells in pancreatic cancer: Current perspectives.Cancers (Basel)2019;11:1659 PMCID:PMC6895979

[61] Hadano N,Uemura K.Prognostic value of circulating tumour DNA in patients undergoing curative resection for pancreatic cancer.Br J Cancer2016;115:59-65 PMCID:PMC4931379

[62] Oellerich M,Beck J.Using circulating cell-free DNA to monitor personalized cancer therapy.Crit Rev Clin Lab Sci2017;54:205-18

[63] Kruger S,Ross C.Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer.Ann Oncol2018;29:2348-55

[64] Wei T,Li X.Monitoring tumor burden in response to FOLFIRINOX chemotherapy via profiling circulating cell-free DNA in pancreatic cancer.Mol Cancer Ther2019;18:196-203

[65] Cheng H,Jiang J.Analysis of ctDNA to predict prognosis and monitor treatment responses in metastatic pancreatic cancer patients.Int J Cancer2017;140:2344-50

[66] Watanabe F,Tamaki S.Longitudinal monitoring of KRAS-mutated circulating tumor DNA enables the prediction of prognosis and therapeutic responses in patients with pancreatic cancer.PLoS One2019;14:e0227366 PMCID:PMC6938323

[67] Del Re M,Rofi E.Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer.Sci Rep2017;7:7931 PMCID:PMC5554237

[68] Zhou X,Wang T,Zhu W.Plasma miRNAs in diagnosis and prognosis of pancreatic cancer: A miRNA expression analysis.Gene2018;673:181-93

[69] Madhavan B,Galli U.Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity.Int J Cancer2015;136:2616-27

[70] Katsiougiannis S,Kim Y,Wong DT.Saliva exosomes from pancreatic tumor-bearing mice modulate NK cell phenotype and antitumor cytotoxicity.FASEB J2017;31:998-1010 PMCID:PMC5295729

[71] Grunvald MW,Kuzel TM,Masood A.Current status of circulating tumor DNA liquid biopsy in pancreatic cancer.Int J Mol Sci2020;21:7651 PMCID:PMC7589736

[72] Edgar JR.Q&A: What are exosomes, exactly?.BMC Biol2016;14:46 PMCID:PMC4906597

[73] Lan B,Grützmann R.The Role of Exosomes in Pancreatic Cancer.Int J Mol Sci2019;20:4332 PMCID:PMC6770781

[74] Abue M,Shibuya R.Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer.Int J Oncol2015;46:539-47 PMCID:PMC4277249

[75] Goto T,Konishi H.An elevated expression of serum exosomal microRNA-191, - 21, -451a of pancreatic neoplasm is considered to be efficient diagnostic marker.BMC Cancer2018;18:116 PMCID:PMC5793347

[76] Xu YF,Zhao YD,Ding WQ.Plasma exosome miR-196a and miR-1246 are potential indicators of localized pancreatic cancer.Oncotarget2017;8:77028-40 PMCID:PMC5652761

[77] Su Q,Qu YL.Serum level of co-expressed hub miRNAs as diagnostic and prognostic biomarkers for pancreatic ductal adenocarcinoma.J Cancer2018;9:3991-9 PMCID:PMC6218787

[78] Zhu Y,Wang F.Differential MicroRNA Expression Profiles as Potential Biomarkers for Pancreatic Ductal Adenocarcinoma.Biochemistry (Mosc)2019;84:575-82

[79] Park JK,Esau C.Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma.Pancreas2009;38:e190-9

[80] Jamieson NB,Morton JP.MicroRNA molecular profiles associated with diagnosis, clinicopathologic criteria, and overall survival in patients with resectable pancreatic ductal adenocarcinoma.Clin Cancer Res2012;18:534-45

[81] Yu J,Mizumoto K,Nakata K.MicroRNA miR-17-5p is overexpressed in pancreatic cancer, associated with a poor prognosis, and involved in cancer cell proliferation and invasion.Cancer Biol Ther2010;10:748-57

[82] Miyamae M,Ichikawa D.Plasma microRNA profiles: identification of miR-744 as a novel diagnostic and prognostic biomarker in pancreatic cancer.Br J Cancer2015;113:1467-76 PMCID:PMC4815891

[83] Preis M,Gordon SR.MicroRNA-10b expression correlates with response to neoadjuvant therapy and survival in pancreatic ductal adenocarcinoma.Clin Cancer Res2011;17:5812-21 PMCID:PMC3167031

[84] Meijer LL,Caparello C.Plasma miR-181a-5p Downregulation Predicts Response and Improved Survival After FOLFIRINOX in Pancreatic Ductal Adenocarcinoma.Ann Surg2020;271:1137-47

[85] Xia QS,Zhao X.Human SMG-1 is involved in gemcitabine-induced primary microRNA-155/BIC up-regulation in human pancreatic cancer PANC-1 cells.Pancreas2011;40:55-60

[86] Melo SA,Kahlert C.Glypican-1 identifies cancer exosomes and detects early pancreatic cancer.Nature2015;523:177-82 PMCID:PMC4825698

[87] Frampton AE,López-Jiménez E.Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden.Oncotarget2018;9:19006-13 PMCID:PMC5922373

[88] Buscail E,Quincy P.High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery.Cancers (Basel)2019;11:1656 PMCID:PMC6895804

[89] Aspe JR,Jutzy JM,Whang S.Enhancement of Gemcitabine sensitivity in pancreatic adenocarcinoma by novel exosome-mediated delivery of the Survivin-T34A mutant.J Extracell Vesicles2014;3:23244 PMCID:PMC3929070

[90] Bernard V,San Lucas FA.Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer.Gastroenterology2019;156:108-118.e4 PMCID:PMC6434712

[91] Mason SD.Proteolytic networks in cancer.Trends Cell Biol2011;21:228-37 PMCID:PMC3840715

[92] Kalubowilage M,Malalasekera AP.Early detection of pancreatic cancers in liquid biopsies by ultrasensitive fluorescence nanobiosensors.Nanomedicine2018;14:1823-32

[93] Rubis G, Rajeev Krishnan S, Bebawy M. Liquid Biopsies in Cancer Diagnosis, Monitoring, and Prognosis.Trends Pharmacol Sci2019;40:172-86