Skip to main content

Advertisement

SpringerLink
Log in

New thoughts and findings on invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC) from comparative proteomics: multi-target therapy

  • REVIEW ARTICLE
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

As one of the most aggressive malignant tumors, pancreatic ductal adenocarcinoma (PDAC) ranks as the fourth cancer-related mortality in the world. The extremely low survival rate is closely related to early invasion and distant metastasis. However, effective target therapy for weakening its malignant behavior remains limited. Over the past decades, many proteins correlating with invasion and metastasis of PDAC have been discovered using proteomics. The discovery of these proteins gives us a deeper understanding of the invasive and migratory processes of PDAC. This review is a systemic integration of these proteomics findings over the past 10 years. The discovered proteins were typically associated with the glycolytic process, hypoxic microenvironment, post-translational modification, extracellular matrix, exosomes, cancer stem cells, and immune escape. Some proteins were found to have multiple functions, and, cooperation between different proteins in the invasive and metastatic processes was found. This cooperation, and not just single protein function, may play a more significant role in the poor prognosis of PDAC. Therefore, multi-target therapy against these cooperative networks should be a primary choice in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The raw date supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

References

  1. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607–20. https://doi.org/10.1016/S0140-6736(10)62307-0.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jin K, Li T, van Dam H, Zhou F, Zhang L. Molecular insights into tumour metastasis: tracing the dominant events. J Pathol. 2017;241(5):567–77. https://doi.org/10.1002/path.4871.

    Article  CAS  PubMed  Google Scholar 

  3. Hanash S, Taguchi A. Application of proteomics to cancer early detection. Cancer J. 2011;17(6):423–8. https://doi.org/10.1097/PPO.0b013e3182383cab.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cox J, Mann M. Is proteomics the new genomics? Cell. 2007;130(3):395–8. https://doi.org/10.1016/j.cell.2007.07.032.

    Article  CAS  PubMed  Google Scholar 

  5. Minden J. Comparative proteomics and difference gel electrophoresis. Biotechniques. 2007;43(6):739 (41, 43 passim).

    Article  CAS  PubMed  Google Scholar 

  6. Sutton CW, Rustogi N, Gurkan C, Scally A, Loizidou MA, Hadjisavvas A, et al. Quantitative proteomic profiling of matched normal and tumor breast tissues. J Proteome Res. 2010;9(8):3891–902. https://doi.org/10.1021/pr100113a.

    Article  CAS  PubMed  Google Scholar 

  7. Bittremieux W, Tabb DL, Impens F, Staes A, Timmerman E, Martens L, et al. Quality control in mass spectrometry-based proteomics. Mass Spectrom Rev. 2018;37(5):697–711. https://doi.org/10.1002/mas.21544.

    Article  CAS  PubMed  Google Scholar 

  8. Schaffer LV, Millikin RJ, Miller RM, Anderson LC, Fellers RT, Ge Y, et al. Identification and quantification of proteoforms by mass spectrometry. Proteomics. 2019;19(10):e1800361. https://doi.org/10.1002/pmic.201800361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124(3215):269–70.

    Article  CAS  PubMed  Google Scholar 

  10. Ganapathy-Kanniappan S. Molecular intricacies of aerobic glycolysis in cancer: current insights into the classic metabolic phenotype. Crit Rev Biochem Mol Biol. 2018;53(6):667–82. https://doi.org/10.1080/10409238.2018.1556578.

    Article  CAS  PubMed  Google Scholar 

  11. Zhou W, Capello M, Fredolini C, Racanicchi L, Piemonti L, Liotta LA, et al. Proteomic analysis reveals Warburg effect and anomalous metabolism of glutamine in pancreatic cancer cells. J Proteome Res. 2012;11(2):554–63. https://doi.org/10.1021/pr2009274.

    Article  CAS  PubMed  Google Scholar 

  12. Ma D, Wang J, Zhao Y, Lee WN, Xiao J, Go VL, et al. Inhibition of glycogen phosphorylation induces changes in cellular proteome and signaling pathways in MIA pancreatic cancer cells. Pancreas. 2012;41(3):397–408. https://doi.org/10.1097/MPA.0b013e318236f022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tan X, Liu P, Huang Y, Zhou L, Yang Y, Wang H, et al. Phosphoproteome analysis of invasion and metastasis-related factors in pancreatic cancer cells. PLoS ONE. 2016;11(3):e0152280. https://doi.org/10.1371/journal.pone.0152280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shih HJ, Chang HF, Chen CL, Torng PL. Differential expression of hypoxia-inducible factors related to the invasiveness of epithelial ovarian cancer. Sci Rep. 2021;11(1):22925. https://doi.org/10.1038/s41598-021-02400-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Baron B, Kitagawa T, Nakamura K, Kuramitsu Y. Isolation of a growth factor stress-induced pancreatic cancer sub-population: insight into changes due to micro-environment. Cancer Genom Proteom. 2015;12(2):49–55.

    CAS  Google Scholar 

  16. Tsai YP, Yang MH, Huang CH, Chang SY, Chen PM, Liu CJ, et al. Interaction between HSP60 and beta-catenin promotes metastasis. Carcinogenesis. 2009;30(6):1049–57. https://doi.org/10.1093/carcin/bgp087.

    Article  CAS  PubMed  Google Scholar 

  17. Piselli P, Vendetti S, Vismara D, Cicconi R, Poccia F, Colizzi V, et al. Different expression of CD44, ICAM-1, and HSP60 on primary tumor and metastases of a human pancreatic carcinoma growing in scid mice. Anticancer Res. 2000;20(2A):825–31.

    CAS  PubMed  Google Scholar 

  18. Bhattacharya K, Picard D. The Hsp70-Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration. Cell Mol Life Sci. 2021;78(23):7257–73. https://doi.org/10.1007/s00018-021-03962-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ji S, Zhang B, Liu J, Qin Y, Liang C, Shi S, et al. ALDOA functions as an oncogene in the highly metastatic pancreatic cancer. Cancer Lett. 2016;374(1):127–35. https://doi.org/10.1016/j.canlet.2016.01.054.

    Article  CAS  PubMed  Google Scholar 

  20. Paolillo M, Schinelli S. Extracellular matrix alterations in metastatic processes. Int J Mol Sci. 2019. https://doi.org/10.3390/ijms20194947.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chen R, Brentnall TA, Pan S, Cooke K, Moyes KW, Lane Z, et al. Quantitative proteomics analysis reveals that proteins differentially expressed in chronic pancreatitis are also frequently involved in pancreatic cancer. Mol Cell Proteomics. 2007;6(8):1331–42. https://doi.org/10.1074/mcp.M700072-MCP200.

    Article  CAS  PubMed  Google Scholar 

  22. Mahajan UM, Goni E, Langhoff E, Li Q, Costello E, Greenhalf W, et al. Cathepsin D expression and gemcitabine resistance in pancreatic cancer. JNCI Cancer Spectr. 2020;4(1):pkz060. https://doi.org/10.1093/jncics/pkz060.

    Article  PubMed  Google Scholar 

  23. Alfano D, Franco P, Stoppelli MP. Modulation of cellular function by the urokinase receptor signalling: a mechanistic view. Front Cell Dev Biol. 2022;10:818616. https://doi.org/10.3389/fcell.2022.818616.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Grossmann NC, Schuettfort VM, Pradere B, Moschini M, Quhal F, Mostafaei H, et al. Further understanding of urokinase plasminogen activator overexpression in urothelial bladder cancer progression, clinical outcomes and potential therapeutic targets. Onco Targets Ther. 2021;14:315–24. https://doi.org/10.2147/OTT.S242248.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kryczka J, Stasiak M, Dziki L, Mik M, Dziki A, Cierniewski C. Matrix metalloproteinase-2 cleavage of the beta1 integrin ectodomain facilitates colon cancer cell motility. J Biol Chem. 2012;287(43):36556–66. https://doi.org/10.1074/jbc.M112.384909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang H, Lv L, Liu H, Cui L, Chen G, Bi P, et al. Profiling the potential biomarkers for cell differentiation of pancreatic cancer using iTRAQ and 2-D LC-MS/MS. Proteomics Clin Appl. 2009;3(7):862–71. https://doi.org/10.1002/prca.200800029.

    Article  CAS  PubMed  Google Scholar 

  27. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020. https://doi.org/10.1126/science.aau6977.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ratajczak MZ, Ratajczak J. Extracellular microvesicles/exosomes: discovery, disbelief, acceptance, and the future? Leukemia. 2020;34(12):3126–35. https://doi.org/10.1038/s41375-020-01041-z.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Guay C, Menoud V, Rome S, Regazzi R. Horizontal transfer of exosomal microRNAs transduce apoptotic signals between pancreatic beta-cells. Cell Commun Signal. 2015;13:17. https://doi.org/10.1186/s12964-015-0097-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Singh R, Pochampally R, Watabe K, Lu Z, Mo YY. Exosome-mediated transfer of miR-10b promotes cell invasion in breast cancer. Mol Cancer. 2014;13:256. https://doi.org/10.1186/1476-4598-13-256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang J, Li S, Li L, Li M, Guo C, Yao J, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genom Proteom Bioinformat. 2015;13(1):17–24. https://doi.org/10.1016/j.gpb.2015.02.001.

    Article  CAS  Google Scholar 

  32. Ciardiello C, Cavallini L, Spinelli C, Yang J, Reis-Sobreiro M, de Candia P, et al. Focus on extracellular vesicles: new frontiers of cell-to-cell communication in cancer. Int J Mol Sci. 2016;17(2):175. https://doi.org/10.3390/ijms17020175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wortzel I, Dror S, Kenific CM, Lyden D. Exosome-mediated metastasis: communication from a distance. Dev Cell. 2019;49(3):347–60. https://doi.org/10.1016/j.devcel.2019.04.011.

    Article  CAS  PubMed  Google Scholar 

  34. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schafer R, Beerling E, et al. In Vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell. 2015;161(5):1046–57. https://doi.org/10.1016/j.cell.2015.04.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Blomme A, Fahmy K, Peulen O, Costanza B, Fontaine M, Struman I, et al. Myoferlin is a novel exosomal protein and functional regulator of cancer-derived exosomes. Oncotarget. 2016;7(50):83669–83. https://doi.org/10.18632/oncotarget.13276.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wang WS, Liu XH, Liu LX, Lou WH, Jin DY, Yang PY, et al. iTRAQ-based quantitative proteomics reveals myoferlin as a novel prognostic predictor in pancreatic adenocarcinoma. J Proteomics. 2013;91:453–65. https://doi.org/10.1016/j.jprot.2013.06.032.

    Article  CAS  PubMed  Google Scholar 

  37. Beck B, Blanpain C. Unravelling cancer stem cell potential. Nat Rev Cancer. 2013;13(10):727–38. https://doi.org/10.1038/nrc3597.

    Article  CAS  PubMed  Google Scholar 

  38. Koren E, Fuchs Y. The bad seed: Cancer stem cells in tumor development and resistance. Drug Resist Updat. 2016;28:1–12. https://doi.org/10.1016/j.drup.2016.06.006.

    Article  PubMed  Google Scholar 

  39. 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. https://doi.org/10.1016/j.stem.2007.06.002.

    Article  CAS  PubMed  Google Scholar 

  40. Sioud M, Mobergslien A, Boudabous A, Floisand Y. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation. Scand J Immunol. 2010;71(4):267–74. https://doi.org/10.1111/j.1365-3083.2010.02378.x.

    Article  CAS  PubMed  Google Scholar 

  41. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23(Suppl 8):viii6-9. https://doi.org/10.1093/annonc/mds256.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Rana R, Chauhan K, Gautam P, Kulkarni M, Banarjee R, Chugh P, et al. Plasma-derived extracellular vesicles reveal galectin-3 binding protein as potential biomarker for early detection of glioma. Front Oncol. 2021;11:778754. https://doi.org/10.3389/fonc.2021.778754.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kobayashi T, Shimura T, Yajima T, Kubo N, Araki K, Tsutsumi S, et al. Transient gene silencing of galectin-3 suppresses pancreatic cancer cell migration and invasion through degradation of beta-catenin. Int J Cancer. 2011;129(12):2775–86. https://doi.org/10.1002/ijc.25946.

    Article  CAS  PubMed  Google Scholar 

  44. Briukhovetska D, Dorr J, Endres S, Libby P, Dinarello CA, Kobold S. Interleukins in cancer: from biology to therapy. Nat Rev Cancer. 2021;21(8):481–99. https://doi.org/10.1038/s41568-021-00363-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cruceriu D, Baldasici O, Balacescu O, Berindan-Neagoe I. The dual role of tumor necrosis factor-alpha (TNF-alpha) in breast cancer: molecular insights and therapeutic approaches. Cell Oncol (Dordr). 2020;43(1):1–18. https://doi.org/10.1007/s13402-019-00489-1.

    Article  CAS  PubMed  Google Scholar 

  46. Syed V. TGF-beta Signaling in Cancer. J Cell Biochem. 2016;117(6):1279–87. https://doi.org/10.1002/jcb.25496.

    Article  CAS  PubMed  Google Scholar 

  47. Baumann P, Cremers N, Kroese F, Orend G, Chiquet-Ehrismann R, Uede T, et al. CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res. 2005;65(23):10783–93. https://doi.org/10.1158/0008-5472.CAN-05-0619.

    Article  CAS  PubMed  Google Scholar 

  48. Zhu J, Nie S, Wu J, Lubman DM. Target proteomic profiling of frozen pancreatic CD24+ adenocarcinoma tissues by immuno-laser capture microdissection and nano-LC–MS/MS. J Proteome Res. 2013;12(6):2791–804. https://doi.org/10.1021/pr400139c.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Geis N, Zell S, Rutz R, Li W, Giese T, Mamidi S, et al. Inhibition of membrane complement inhibitor expression (CD46, CD55, CD59) by siRNA sensitizes tumor cells to complement attack in vitro. Curr Cancer Drug Targets. 2010;10(8):922–31. https://doi.org/10.2174/156800910793357952.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang R, Liu Q, Liao Q, Zhao Y. CD59: a promising target for tumor immunotherapy. Future Oncol. 2018;14(8):781–91. https://doi.org/10.2217/fon-2017-0498.

    Article  CAS  PubMed  Google Scholar 

  51. Diegmann J, Junker K, Loncarevic IF, Michel S, Schimmel B, von Eggeling F. Immune escape for renal cell carcinoma: CD70 mediates apoptosis in lymphocytes. Neoplasia. 2006;8(11):933–8. https://doi.org/10.1593/neo.06451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kashima J, Hishima T, Okuma Y, Horio H, Ogawa M, Hayashi Y, et al. CD70 in thymic squamous cell carcinoma: potential diagnostic markers and immunotherapeutic targets. Front Oncol. 2021;11:808396. https://doi.org/10.3389/fonc.2021.808396.

    Article  PubMed  Google Scholar 

  53. Czernek L, Duchler M. Functions of cancer-derived extracellular vesicles in immunosuppression. Arch Immunol Ther Exp (Warsz). 2017;65(4):311–23. https://doi.org/10.1007/s00005-016-0453-3.

    Article  CAS  PubMed  Google Scholar 

  54. Hiroshima Y, Kasajima R, Kimura Y, Komura D, Ishikawa S, Ichikawa Y, et al. Novel targets identified by integrated cancer-stromal interactome analysis of pancreatic adenocarcinoma. Cancer Lett. 2020;469:217–27. https://doi.org/10.1016/j.canlet.2019.10.031.

    Article  CAS  PubMed  Google Scholar 

  55. Tiwari A, Tashiro K, Dixit A, Soni A, Vogel K, Hall B, et al. Loss of HIF1A from pancreatic cancer cells increases expression of PPP1R1B and degradation of p53 to promote invasion and metastasis. Gastroenterology. 2020;159(5):1882–97. https://doi.org/10.1053/j.gastro.2020.07.046.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

The authors declare that no funds, grants, or other support was received during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. 1st Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China

    Xinlu Liu

  2. Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China

    Na Li

Authors
  1. Xinlu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Na Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XL: involved in acquisition of data, analysis of data and drafting of the manuscript. NL: involved in critical revision of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Na Li.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Li, N. New thoughts and findings on invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC) from comparative proteomics: multi-target therapy. Clin Transl Oncol 25, 1991–1998 (2023). https://doi.org/10.1007/s12094-023-03106-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-023-03106-8

Keywords

Search

Navigation