Expression of PTEN and pAKT in Non-Small Cell Lung Cancer

  • Carina Antfang, MD Institute of Surgical Pathology, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
  • Agnes Csanadi, MD Institute of Surgical Pathology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Gian Kayser Institute of Surgical Pathology, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
DOI: https://doi.org/10.17629/www.diagnosticpathology.eu-2019-5:272

Abstract

Background: Alterations in the PTEN-AKT pathway play important roles indifferent solid carcinomas, e. g. of the breast, prostate and GI-tract. Since contradictory results have been reported for lung cancer mostly studying only one of the two proteins, we aim to elucidate the biological effects of alterations in this pathway in a large and well characterized cohort of non-small cell lung cancer.
Material and Methods: We established an immunohistochemical double stain for PTEN and p-AKT in non-small cell lung carcinomas (NSCLC). This was applied to tissue-microarrays (TMA) including 44 patients.
Results: Our results indicate, that not only alterations in one marker are of biological significance but rather the combination of PTEN-loss and p-AKT overexpression, as well as the intracellular localization of the protein staining. Patients with low-grade histological differentiation, negative lymphonodal status and PTEN-expression showed a significant better overall survival.
Conclusion: We conclude, that PTEN-(over-)expression leads to p-AKT downregulation with better overall survival in nodal negative NSCLC patients.
Virtual Slides:  


 

Downloads

Download data is not yet available.

References

1. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes & development. 2004;18(16):1926–45. PMCID: 15314020.
2. Heukamp LC, Büttner R. Molekulardiagnostik des Lungenkarzinoms zur Therapiestratifizierung. Der Pathologe. 2010;31(1):22–8. PMCID: 19997736.
3. Maehama T, Dixon JE. PTEN tumor suppressor: functions as a lipid phosphatase. Tanpakushitsu kakusan koso Protein, nucleic acid, enzyme. 2000;45(14):2405–14. PMCID: 11051842.
4. Liao Y, Hung M-C. Physiological regulation of Akt activity and stability. American journal of translational research. 2010;2(1):19–42. PMCID: 20182580.
5. Cantley LC. The phosphoinositide 3-kinase pathway. Science (New York, NY). 2002;296(5573):1655–7. PMCID: 12040186.
6. Ibeawuchi C, Schmidt H, Voss R, Titze U, Abbas M, Neumann J, et al. Exploring prostate cancer genome reveals simultaneous losses of PTEN, FAS and PAPSS2 in patients with PSA recurrence after radical prostatectomy. International journal of molecular sciences. 2015;16(2):3856–69. PMCID: 25679447.
7. Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer research. 1997;57(11):2124–9. PMCID: 9187108.
8. Wang J, Chen H, Liao Y, Chen N, Liu T, Zhang H, et al. Expression and clinical evidence of miR-494 and PTEN in non-small cell lung cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2015;36(9):6965–72. PMCID: 25861022.
9. Freeman DJ, Li AG, Wei G, Li H-H, Kertesz N, Lesche R, et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer cell. 2003;3(2):117–30. PMCID: 12620407.
10. Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, et al. Regulation of PTEN transcription by p53. Molecular cell. 2001;8(2):317–25. PMCID: 11545734.
11. Martelli AM, Faenza I, Billi AM, Manzoli L, Evangelisti C, Falà F, et al. Intranuclear 3'-phosphoinositide metabolism and Akt signaling: new mechanisms for tumorigenesis and protection against apoptosis? Cellular signalling. 2006;18(8):1101–7. PMCID: 16516442.
12. Hu Y, Yao J, Liu Z, Liu X, Fu H, Ye K. Akt phosphorylates acinus and inhibits its proteolytic cleavage, preventing chromatin condensation. The EMBO journal. 2005;24(20):3543–54. PMCID: 16177823.
13. Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KD, Schaefer E, et al. Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circulation research. 2001;88(10):1020–7. PMCID: 11375271.
14. Yang SX, Costantino JP, Kim C, Mamounas EP, Nguyen D, Jeong J-H, et al. Akt phosphorylation at Ser473 predicts benefit of paclitaxel chemotherapy in node-positive breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(18):2974–81. PMCID: 20479407.
15. Mistafa O, Ghalali A, Kadekar S, Högberg J, Stenius U. Purinergic receptor-mediated rapid depletion of nuclear phosphorylated Akt depends on pleckstrin homology domain leucine-rich repeat phosphatase, calcineurin, protein phosphatase 2A, and PTEN phosphatases. The Journal of biological chemistry. 2010;285(36):27900–10. PMCID: 20605778.
16. Shin E, Choi CM, Kim HR, Jang SJ, Park YS. Immunohistochemical characterization of the mTOR pathway in stage-I non-small-cell lung carcinoma. Lung cancer (Amsterdam, Netherlands). 2015;89(1):13–8. PMCID: 25936472.
17. Yun F, Jia Y, Li X, Yuan L, Sun Q, Yu H, et al. Clinicopathological significance of PTEN and PI3K/AKT signal transduction pathway in non-small cell lung cancer. International journal of clinical and experimental pathology. 2013;6(10):2112–20. PMCID: 24133589.
18. Badve S, Collins NR, Bhat-Nakshatri P, Turbin D, Leung S, Thorat M, et al. Subcellular localization of activated AKT in estrogen receptor- and progesterone receptor-expressing breast cancers: potential clinical implications. The American journal of pathology. 2010;176(5):2139–49. PMCID: 20228224.
19. He X, Saji M, Radhakrishnan D, Romigh T, Ngeow J, Yu Q, et al. PTEN lipid phosphatase activity and proper subcellular localization are necessary and sufficient for down-regulating AKT phosphorylation in the nucleus in Cowden syndrome. The Journal of clinical endocrinology and metabolism. 2012;97(11):E2179-87. PMCID: 22962422.
20. Shen Q, Stanton ML, Feng W, Rodriguez ME, Ramondetta L, Chen L, et al. Morphoproteomic analysis reveals an overexpressed and constitutively activated phospholipase D1-mTORC2 pathway in endometrial carcinoma. International journal of clinical and experimental pathology. 2010;4(1):13–21. PMCID: 21228924.
21. Hu J, Liu Y-L, Piao S-l, Yang D-d, Yang Y-M, Cai L. Expression patterns of USP22 and potential targets BMI-1, PTEN, p-AKT in non-small-cell lung cancer. Lung cancer (Amsterdam, Netherlands). 2012;77(3):593–9. PMCID: 22717106.
22. Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H, et al. COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic acids research. 2015;43(Database issue):D805-11. PMCID: 25355519.
23. Lou H, Villagran G, Boland JF, Im KM, Polo S, Zhou W, et al. Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(23):5360–70. PMCID: 26080840.
24. Sukawa Y, Yamamoto H, Nosho K, Kunimoto H, Suzuki H, Adachi Y, et al. Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer. World journal of gastroenterology. 2012;18(45):6577–86. PMCID: 23236232.
25. Yip WK, He PY, Abdullah MA, Yusoff S, Seow HF. Increased Expression of Phosphatidylinositol 3-Kinase p110α and Gene Amplification of PIK3CA in Nasopharyngeal Carcinoma. Pathology oncology research : POR. 2016;22(2):413–9. PMCID: 26581613.
26. Bago-Horvath Z, Sieghart W, Grusch M, Lackner A, Hayden H, Pirker C, et al. Synergistic effects of erlotinib and everolimus on bronchial carcinoids and large-cell neuroendocrine carcinomas with activated EGFR/AKT/mTOR pathway. Neuroendocrinology. 2012;96(3):228–37. PMCID: 22378048.
27. Rekhtman N, Pietanza MC, Hellmann MD, Naidoo J, Arora A, Won H, et al. Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;22(14):3618–29. PMCID: 26960398.
28. Yanagawa N, Leduc C, Kohler D, Saieg MA, John T, Sykes J, et al. Loss of phosphatase and tensin homolog protein expression is an independent poor prognostic marker in lung adenocarcinoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2012;7(10):1513–21. PMCID: 22982652.
29. Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK, et al. PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Human pathology. 2005;36(7):768–76. PMCID: 16084946.
30. Yoshizawa A, Fukuoka J, Shimizu S, Shilo K, Franks TJ, Hewitt SM, et al. Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(1):240–8. PMCID: 20008839.
Published
2019-08-22
How to Cite
ANTFANG, Carina; CSANADI, Agnes; KAYSER, Gian. Expression of PTEN and pAKT in Non-Small Cell Lung Cancer. Diagnostic Pathology, [S.l.], v. 5, n. 1, aug. 2019. ISSN 2364-4893. Available at: <https://www.diagnosticpathology.eu/content/index.php/dpath/article/view/272>. Date accessed: 08 sep. 2024. doi: https://doi.org/10.17629/www.diagnosticpathology.eu-2019-5:272.
Citation Formats
Issue
Vol 5 No 1 (2019): Vol. 5 No. 1 2019
Section
Short Report
Creative Commons License

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

Authors who publish with this journal agree to the following terms:


1. Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.

3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).

4. In case of virtual slide publication the authors agree to copy the article in a structural modified version to the journal's VS archive.