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The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance

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Abstract

Signaling pathway alterations are important in the development of gastric cancer (GC). Deregulation of the PI3K/AKT/mTOR pathway plays a crucial role in the regulation of multiple cellular functions including cell growth, proliferation, metabolism, and angiogenesis. Our goal was to assess expression of proteins involved in the PI3K/AKT/mTOR pathway by immunohistochemistry (IHC) in tumor and nontumor gastric mucosa from patients with advanced GC. We evaluated 71 tumor and 71 nontumor gastric mucosa samples from advanced GC patients, selected from Hernán Henríquez Aravena Hospital (Temuco, Chile). The targets studied were PI3K, AKT, p-AKT, PTEN, mTOR, p-mTOR, P70S6K1, p-P70S6K1, 4E-BP1, p-4E-BP1, eIF4E, and p-eIF4E. Expression data were correlated with clinicomorphological data. Descriptive and analytical statistics were used (95 % confidence interval, p < 0.05). For survival analyses, the Kaplan–Meier method and the log-rank test were used. PI3K, AKT, p-AKT, p-mTOR, p-4E-BP1, P70S6K1, p-P70S6K1, eIF-4E, and p-eIF-4E proteins were significantly overexpressed in tumor tissue. Conversely, PTEN was underexpressed in tumor tissue, notably in pT3-pT4 tumors (p = 0.02) and tumors with lymph node metastases (p < 0.001). P70S6K1 expression was associated with pT3-pT4 tumors (p = 0.03). Moreover, PI3K (p = 0.004), AKT (p = 0.01), p-AKT (p = 0.01), P70S6K1 (p = 0.04), p-P70S6K1 (p = 0.001), and eIF-4E (p = 0.004) were overexpressed in tumors with lymph node metastases. Low expression of 4E-BP1 was associated with poor overall survival (p = 0.03). Our results suggest that the PI3K/AKT/mTOR pathway is activated in GC, with overexpression in tumor tissue of most of the studied proteins (total and phosphorylated). These might be considered as target for specific targeted therapy in GC.

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References

  1. Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Heise K, Bertran E, Andia ME, Ferreccio C (2009) Incidence and survival of stomach cancer in a high-risk population of Chile. World J Gastroenterol 15:1854–1862

    Article  PubMed Central  PubMed  Google Scholar 

  3. Recommendations for clinical practice: 2004 Standards, Options and Recommendations for management of patients with adenocarcinomas of the stomach (excluding cardial and other histological forms of cancer) Federation nationale des centres de lutte contre le cancer]. (2005) Gastroenterol Clin Biol 29: 41–55

  4. Allum WH, Griffin SM, Watson A, Colin-Jones D (2002) Guidelines for the management of oesophageal and gastric cancer. Gut 50(Suppl 5):v1–v23

    Article  PubMed Central  PubMed  Google Scholar 

  5. Nakajima T (2002) Gastric cancer treatment guidelines in Japan. Gastric Cancer 5:1–5

    Article  PubMed  Google Scholar 

  6. Al-Batran SE, Ducreux M, Ohtsu A (2012) mTOR as a therapeutic target in patients with gastric cancer. Int J Cancer 130:491–496

    Article  CAS  PubMed  Google Scholar 

  7. Easton JB, Houghton PJ (2006) mTOR and cancer therapy. Oncogene 25:6436–6446

    Article  CAS  PubMed  Google Scholar 

  8. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30:193–204

    Article  PubMed  Google Scholar 

  9. Rosen N, She QB (2006) AKT and cancer—is it all mTOR? Cancer Cell 10:254–256

    Article  CAS  PubMed  Google Scholar 

  10. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR (2005) Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94:29–86

    Article  CAS  PubMed  Google Scholar 

  11. Garcia P, Leal P, Alvarez H, Brebi P, Ili C, Tapia O et al (2013) Connective tissue growth factor immunohistochemical expression is associated with gallbladder cancer progression. Arch Pathol Lab Med 137:245–250

    Article  CAS  PubMed  Google Scholar 

  12. Xiao L, Wang YC, Li WS, Du Y (2009) The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray. J Exp Clin Cancer Res 28:152

    Article  PubMed Central  PubMed  Google Scholar 

  13. Van den Brandt PA, Botterweck AA, Goldbohm RA (2003) Salt intake, cured meat consumption, refrigerator use and stomach cancer incidence: a prospective cohort study (Netherlands). Cancer Causes Control 14:427–438

    Article  PubMed  Google Scholar 

  14. Mayne ST, Risch HA, Dubrow R, Chow WH, Gammon MD, Vaughan TL et al (2001) Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev 10:1055–1062

    CAS  PubMed  Google Scholar 

  15. Knekt P, Jarvinen R, Dich J, Hakulinen T (1999) Risk of colorectal and other gastro-intestinal cancers after exposure to nitrate, nitrite and N-nitroso compounds: a follow-up study. Int J Cancer 80:852–856

    Article  CAS  PubMed  Google Scholar 

  16. La Vecchia C, Negri E, Franceschi S, Gentile A (1992) Family history and the risk of stomach and colorectal cancer. Cancer 70:50–55

    Article  PubMed  Google Scholar 

  17. Palli D, Russo A, Ottini L, Masala G, Saieva C, Amorosi A et al (2001) Red meat, family history, and increased risk of gastric cancer with microsatellite instability. Cancer Res 61:5415–5419

    CAS  PubMed  Google Scholar 

  18. Huang JQ, Zheng GF, Sumanac K, Irvine EJ, Hunt RH (2003) Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 125:1636–1644

    Article  PubMed  Google Scholar 

  19. Sayed D, Abdellatif M (2010) AKT-ing via microRNA. Cell Cycle 9:3213–3217

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Ambros V (2004) The functions of animal micro-RNAs. Nature 431:350–355

    Article  CAS  PubMed  Google Scholar 

  21. Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866

    Article  CAS  PubMed  Google Scholar 

  22. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    Article  CAS  PubMed  Google Scholar 

  23. Kozomara A, Griffiths-Jones S (2011) miRBase: integrating microRNA annotation and deepsequencing data. Nucleic Acids Res 39:D152–D157

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522–531

    Article  CAS  PubMed  Google Scholar 

  25. Edinger AL, Thompson CB (2002) Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 13:2276–2288

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484

    Article  CAS  PubMed  Google Scholar 

  27. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945

    Article  CAS  PubMed  Google Scholar 

  28. Caron E, Ghosh S, Matsuoka Y, Ashton-Beaucage D, Therrien M, Lemieux S et al (2010) A comprehensive map of the mTOR signaling network. Mol Syst Biol 6:453

    Article  PubMed Central  PubMed  Google Scholar 

  29. Foster KG, Fingar DC (2010) Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J Biol Chem 285:14071–14077

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Yang Q, Guan KL (2007) Expanding mTOR signaling. Cell Res 17:666–681

    Article  CAS  PubMed  Google Scholar 

  31. Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464

    Article  CAS  PubMed  Google Scholar 

  32. Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA et al (1995) Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64:280–285

    Article  CAS  PubMed  Google Scholar 

  33. Altomare DA, You H, Xiao GH, Ramos-Nino ME, Skele KL, De Rienzo A et al (2005) Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene 24:6080–6089

    Article  CAS  PubMed  Google Scholar 

  34. Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK et al (2004) AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 23:5853–5857

    Article  CAS  PubMed  Google Scholar 

  35. Altomare DA, Tanno S, De Rienzo A, Klein-Szanto AJ, Tanno S, Skele KL et al (2002) Frequent activation of AKT2 kinase in human pancreatic carcinomas. J Cell Biochem 87:470–476

    Article  PubMed  Google Scholar 

  36. Robertson GP (2005) Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev 24:273–285

    Article  CAS  PubMed  Google Scholar 

  37. Oki E, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M et al (2005) AKT phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer 117:376–380

    Article  CAS  PubMed  Google Scholar 

  38. Liu JF, Zhou XK, Chen JH, Yi G, Chen HG, Ba MC et al (2010) Up-regulation of PIK3CA promotes metastasis in gastric carcinoma. World J Gastroenterol 16:4986–4991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Cinti C, Vindigni C, Zamparelli A, La Sala D, Epistolato MC, Marrelli D et al (2008) Activated Akt as an indicator of prognosis in gastric cancer. Virchows Arch 453:449–455

    Article  CAS  PubMed  Google Scholar 

  40. Morgensztern D, McLeod HL (2005) PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs 16:797–803

    Article  CAS  PubMed  Google Scholar 

  41. Murayama T, Inokuchi M, Takagi Y, Yamada H, Kojima K, Kumagai J et al (2009) Relation between outcomes and localisation of p-mTOR expression in gastric cancer. Br J Cancer 100:782–788

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Xiao L, Wang YC, Li WS, Du Y (2009) The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray. J Exp Clin Cancer Res 28:152

    Article  PubMed Central  PubMed  Google Scholar 

  43. Ye B, Jiang LL, Xu HT, Zhou DW, Li ZS (2012) Expression of PI3K/AKT pathway in gastric cancer and its blockade suppresses tumor growth and metastasis. Int J Immunopathol Pharmacol 25(3):627–636

    CAS  PubMed  Google Scholar 

  44. Wen YG, Wang Q, Zhou CZ, Qiu GQ, Peng ZH, Tang HM (2010) Mutation analysis of tumor suppressor gene PTEN in patients with gastric carcinomas and its impact on PI3K/AKT pathway. Oncol Rep 24:89–95

    CAS  PubMed  Google Scholar 

  45. Dreesen O, Brivanlou AH (2007) Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev 3:7–17

    Article  CAS  PubMed  Google Scholar 

  46. Kang YH, Lee HS, Kim WH (2002) Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Invest 82:285–291

    Article  CAS  PubMed  Google Scholar 

  47. Lang SA, Gaumann A, Koehl GR, Seidel U, Bataille F, Klein D, Ellis LM, Bolder U, Hofstaedter F et al (2007) Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. Int J Cancer 120:1803–1810

    Article  CAS  PubMed  Google Scholar 

  48. Sun DF, Zhang YJ, Tian XQ, Chen YX, Fang JY (2013) Inhibition of mTOR signalling potentiates the effects of trichostatin A in human gastric cancer cell lines by promoting histone acetylation. Cell Biol Int. doi:10.1002/cbin.10179

    Google Scholar 

  49. Yang HY, Xue LY, Xing LX, Wang J, Wang JL (2013) Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma. Mol Med Rep 7(2):537–542

    CAS  PubMed  Google Scholar 

  50. Fan S, Ramalingam SS, Kauh J, Xu Z, Khuri FR, Sun SY (2009) Phosphorylated eukaryotic translation initiation factor 4 (eIF4E) is elevated in human cancer tissues. Cancer Biol Ther 8(15):1463–1469

    Article  PubMed Central  PubMed  Google Scholar 

  51. Chen CN, Hsieh FJ, Cheng YM, Lee PH, Chang KJ (2004) Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J Surg Oncol 86:22–27

    Article  CAS  PubMed  Google Scholar 

  52. Liang S, Guo R, Zhang Z, Liu D, Xu H, Xu Z, Wang X, Yang L (2013) Upregulation of the eIF4E signaling pathway contributes to the progression of gastric cancer, and targeting eIF4E by perifosine inhibits cell growth. Oncol Rep 29(6):2422–2430

    CAS  PubMed  Google Scholar 

  53. Yap TA, Garrett MD, Walton MI, Florence Raynaud F, de Bono FS, Workman P (2008) Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 8:393–412

    Article  CAS  PubMed  Google Scholar 

  54. Fruman DA, Rommel CR (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13:140–156

    Article  CAS  PubMed  Google Scholar 

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile

    Oscar Tapia, Ismael Riquelme, Pamela Leal, Alejandra Sandoval, Susana Aedo, Helga Weber, Pablo Letelier, Enrique Bellolio & Miguel Villaseca

  2. School of Health Sciences, Universidad Católica de Temuco, Temuco, Chile

    Pablo Letelier

  3. Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 377, 8330024, Santiago, Chile

    Patricia Garcia & Juan Carlos Roa

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  1. Oscar Tapia
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Correspondence to Juan Carlos Roa.

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Oscar Tapia and Ismael Riquelme are both first authors because they contributed equally to the realization of this work.

Founded by FONDECYT Grant No 11110239.

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Tapia, O., Riquelme, I., Leal, P. et al. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch 465, 25–33 (2014). https://doi.org/10.1007/s00428-014-1588-4

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  • DOI: https://doi.org/10.1007/s00428-014-1588-4

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