Regulation of the Tumor Suppressor PTEN Through Exosomes: a Diagnostic Potential for Prostate Cancer

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Aug 13

PMID 23936141

Citations 54

Authors

Kathleen Gabriel

Alistair Ingram

Richard Austin

Anil Kapoor

Damu Tang

Fadwa Majeed

Talha Qureshi

Khalid Al-Nedawi

Affiliations

Soon will be listed here.

Abstract

PTEN is a potent tumor-suppressor protein. Aggressive and metastatic prostate cancer (PC) is associated with a reduction or loss of PTEN expression. PTEN reduction often occurs without gene mutations, and its downregulation is not fully understood. Herein, we show that PTEN is incorporated in the cargo of exosomes derived from cancer cells. PTEN is not detected in exosomes derived from normal, noncancerous cells. We found that PTEN can be transferred to other cells through exosomes. In cells that have a reduction or complete loss of PTEN expression, the transferred PTEN is competent to confer tumor-suppression activity to acceptor cells. In PC patients, we show that PTEN is incorporated in the cargo of exosomes that circulate in their blood. Interestingly, normal subjects have no PTEN expression in their blood exosomes. Further, we found that the prostate-specific antigen (PSA) is incorporated in PC patients' and normal subjects' blood exosomes. These data suggest that exosomal PTEN can compensate for PTEN loss in PTEN deficient cells, and may have diagnostic value for prostate cancer.

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References

Stambolic V, Suzuki A, de la Pompa J, Brothers G, Mirtsos C, Sasaki T . Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998; 95(1):29-39. DOI: 10.1016/s0092-8674(00)81780-8. View

Wen S, Stolarov J, Myers M, Su J, Wigler M, Tonks N . PTEN controls tumor-induced angiogenesis. Proc Natl Acad Sci U S A. 2001; 98(8):4622-7. PMC: 31884. DOI: 10.1073/pnas.081063798. View

De Visschere P, Oosterlinck W, De Meerleer G, Villeirs G . Clinical and imaging tools in the early diagnosis of prostate cancer, a review. JBR-BTR. 2010; 93(2):62-70. DOI: 10.5334/jbr-btr.121. View

Weng L, Brown J, Eng C . PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum Mol Genet. 2001; 10(6):599-604. DOI: 10.1093/hmg/10.6.599. View

Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi P . Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998; 19(4):348-55. DOI: 10.1038/1235. View

Nagy J, Dvorak H . Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets. Clin Exp Metastasis. 2012; 29(7):657-62. PMC: 3484269. DOI: 10.1007/s10585-012-9500-6. View

Harvey P, Basuita A, Endersby D, Curtis B, Iacovidou A, Walker M . A systematic review of the diagnostic accuracy of prostate specific antigen. BMC Urol. 2009; 9:14. PMC: 2753579. DOI: 10.1186/1471-2490-9-14. View

Muralidharan-Chari V, Clancy J, Sedgwick A, DSouza-Schorey C . Microvesicles: mediators of extracellular communication during cancer progression. J Cell Sci. 2010; 123(Pt 10):1603-11. PMC: 2864708. DOI: 10.1242/jcs.064386. View

Ross A, Gericke A . Phosphorylation keeps PTEN phosphatase closed for business. Proc Natl Acad Sci U S A. 2009; 106(5):1297-8. PMC: 2635795. DOI: 10.1073/pnas.0812473106. View

10.

Whang Y, Wu X, Suzuki H, Reiter R, Tran C, Vessella R . Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci U S A. 1998; 95(9):5246-50. PMC: 20246. DOI: 10.1073/pnas.95.9.5246. View

11.

Collino F, Deregibus M, Bruno S, Sterpone L, Aghemo G, Viltono L . Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One. 2010; 5(7):e11803. PMC: 2910725. DOI: 10.1371/journal.pone.0011803. View

12.

Catalona W, Partin A, Slawin K, Brawer M, Flanigan R, Patel A . Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA. 1998; 279(19):1542-7. DOI: 10.1001/jama.279.19.1542. View

13.

Maccario H, Perera N, Davidson L, Downes C, Leslie N . PTEN is destabilized by phosphorylation on Thr366. Biochem J. 2007; 405(3):439-44. PMC: 2267318. DOI: 10.1042/BJ20061837. View

14.

Al-Nedawi K, Meehan B, Kerbel R, Allison A, Rak J . Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci U S A. 2009; 106(10):3794-9. PMC: 2656159. DOI: 10.1073/pnas.0804543106. View

15.

Halvorsen O, Haukaas S, Akslen L . Combined loss of PTEN and p27 expression is associated with tumor cell proliferation by Ki-67 and increased risk of recurrent disease in localized prostate cancer. Clin Cancer Res. 2003; 9(4):1474-9. View

16.

Suzuki H, Freije D, Nusskern D, Okami K, Cairns P, Sidransky D . Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res. 1998; 58(2):204-9. View

17.

Al-Nedawi K, Meehan B, Rak J . Microvesicles: messengers and mediators of tumor progression. Cell Cycle. 2009; 8(13):2014-8. DOI: 10.4161/cc.8.13.8988. View

18.

McDavid K, Lee J, Fulton J, Tonita J, Thompson T . Prostate cancer incidence and mortality rates and trends in the United States and Canada. Public Health Rep. 2004; 119(2):174-86. PMC: 1497609. DOI: 10.1177/003335490411900211. View

19.

Putz U, Howitt J, Doan A, Goh C, Low L, Silke J . The tumor suppressor PTEN is exported in exosomes and has phosphatase activity in recipient cells. Sci Signal. 2012; 5(243):ra70. DOI: 10.1126/scisignal.2003084. View

20.

Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler P . PTEN promoter is methylated in a proportion of invasive breast cancers. Int J Cancer. 2004; 112(3):407-10. DOI: 10.1002/ijc.20447. View