نوع مقاله : مقاله مروری

نویسندگان

1 دانشجوی کارشناسی، گروه علوم زیستی، دانشکده علوم پایه، موسسه آموزش عالی ربع رشید، تبریز، ایران

2 استادیار، گروه علوم زیستی، دانشکده علوم پایه، موسسه آموزش عالی ربع رشید، تبریز، ایران

چکیده

سرطان پانکراس رتبه چهارم مرگ‌و‌میرهای ناشی از سرطان را به خود اختصاص داده است. بقای مبتلایان به آن بسیار پایین بوده و میزان مرگ‌و‌میر آن در مردان بیش‌تر از زنان می‌باشد. عوامل مختلف ارثی و غیرارثی در شکل‌گیری سرطان پانکراس دخیل هستند که از جمله عوامل مهم غیرارثی می‌توان به سیگار کشیدن اشاره نمود. علاوه بر این، مشخص شده است که خطر ابتلا به سرطان پانکراس در بیماران مبتلا به دیابت ملیتوس دو برابر افرادی است که دیابت ملیتوس ندارند. از شرایط ارثی نیز می‌توان به تغییرات ژنتیکی (فعال شدن آنکوژن‌ها و غیرفعال شدن ژن‌های سرکوبگر تومور) و اپی ژنتیکی (ncRNA) اشاره کرد. جهش در آنکوژن KRAS در 95 درصد مبتلایان به سرطان پانکراس دیده می‌شود. علی‌رغم کاربرد معمول سونوگرافی و نشانگرهای تومور در تشخیص سرطان پانکراس، اهمیت آن‌ها به عنوان ابزار تشخیصی قدرتمند دچار چالش شده است. نوآوری در استراتژی‌های درمانی رایج مثل شیمی‌درمانی و ایمنی‌درمانی و نیز ژن‌درمانی بر پایه حامل‌های ژنتیکی ابزار نوید‌بخشی را برای درمان فراهم کرده است. استفاده از ویروس‌های آنکولیتیک با ویژگی تکثیر انتخابی در سلول‌های سرطانی و عوارض جانبی حداقل، چشم‌انداز جدیدی را برای آینده درمانی این سرطان گشوده است. علاوه بر این، فناوری‌های نوین ویرایش ژنی از جمله کریسپر دست‌ورزی ژنوم سلول‌های سرطانی را در جهت شناسایی و تنظیم مسیرهای مولکولی دخیل در سرطان پانکراس ممکن کرده است. با توجه به اینکه تغییرات ژنتیکی و اپی ژنتیکی متعدد در بیماری‌زایی این سرطان نقش دارد، کنترل همزمان این مسیرها با روش‌های درمانی متعدد می‌تواند استراتژی درمانی مفیدی برای سرطان پانکراس باشد.

کلیدواژه‌ها

عنوان مقاله [English]

Pancreatic Cancer: From Genome to New Therapies

نویسندگان [English]

  • Mahsa Moshari 1
  • Asiyeh Jebelli 2

1 Student of B.Sc., Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid, Tabriz, Iran

2 Assistant Professor, Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid, Tabriz, Iran

چکیده [English]

Pancreatic cancer is ranked as the fourth leading cause of cancer related death. The survival rate of patients is very low and the mortality rate in men is higher than that of women. Various hereditary and non- hereditary factors are involved in the formation of pancreatic cancer; one of the important non- hereditary factors is smoking. Besides, it is known that the risk of pancreatic cancer in patients with diabetes mellitus is twice as high as in the non-diabetic population. Hereditary conditions also include genetic (activation of oncogenes and inactivation of tumor suppressor genes) and epigenetic changes (lncRNA). The mutation in KRAS oncogene is observed in 95% of the patients with pancreatic cancer. Despite the common use of ultrasound and tumor markers in diagnosing pancreatic cancer, their importance as powerful diagnostic tools has been challenged. An innovation in common therapeutic strategies such as chemotherapy, immunotherapy, and gene therapy based on genetic vectors has provided a promising tool for treatment.  Using oncolytic viruses with selective proliferation in cancer cells and minimal adverse effects has opened a new perspective on the future of treatment of this cancer. In addition, novel technologies in gene editing including CRISPR have allowed the genome manipulation of cancer cells to identify and regulate the molecular pathways involved in pancreatic cancer. Considering that multiple genetic and epigenetic changes play a role in the pathogenesis of this cancer, simultaneous control of these pathways with multiple therapies can be a useful therapeutic strategy for pancreatic cancer.

کلیدواژه‌ها [English]

  • Pancreatic cancer
  • Genetics
  • Oncolytic Viruses
  • CRISPR
  1. Kanji ZS, Gallinger S. Diagnosis and management of pancreatic cancer. CMAJ. 2013;185(14):1219-26.
  2. Salem AA, Mackenzie GG. Pancreatic cancer: A critical review of dietary risk. Nutrition Research. 2018;52:1-13.
  3. Del Chiaro M, Segersvärd R, Lohr M, Verbeke C. Early detection and prevention of pancreatic cancer: is it really possible today? World J Gastroenterol 2014;20(34):12118-30.
  4. Pourshams A, Kazemi B, Kalantari S. A review of the etiology and biomarkers of pancreatic cancer, with emphasis on the role of diabetes: review article. Tehran Univ Med J. 2018;75(11):773-8.
  5. Fazeli Z, Fazeli Bavandpour F, Abdi A, Pour Hosaingholi M, Bastaminezhad. Trend analysis of Pancreatic Cancer Mortality in Iran. JIUMS. 2013;20(4):239-45.
  6. Pourhoseingholi MA, Fazeli Z, Ashtari S, Bavand-Pour FSF. Mortality trends of gastrointestinal cancers in Iranian population. Gastroenterol Hepatol Bed Bench. 2013;6(Suppl 1):52-7.
  7. Taefi A, Noraee M, Ghorbani A, Fakheri H, Zaheri MJ, Semnani A, et al. Investigation of the incidence of pancreatic and bile ducts cancers in Iran: a population-based study. Govaresh. 2008;13(4):217-22.
  8. Thomas C. Risk factors, biomarker and imaging techniques used for pancreatic cancer screening. Chin Clin Oncol. 2017;6(6):1-10.
  9. Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, et al. Pancreatic cancer. Nat Rev Dis Primers. 2016;2:16022-35.
  10. Kikuyama M, Kamisawa T, Kuruma S, Chiba K, Kawaguchi S, Terada S, et al. Early Diagnosis to Improve the Poor Prognosis of Pancreatic Cancer. Cancers. 2018;10(2):48-54.
  11. Freelove R, Walling A. Pancreatic Cancer: Diagnosis and Management. Am Fam Physician. 2006;73(3):485-92.
  12. Cicenas J, Kvederaviciute K, Meskinyte I, Meskinyte-Kausiliene E, Skeberdyte A, Cicenas J. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 mutations in pancreatic cancer. Cancers. 2017;9(5):42-7.
  13. Khan MA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, et al. Molecular drivers of pancreatic cancer pathogenesis: looking inward to move forward. Int J Mol Sci. 2017;18(4):779-86.
  14. Eser S, Schnieke A, Schneider G, Saur D. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014;111:817-22.
  15. Muzumdar MD, Chen P-Y, Dorans KJ, Chung KM, Bhutkar A, Hong E, et al. Survival of pancreatic cancer cells lacking KRAS function. Nat Commun. 2017;8(1):1090-101.
  16. Srivastava SK, Bhardwaj A, Arora S, Singh S, Azim S, Tyagi N, et al. MYB is a novel regulator of pancreatic tumour growth and metastasis. Br J Cancer. 2015;113(12):1694-703.
  17. Tyagi N, Marimuthu S, Bhardwaj A, Deshmukh SK, Srivastava SK, Singh AP, et al. p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling. Cancer lett. 2016;370(2):260-7.
  18. Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer. 2013;108(2):469-76.
  19. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14(2):130-46.
  20. Naderi E, Mostafaei M, Pourshams A, Mohamadkhani A. Network of microRNAs-mRNAs interactions in pancreatic cancer. Biomed Res Int. 2014;2014:1-8.
  21. Moschovis D, Gazouli M, Tzouvala M, Vezakis A, Karamanolis G. Long non-coding RNA in pancreatic adenocarcinoma and pancreatic neuroendocrine tumors. Annals of Gastroenterology. 2017;30(6):622-8.
  22. Wang F, Herrington M, Larsson J, Permert J. The relationship between diabetes and pancreatic cancer. Mol cancer. 2003;2(1):4-9.
  23. Mizuno S, Nakai Y, Isayama H, Yanai A, Takahara N, Miyabayashi K, et al. Risk factors and early signs of pancreatic cancer in diabetes: screening strategy based on diabetes onset age. Am J Gastroenterol. 2013;48(2):238-46.
  24. Darmawan G, Simadibrata M. Pancreatic Cancer: Review of Etiology, Clinical Features, Diagnostic Procedures, Treatment and Mesothelin Role. Indo J Gastro Hepa Diges Endo. 2011;12(1):44-9.
  25. Chang JC, Kundranda M. Novel diagnostic and predictive biomarkers in pancreatic adenocarcinoma. Int J Mol Sci. 2017;18(3):667-71.
  26. Rouanet M, Lebrin M, Gross F, Bournet B, Cordelier P, Buscail L. Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes. Int J Mol Sci. 2017;18(6):1231-40.
  27. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014;15(8):541-55.
  28. Midoux P, Pichon C, Yaouanc JJ, Jaffrès PA. Chemical vectors for gene delivery: a current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers. Br J Pharmacol. 2009;157(1):166-78.
  29. Bertrand E, Gonçalves C, Billiet L, Gomez JP, Pichon C, Cheradame H, et al. Histidinylated linear PEI: a new efficient non-toxic polymer for gene transfer. Chem comm. 2011;47(46):12547-9.
  30. Kasuya H, Takeda S, Nomoto S, Nakao A. The potential of oncolytic virus therapy for pancreatic cancer. Cancer Gene Ther. 2005;12:725-36.
  31. Nishimoto T, Yoshida K, Miura Y, Kobayashi A, Hara H, Ohnami S, et al. Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob. Gene Ther. 2009;16:669-80.
  32. Nakao A, Takeda S, Shimoyama S, Kasuya H, Kimata H, Teshigahara O, et al. Clinical experiment of mutant herpes simplex virus HF10 therapy for cancer. Curr Cancer Drug Targets. 2007;7(2):169-74.
  33. Nakao A, Kasuya H, Sahin T, Nomura N, Kanzaki A, Misawa M, et al. A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer. Cancer Gene Ther. 2011;18(3):167-75.
  34. O’Leary MP, Choi AH, Kim S-I, Chaurasiya S, Lu J, Park AK, et al. Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal effect at a single low dose. J Transl Med 2018;16(1):110-8.
  35. Butler K. Reviews of Science for Science Librarians: CRISPR-Cas9 Revolutionizes Gene Editing. Sci & Tech Libraries. 2016;35(3):221-7.
  36. Garneau JE, Dupuis M-È, Villion M, Romero DA, Barrangou R, Boyaval P, et al. The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. Nature. 2010;468:67.
  37. Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA, Mikkelson T, et al. Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells. Sci. 2013;343:84-7.
  38. Kelley ML, Strezoska Ž, He K, Vermeulen A, Smith AvB. Versatility of chemically synthesized guide RNAs for CRISPR-Cas9 genome editing. Journal of Biotechnology. 2016;233:74-83.
  39. Chiou S-H, Winters IP, Wang J, Naranjo S, Dudgeon C, Tamburini FB, et al. Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing. Genes Dev. 2015;29:1-10.
  40. Maresch R, Mueller S, Veltkamp C, Öllinger R, Friedrich M, Heid I, et al. Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice. Nat Commun. 2016;7:10777-86.
  41. Lehner F, Kulik U, Klempnauer J, Borlak J. The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. The FASEB Journal. 2007;21(7):1445-62.
  42. Li J, Zhang Y, Gao Y, Cui Y, Liu H, Li M, et al. Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer. Oncology reports. 2014;32(3):979-88.
  43. Vorvis C, Hatziapostolou M, Mahurkar-Joshi S, Koutsioumpa M, Williams J, Donahue TR, et al. Transcriptomic and CRISPR/Cas9 technologies reveal FOXA2 as a tumor suppressor gene in pancreatic cancer. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2016;310(11):G1124-G37.
  44. Seino T, Kawasaki S, Shimokawa M, Tamagawa H, Toshimitsu K, Fujii M, et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell stem cell. 2018;22(3):454-67.