Systems Oncology: Bridging Pancreatic and Castrate Resistant Prostate Cancer

  • A. FucicEmail author
  • A. Aghajanyan
  • Z. Culig
  • N. Le Novere


Large investments by pharmaceutical companies in the development of new antineoplastic drugs have not been resulting in adequate advances of new therapies. Despite the introduction of new methods, technologies, translational medicine and bioinformatics, the usage of collected knowledge is unsatisfactory. In this paper, using examples of pancreatic ductal adenocarcinoma (PaC) and castrate-resistant prostate cancer (CRPC), we proposed a concept showing that, in order to improve applicability of current knowledge in oncology, the re-clustering of clinical and scientific data is crucial. Such an approach, based on systems oncology, would include bridging of data on biomarkers and pathways between different cancer types. Proposed concept would introduce a new matrix, which enables combining of already approved therapies between cancer types. Paper provides a (a) detailed analysis of similarities in mechanisms of etiology and progression between PaC and CRPC, (b) diabetes as common hallmark of both cancer types and (c) knowledge gaps and directions of future investigations. Proposed horizontal and vertical matrix in cancer profiling has potency to improve current antineoplastic therapy efficacy. Systems biology map using Systems Biology Graphical Notation Language is used for summarizing complex interactions and similarities of mechanisms in biology of PaC and CRPC.


Pancreatic cancer Castrate resistant prostate cancer Cancer marker Systems oncology Cancer profiling 



Study was funded by institutional funds of Institute for Medical Research and Occupational Health through Croatian Ministry of Science and Education.

Compliance with Ethical Standards

Conflict of Interest

Authors declare no conflict of interest.


  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global Cancer statistics CA. Cancer J Clin 61:69–90CrossRefGoogle Scholar
  2. 2.
    Xiao AY, Tan ML, Wu LM, Asrani VM, Windsor JA, Yadav D, Petrov MS (2016) Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol 1(1):45–55CrossRefPubMedGoogle Scholar
  3. 3.
    Hirst CJ, Cabrera C, Kirby M (2012) Epidemiology of castration resistant prostate cancer: a longitudinal analysis using a UK primary care database. Cancer Epidemiol 36(6):e349–e353CrossRefPubMedGoogle Scholar
  4. 4.
    Steinkamp MP, O'Mahony OA, Brogley M, Rehman H, Lapensee EW, Dhanasekaran S, Hofer MD, Kuefer R, Chinnaiyan A, Rubin MA, Pienta KJ, Robins DM (2009) Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res 69(10):4434–4442CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    So A, Gleave M, Hurtado-Col A, Nelson C (2005) Mechanisms of the development of androgen independence in prostate cancer. World J Urol 23(1):1–9CrossRefPubMedGoogle Scholar
  6. 6.
    Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, Knudsen B, Hess DL, Nelson CC, Matsumoto AM, Bremner WJ, Gleave ME, Nelson PS (2007) Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res 67(10):5033–5041CrossRefPubMedGoogle Scholar
  7. 7.
    Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, Nelson PS (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68(11):4447–4454CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, Ettinger SL, Gleave ME, Nelson CC (2008) Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 68(15):6407–6415CrossRefPubMedGoogle Scholar
  9. 9.
    Leon CG, Locke JA, Adomat HH, Etinger SL, Twiddy AL, Neumann RD, Nelson CC, Guns ES, Wasan KM (2010) Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model. Prostate 70(4):390–400PubMedGoogle Scholar
  10. 10.
    Kolodecik T, Shugrue C, Ashat M, Thrower EC (2014) Risk factors for pancreatic cancer: underlying mechanisms and potential targets. Front Physiol 4:415CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bardeesy N, DePinho RA (2002) Pancreatic cancer biology and genetics. Nat Rev Cancer 2:897–909CrossRefPubMedGoogle Scholar
  12. 12.
    Polireddy K, Chen Q (2016) Cancer of the pancreas: molecular pathways and current advancement in treatment. J Cancer 7(11):1497–1514CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Becker AE, Hernandez YG, Frucht H, Lucas AL (2014) Pancreatic ductal adenocarcinoma: risk factors, screening, and early detection. World J Gastroenterol 20(32):11182–11198CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Rhee H, Gunter JH, Heathcote P, Ho K, Stricker P, Corcoran NM, Nelson CC (2015) Adverse effects of androgen-deprivation therapy in prostate cancer and their management. BJU Int 5(115 Supplement):3–13CrossRefGoogle Scholar
  15. 15.
    Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I (2002) Estradiol in elderly men. Aging Male 5:98–102CrossRefPubMedGoogle Scholar
  16. 16.
    Navarro Silvera SA, Miller AB, Rohan TE (2005) Hormonal and reproductive factors and pancreatic cancer risk: a prospective cohort study. Pancreas 30(4):369–374CrossRefPubMedGoogle Scholar
  17. 17.
    Sun F, Zhang ZW, Tan EM, Lim ZL, Li Y, Wang XC, Chua SE, Li J, Cheung E, Yong EL (2016) Icaritin suppresses development of neuroendocrine differentiation of prostate cancer through inhibition of IL-6/STAT3 and aurora kinase a pathways in TRAMP mice. Carcinogenesis 37(7):701–711CrossRefPubMedGoogle Scholar
  18. 18.
    Kovvali G (2014) Systems oncology: a new paradigm in cancer research. J Carcinog 13:6CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chung WS, Stainier DY (2008) Intra-endodermal interactions are required for pancreatic beta cell induction. Dev Cell 14(4):582–593CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Habener JF, Kemp DM, Thomas MK (2005) Minireview: transcriptional regulation in pancreatic development. Endocrinology 146(3):1025–1034CrossRefPubMedGoogle Scholar
  21. 21.
    Kim SK, MacDonald RJ (2002) Signaling and transcriptional control of pancreatic organogenesis. Curr Opin Genet Dev 12(5):540–547CrossRefPubMedGoogle Scholar
  22. 22.
    Sugiyama T, Benitez CM, Ghodasara A, Liu L, McLean GW, Lee J, Blauwkamp TA, Nusse R, Wright CV, Gu G, Kim SK (2013) Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. Proc Natl Acad Sci U S A 110(31):12691–12696CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kim MS, Lee DY (2015) Insulin-like growth factor (IGF)-I and IGF binding proteins axis in diabetes mellitus. Ann Pediatr Endocrinol Metab 20(2):69–73CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Murtaugh LC (2008) The what, where, when and how of Wnt/β-catenin signaling in pancreas development. Organogenesis 4(2):81–86CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lee SH, Johnson DT, Luong R, Yu EJ, Cunha GR, Nusse R, Sun Z (2015) Wnt/β-catenin-responsive cells in prostatic development and regeneration. Stem Cells 33(11):3356–3367CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Prins GS, Putz O (2008) Review molecular signaling pathways that regulate prostate gland development. Differentiation 76(6):641–659CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ma F, Ye H, He HH, Gerrin SJ, Chen S, Tanenbaum BA, Cai C, Sowalsky AG, He L, Wang H, Balk SP, Yuan X (2016) SOX9 drives WNT pathway activation in prostate cancer. J Clin Invest 126(5):1745–1758CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Su Q, Xin L (2016) Notch signaling in prostate cancer: refining a therapeutic opportunity. Histol Histopathol 31(2):149–157PubMedGoogle Scholar
  29. 29.
    Gajula RP, Chettiar ST, Williams RD, Nugent K, Kato Y, Wang H, Malek R, Taparra K, Cades J, Annadanam A, Yoon AR, Fertig E, Firulli BA, Mazzacurati L, Burns TF, Firulli AB, An SS, Tran PT (2015) Structure-function studies of the bHLH phosphorylation domain of TWIST1 in prostate cancer cells. Neoplasia 17(1):16–31CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhu G, Zhau HE, He H, Zhang L, Shehata B, Wang X, Cerwinka WH, Elmore J, He D (2007) Sonic and desert hedgehog signaling in human fetal prostate development. Prostate 67(6):674–684CrossRefPubMedGoogle Scholar
  31. 31.
    Jo A, Denduluri S, Zhang B, Wang Z, Yin L, Yan Z, Kang R, Shi LL, Mok J, Lee MJ, Haydon RC (2014) The versatile functions of Sox9 in development, stem cells, and human diseases. Genes Diseases 1(2):149–161CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Yu M, Gipp J, Yoon JW, Iannaccone P, Walterhouse D, Bushman W (2009) Sonic hedgehog-responsive genes in the fetal prostate. J Biol Chem 284(9):5620–5629CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Verras M, Brown J, Li X et al (2004) Wnt3a growth factor induces androgen receptor-mediated transcription and enhances cell growth in human prostate cancer cells. Cancer Res 64(24):8860–8866CrossRefPubMedGoogle Scholar
  34. 34.
    Nakamoto M, Hisaoka M (2016) Clinicopathological implications of wingless/int1 (WNT) signaling pathway in pancreatic ductal adenocarcinoma. J UOEH 38(1):1–8CrossRefPubMedGoogle Scholar
  35. 35.
    Terris B, Cavard C (2014) Diagnosis and molecular aspects of solid- pseudopapillary neoplasms of the pancreas. Semin Diagn Pathol 31(6):484–490CrossRefPubMedGoogle Scholar
  36. 36.
    Corbishley TP, Iqbal MJ, Wilkinson ML et al (1986) Androgen receptor in human normal and malignant pancreatic tissue and cell lines. Cancer 57(10):1992–1995CrossRefPubMedGoogle Scholar
  37. 37.
    Glass JP, Parasher G, Arias-Pulido H et al (2011) Mesothelin and GPR30 staining among a spectrum of pancreatic epithelial neoplasms. Int J Surg Pathol 19(5):588–596CrossRefPubMedGoogle Scholar
  38. 38.
    Yeh S, Miyamoto H, Shima H et al (1998) From estrogen to androgen receptor: a new pathway for sex hormones in prostate. Proc Natl Acad Sci U S A 95(10):5527–5532CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhang Y, Coogan PF, Palmer JR et al (2010) A case–control study of reproductive factors, female hormone use, and risk of pancreatic cancer. Cancer Causes Control 21(3):473–478CrossRefPubMedGoogle Scholar
  40. 40.
    Jansa R, Prezelj J, Kocijancic A et al (1996) Androstanediol glucuronide in patients with pancreatic cancer and in those with chronic pancreatitis. Horm Metab Res 28(8):381–383CrossRefPubMedGoogle Scholar
  41. 41.
    Hsieh CL, Fei T, Chen Y et al (2014) RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc Natl Acad Sci U S A 111(20):7319–7324CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Dong Y, Matigian N et al (2008) Tissue-specific promoter utilisation of the kallikrein-related peptidase genes, KLK5 and KLK7, and cellular localisation of the encoded proteins suggest roles in exocrine pancreatic function. Biol Chem 389:99–109CrossRefPubMedGoogle Scholar
  43. 43.
    Iakovlev V, Siegel ER, Tsao MS et al (2012) Expression of kallikrein-related peptidase 7 predicts poor prognosis in patients with unresectable pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomark Prev 21(7):1135–1142CrossRefGoogle Scholar
  44. 44.
    Sandhu V, Wedge DC (2016) The genomic landscape of pancreatic and Periampullary adenocarcinoma. Cancer Res 76(17):5092–5102CrossRefPubMedGoogle Scholar
  45. 45.
    Parikh H, Wang Z, Pettigrew KA et al (2011) Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels. Hum Genet 129(6):675–685CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Raju I, Kaushal GP, Haun RS (2016) Epigenetic regulation of KLK7 gene expression in pancreatic and cervical cancer cells. Biol Chem 397(11):1135–1146CrossRefPubMedGoogle Scholar
  47. 47.
    Konduri S, Schwarz MA, Cafasso D et al (2007) Androgen receptor blockade in experimental combination therapy of pancreatic cancer. J Surg Res 142(2):378–386CrossRefPubMedGoogle Scholar
  48. 48.
    Qu Y, Dai B, Ye D et al (2015) Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep 5:7654CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zhang Z, Chen L, Wang H et al (2015) Inhibition of Plk1 represses androgen signaling pathway in castration-resistant prostate cancer. Cell Cycle 14(13):2142–2148CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Mao Y, Xi L, Li Q et al (2016) Regulation of cell apoptosis and proliferation in pancreatic cancer through PI3K/Akt pathway via polo-like kinase 1. Oncol Rep 36(1):49–56CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Song B, Liu XS, Rice SJ et al (2013) Plk1 phosphorylation of orc2 and hbo1 contributes to gemcitabine resistance in pancreatic cancer. Mol Cancer Ther 12(1):58–68CrossRefPubMedGoogle Scholar
  52. 52.
    Shao C, Ahmad N, Hodges K et al (2015) Inhibition of polo-like kinase 1 (Plk1) enhances the antineoplastic activity of metformin in prostate Cancer. J Biol Chem 290(4):2024–2033CrossRefPubMedGoogle Scholar
  53. 53.
    Sharifi N (2012) The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer. J Investig Med 60(2). CrossRefPubMedGoogle Scholar
  54. 54.
    Fernández-del Castillo C, Robles-Díaz G et al (1990) Pancreatic cancer and androgen metabolism: high androstenedione and low testosterone serum levels. Pancreas 5(5):515–518CrossRefPubMedGoogle Scholar
  55. 55.
    Chang TC, Lin H, Rogers KA et al (2013) Expression of aldo-keto reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung. Int J Clin Exp Pathol 6(11):2419–2429PubMedPubMedCentralGoogle Scholar
  56. 56.
    Zhu X, Leav I, Leung YK et al (2004) Dynamic regulation of estrogen receptor-β expression by DNA methylation during prostate cancer development and metastasis. Am J Pathol 164:2003–2012CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yeh TS, Jan YY, Chiu CT et al (2002) Characterisation of oestrogen receptor, progesterone receptor, trefoil factor 1, and epidermal growth factor and its receptor in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma. Gut 51(5):712–716CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Di Zazzo E, Galasso G et al (2016) Prostate cancer stem cells: the role of androgen and estrogen receptors. Oncotarget 7(1):193–208CrossRefPubMedGoogle Scholar
  59. 59.
    Sinha et al (2016) Concurrent androgen and estrogen ablation and inhibition of steroid biosynthetic enzyme treatment for castration-resistant prostate Cancer. Anticancer Res 36(8):3847–3854Google Scholar
  60. 60.
    Kanda T, Jiang X, Yokosuka O (2014) Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers. World J Gastroenterol 20(28):9229–9236PubMedPubMedCentralGoogle Scholar
  61. 61.
    Culig Z, Pencik J, Merkel O et al (2016) Breaking a paradigm: IL-6/STAT3 signaling suppresses metastatic prostate cancer upon ARF expression. Mol Cell Oncol 3(2):e1090048CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Matei DV, Renne G, Pimentel M et al (2012) Neuroendocrine differentiation in castration-resistant prostate cancer: a systematic diagnostic attempt. Clin Genitourin Cancer 10(3):164–173CrossRefPubMedGoogle Scholar
  63. 63.
    Parimi V, Goyal R, Poropatich K et al (2014) Neuroendocrine differentiation of prostate cancer: a review. Am J Clin Exp Urol 2(4):273–285PubMedPubMedCentralGoogle Scholar
  64. 64.
    Buchler P, Gukovskaya AS, Mouria M et al (2003) Prevention of metastatic pancreatic cancer growth in vivo by induction of apoptosis with genistein, a naturally occurring is flavonoid. Pancreas 26(3):264–273CrossRefPubMedGoogle Scholar
  65. 65.
    Ma HP, Ming LG, Ge BF et al (2011) Icariin is more potent than genistein in promoting osteoblast differentiation and mineralization in vitro. J Cell Biochem 112(3):916–923CrossRefPubMedGoogle Scholar
  66. 66.
    Chun JY, Nadiminty N, Dutt S et al (2009) Interleukin-6 regulates androgen synthesis in prostate Cancer cells. Clin Cancer Res 15(15):4815–4822CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Rojas A, Liu G, Coleman I et al (2011) IL-6 promotes prostate tumorigenesis and progression through autocrine cross-activation of IGF-IR. Oncogene 30(20):2345–2355CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Chandrasekar T, Yang JC, Gao AC et al (2015) Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol 4(3):365–380PubMedPubMedCentralGoogle Scholar
  69. 69.
    Ono H, Basson MD, Ito H (2016) P300 inhibition enhances gemcitabine-induced apoptosis of pancreatic cancer. Oncotarget 7(32):51301–51310CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Paladino D, Yue P, Furuya H et al (2016) A novel nuclear Src and p300 signaling axis controls migratory and invasive behavior in pancreatic cancer. Oncotarget 7(6):7253–7267CrossRefPubMedGoogle Scholar
  71. 71.
    Muniraj T, Chari ST (2012) Diabetes and pancreatic cancer. Minerva Gastroenterol Dietol 58(4):331–345PubMedPubMedCentralGoogle Scholar
  72. 72.
    Barnard RJ, Aronson WJ, Tymchuk CN et al (2002) Prostate cancer: another aspect of the insulin-resistance syndrome? Obes Rev 3(4):303–308CrossRefPubMedGoogle Scholar
  73. 73.
    Shevach J, Gallagher EJ, Kochukoshy T et al (2015) Concurrent diabetes mellitus may negatively influence clinical progression and response to androgen deprivation therapy in patients with advanced prostate. Cancer Front Oncol 5:129PubMedGoogle Scholar
  74. 74.
    Daka B, Rosen T, Jansson PA et al (2012) Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden. Endocr Connect 2(1):18–22CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Monteiro C, Sousa MV, Ribeiro R et al (2013) Genetic variants in AR and SHBG and resistance to hormonal castration in prostate cancer. Med Oncol 30(1):490CrossRefPubMedGoogle Scholar
  76. 76.
    Chuu CP, Kokontis JM, Hiipakka RA et al (2011) Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer. J Biomed Sci 23:18–63Google Scholar
  77. 77.
    Mayer MJ, Klotz LH, Venkateswaran V (2015) Metformin and prostate cancer stem cells: a novel therapeutic target. Prostate Cancer Prostatic Dis 18:303–309CrossRefPubMedGoogle Scholar
  78. 78.
    Duan W, Chen K et al (2017) Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression. Cancer Lett 385:225–233CrossRefPubMedGoogle Scholar
  79. 79.
    Schiewer MJ, Knudsen KEAM (2014) Ped up to treat prostate cancer: novel AMPK activators emerge for cancer therapy. EMBO Mol Med 6(4):439–441PubMedPubMedCentralGoogle Scholar
  80. 80.
    Ko AH, Wang F, Holly EA (2007) Pancreatic cancer and medical history in a population-based case-control study in the San Francisco Bay Area. California. Cancer Causes Control 18(8):809–819CrossRefPubMedGoogle Scholar
  81. 81.
    Sarosiek K, Gandhi AV, Saxena S, Kang CY, Chipitsyna GI, Yeo CJ, Arafat HA (2016) Hypothyroidism in pancreatic cancer: role of exogenous thyroid hormone in tumor invasion-preliminary observations. J Thyroid Res 2016:2454989. CrossRefGoogle Scholar
  82. 82.
    Morote J, Esquena S, Orsola A et al (2005) Effect of androgen deprivation therapy in the thyroid function test of patients with prostate cancer. Anti-Cancer Drugs 16(8):863–866CrossRefPubMedGoogle Scholar
  83. 83.
    Heidegger I, Nagele U, Pircher A et al (2014) Latent hypothyreosis as a clinical biomarker for therapy response under abiraterone acetate therapy. Anticancer Res 34(1):307–311PubMedGoogle Scholar
  84. 84.
    Yip YL, Novothy J, Edwards M et al (2003) Structural analysis of the erbb-2 receptor using monoclonal antibodies: implications for receptor signaling. Int J Cancer 104:303–309CrossRefPubMedGoogle Scholar
  85. 85.
    Craft N, Shostak Y, Carey M et al (1999) A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 5:280–285CrossRefPubMedGoogle Scholar
  86. 86.
    Choi HJ, Hong JK, Sung SY et al (2007) Expression of c-erbB-2 and Cyclooxygenase-2 in pancreatic ductal adenocarcinoma. Korean J Pathol 41:171–175Google Scholar
  87. 87.
    Hemi R, Paz K, Wertheim N et al (2002) Transactivation of ErbB2 and ErbB3 by tumor necrosis factor-alpha and anisomycin leads to impaired insulin signaling through serine/threonine phosphorylation of IRS proteins. J Biol Chem 277(11):8961–8969CrossRefPubMedGoogle Scholar
  88. 88.
    Komoto M, Nakata B, Amano R et al (2009) HER2 overexpression correlates with survival after curative resection of pancreatic cancer. Cancer Sci 100(7):1243–1247CrossRefPubMedGoogle Scholar
  89. 89.
    Murray NP, Reyes E, Fuentealba C et al (2015) Possible role of HER-2 in the progression of prostate Cancer from primary tumor to androgen independence. Asian Pac J Cancer Prev 16(15):6615–6619CrossRefPubMedGoogle Scholar
  90. 90.
    Fyssas I, Syrigos KN, Konstandoulakis MM et al (1997) Sex hormone levels in the serum of patients with pancreatic adenocarcinoma. Horm Metab Res 29(3):115–118CrossRefPubMedGoogle Scholar
  91. 91.
    Robles-Diaz G, Duarte-Rojo A (2001) Pancreas: a sex steroid-dependent tissue. Isr Med Assoc J 3(5):364–368PubMedGoogle Scholar
  92. 92.
    Hoare D, Skinner TA, Black A et al (2015) Serum follicle-stimulating hormone levels predict time to development of castration-resistant prostate cancer. Can Urol Assoc J 9(3–4):122–127PubMedPubMedCentralGoogle Scholar
  93. 93.
    Pinthus JH (2015) Follicle-stimulating hormone: a potential surrogate marker for androgen deprivation therapy oncological and systemic effects. Can Urol Assoc J 9(3–4):E226–E227CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Lepor H, Neal D, Shore ND (2012) LHRH agonists for the treatment of prostate Cancer: 2012. Rev Urol 14(1–2):1–12PubMedPubMedCentralGoogle Scholar
  95. 95.
    Bernardo GM, Keri RA (2012) FOXA1: a transcription factor with parallel functions in development and cancer. Biosci Rep 32(2):113–130CrossRefPubMedGoogle Scholar
  96. 96.
    Jin HJ, Zhao JC, Wu L et al (2014) Cooperativity and equilibrium with FOXA1 define the androgen receptor transcritptional program. Nature Comm 5:3972CrossRefGoogle Scholar
  97. 97.
    Wang J, Nikhil K, Viccaro K, Chang L, Jacobsen M, Sandusky G, Shah K (2017) The Aurora-ATwist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma. J Cell Sci 130(6):1078–1093Google Scholar
  98. 98.
    Sen-Yo M, Suehiro Y, Kaino S et al (2013) TWIST1 hypermethylation is observed in pancreatic cancer. Biomed Rep 1(1):31–33CrossRefPubMedGoogle Scholar
  99. 99.
    Shiota M, Yokomizo A, Tada Y et al (2010) Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression. Oncogene 29:237–250CrossRefPubMedGoogle Scholar
  100. 100.
    Takeuchi A, Shiota M, Beraldi E et al (2014) Insulin-like growth factor-I induces CLU expression through Twist1 to promote prostate cancer growth. Mol Cell Endocrinol 384(1–2):117–125CrossRefPubMedGoogle Scholar
  101. 101.
    Shiota M, Itsumi M, Takeuchi A et al (2015) Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer. Endocr Relat Cancer 22(6):889–900CrossRefPubMedGoogle Scholar
  102. 102.
    Mahajan K, Coppola D, Chen YA et al (2012) Ack1 tyrosine kinase activation correlates with pancreatic cancer progression. Am J Pathol 180(4):1386–1393CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Wu X, Cao Y, Het al X (2016) Bazedoxifene as a novel GP130 inhibitor for pancreatic Cancer therapy. Mol Cancer Ther 15(11):2609–2619CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Yanagisawa N, Ichinoe M, Mikami T et al (2012) High expression of L-type amino acid transporter 1 (LAT1) predicts poor prognosis in pancreatic ductal adenocarcinomas. J Clin Pathol 65(11):1019–1023CrossRefPubMedGoogle Scholar
  105. 105.
    Wang Q, Bailey CG, Ng C et al (2011) Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acidtransport during prostate cancer progression. Cancer Res 71(24):7525–7536CrossRefPubMedGoogle Scholar
  106. 106.
    Tursynbay Y, Zhang J, Li Z et al (2016) Tokay T, Zhumadilov Z, Wu D, Xie Y.Pim-1 kinase as cancer drug target: an update. Biomed Rep 4(2):140–146CrossRefPubMedGoogle Scholar
  107. 107.
    Xu J, Xiong G, Cao Z et al (2016) PIM-1 contributes to the malignancy of pancreatic cancer and displays diagnostic and prognostic value. J Exp Clin Cancer Res 35(1):133CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Block KM, Hanke NT, Maine EA et al (2012) IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines. Pancreas 41(5):773–781PubMedPubMedCentralGoogle Scholar
  109. 109.
    Linn DE, Yang X, Xie Y et al (2012) Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases. J Biol Chem 287(27):22959–22968CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Holder SL, Abdulkadir SA (2014) PIM1 kinase as a target in prostate cancer: roles in tumorigenesis, castration resistance, and docetaxel resistance. Curr Cancer Drug Targets 14(2):105–114CrossRefPubMedGoogle Scholar
  111. 111.
    Wang J, Quan CY, Chang WL et al (2015) Correlation between the expression of Pim-1 and androgen-deprivation therapy for prostate cancer. Zhonghua Nan Ke Xue 21(9):775–781PubMedGoogle Scholar
  112. 112.
    Jin UH, Kim SB, Safe S (2015) Omeprazole inhibits pancreatic Cancer cell invasion through a nongenomic aryl hydrocarbon receptor pathway. Chem Res Toxicol 28(5):907–918CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Le Novère N, Hucka M, Mi H, Moodie S, Schreiber F, Sorokin A, Demir E (2009) The systems biology graphical notation. Nat Biotechnol 27(8):735–741CrossRefPubMedGoogle Scholar
  114. 114.
    Szende B, Srkalovic G, Timar J et al (1991) Localization of receptors for luteinizing hormone-releasing hormone in pancreatic and mammary cancer cells. Proc Natl Acad Sci U S A 88(10):4153–4156CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Salonia A, Abdollah F, Capitanio U et al (2012) Serum sex steroids depict a nonlinear u-shaped association with high-risk prostate cancer at radical prostatectomy. Clin Cancer Res 18(13):3648–3657CrossRefPubMedGoogle Scholar
  116. 116.
    Iqbal MJ, Greenway B, Wilkinson ML et al (1983) Sex-steroid enzymes, aromatase and 5 alpha-reductase in the pancreas: a comparison of normal adult, foetal and malignant tissue. Clin Sci (Lond) 65(1):71–75CrossRefGoogle Scholar
  117. 117.
    Shiota M, Fujimoto N, Yokomizo A et al (2015) SRD5A gene polymorphism in Japanese men predicts prognosis of metastatic prostate cancer with androgen-deprivation therapy. Eur J Cancer 51(14):1962–1969CrossRefPubMedGoogle Scholar
  118. 118.
    Cai C, Chen S, Ng P et al (2011) Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res 71(20):6503–6513CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Latil A, Bièche I, Vidaud D et al (2001) Evaluation of androgen, estrogen (ERα and ERβ), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays. Cancer Res 61(5):1919–1926PubMedGoogle Scholar
  120. 120.
    Greenway B, Iqbal MJ, Johnson PJ et al (1981) Oestrogen receptor proteins in malignant and fetal pancreas. Br Med J (Clin Res Ed) 283(6294):751–753CrossRefGoogle Scholar
  121. 121.
    Christoforou P, Christopoulos PF, Koutsilieris M (2014) The role of estrogen receptor β in prostate Cancer. Mol Med 20(1):427–434CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Ellem SJ, Schmitt JF et al (2004) Local aromatase expression in human prostate is altered in malignancy. J Clin Endocrinol Metab 89:2434–2441CrossRefPubMedGoogle Scholar
  123. 123.
    Balk SP, Ko YJ, Bubley GJ (2003) Biology of prostate-specific antigen. J Clin Oncol 21(2):383–391CrossRefPubMedGoogle Scholar
  124. 124.
    Ren H, Zhang H, Wang X et al (2014) Prostate-specific membrane antigen as a marker of pancreatic cancer cells. Med Oncol 31(3):857CrossRefPubMedGoogle Scholar
  125. 125.
    Chou A, Waddell N, Cowley MJ et al (2013) Clinical and molecular characterization of HER2 amplified-pancreatic cancer. Genome Med 5(8):78CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Vaishampayan U, Thakur A, Rathore R, Kouttab N, Lum LG (2015) Phase I Study of anti-CD3 x anti-Her2 bispecific antibody in metastatic castrate resistant prostate cancer patients. Prostate Cancer 2015:285193. CrossRefGoogle Scholar
  127. 127.
    Tien JC, Liu Z, Liao L et al (2013) The steroid receptor Coactivator-3 is required for the development of castration-resistant prostate Cancer. Cancer Res 73(13):3997–4008CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Lam HM, Ouyang B, Chen J et al (2014) Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer. Endocr Relat Cancer 21(6):903–914CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Kimbara S, Kondo S (2016) Immune checkpoint and inflammation as therapeutic targets in pancreatic carcinoma. World J Gastroenterol 22(33):7440–7452CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Hustinx SR, Leoni LM, Yeo CJ et al (2005) Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol 18(7):959–963CrossRefPubMedGoogle Scholar
  131. 131.
    Collins CC, Volik SV, Lapuk AV et al (2012) Next generation sequencing of prostate Cancer from a patient identifies a deficiency of Methylthioadenosine phosphorylase (MTAP), an exploitable tumor target. Mol Cancer Ther 11(3):775–783CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Azzopardi S, Pang S, Klimstra DS et al (2016) p53 and p16Ink4a/p19Arf Loss Promotes Different Pancreatic Tumor Types from PyMT-Expressing Progenitor Cells. Neoplasia 18(10):610–617CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Deng Y, Lu J (2015) Targeting hexokinase 2 in castration-resistant prostate cancer. Mol Cell Oncol 2(3):e974465CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Cozzi PJ, Wang J, Delprado W et al (2005) MUC1, MUC2, MUC4, MUC5AC and MUC6 expression in the progression of prostate cancer. Clin Exp Metastasis 22(7):565–573CrossRefPubMedGoogle Scholar
  135. 135.
    Park JY, Hiroshima Y, Lee JY, MUC1 et al (2015) Selectively targets human pancreatic Cancer in Orthotopic nude mouse models. PLoS One 10(3):e0122100CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Drivdahl R, Haugk KH et al (2004) Suppression of growth and tumorigenicity in the prostate tumor cell line M12 by overexpression of the transcription factor SOX9. Oncogene 23:4584–4593CrossRefPubMedGoogle Scholar
  137. 137.
    Nagathihalli NS, Castellanos JA, VanSaun MN et al (2016) Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells. Oncotarget 7(40):65982–65992CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Schweizer L, Rizzo CA, Spires TE et al (2008) The androgen receptor can signal through Wnt/beta-catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens. BMC Cell Biol 9:4CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    The Cancer Genome Atlas Research (2017) Network Integrated Genomic Characterisation of PAncreatic Ductal Adenocarcinom. Cancer Cell 32(3):185–203 e13Google Scholar
  140. 140.
    Kasina S, Macoska JA (2012) The CXCL12/CXCR4 axis promotes ligand-independent activation of the androgen receptor. Mol Cell Endocrinol 351(2):249–263CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Deng L, Shang Y, Guo S et al (2014) Ran GTPase protein promotes metastasis and invasion in pancreatic cancer by deregulating the expression of AR and CXCR4. Cancer Biol Ther 15(8):1087–1093CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Yang YA, Yu J (2015) Current perspectives on FOXA1 regulation of androgen receptor signaling and prostate cancer. Genes Dis 2(2):144–151CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Behnsawy HM, Miyake H, Harada K et al (2013) Expression patterns of epithelial-mesenchymal transition markers in localized prostate cancer: significance in clinicpathological outcomes following radical prostatectomy. BJU 111(1):30–37CrossRefGoogle Scholar
  144. 144.
    Chen S, Chen JZ, Zhang JQ et al (2016) Hypoxia induces TWIST-activated epithelial-mesenchymal transition and proliferation of pancreatic cancer cells in vitro and in nude mice. Cancer Lett 383(1):73–84CrossRefPubMedGoogle Scholar
  145. 145.
    Gao S, Sun Y, Zhang X et al (2016) IGFBP2 activates the NF-κB pathway to drive epithelial-mesenchymal transition and invasive character in pancreatic ductal adenocarcinoma. Cancer Res 76(22):6543–6554CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2018

Authors and Affiliations

  • A. Fucic
    • 1
    Email author
  • A. Aghajanyan
    • 2
  • Z. Culig
    • 3
  • N. Le Novere
    • 4
  1. 1.Institute for Medical Research and Occupational HealthZagrebCroatia
  2. 2.Institute of MedicinePeoples’ Friendship University of RussiaMoscowRussian Federation
  3. 3.Department of UrologyMedical University of InnsbruckInnsbruckAustria
  4. 4.Babraham InstituteCambridgeUK

Personalised recommendations