Fatty acid amide hydrolase in prostate cancer: association with disease severity and outcome, CB1 receptor expression and regulation by IL-4.
BACKGROUND
Recent data have indicated that there may be a dysregulation of endocannabinoid metabolism in cancer. Here we have investigated the expression of the endocannabinoid metabolising enzyme fatty acid amide hydrolase (FAAH) in a well characterised tissue microarray from patients diagnosed with prostate cancer at transurethral resection for voiding problems.


RESULTS
FAAH immunoreactivity (FAAH-IR) was assessed in formalin-fixed paraffin-embedded non-malignant and tumour cores from 412 patients with prostate cancer. CB(1) receptor immunoreactivity (CB(1)IR) scores were available for this dataset. FAAH-IR was seen in epithelial cells and blood vessel walls but not in the stroma. Tumour epithelial FAAH-IR was positively correlated with the disease severity at diagnosis (Gleason score, tumour stage, % of the specimen that contained tumour) for cases with mid-range CB(1)IR scores, but not for those with high CB(1)IR scores. For the 281 cases who only received palliative therapy at the end stages of the disease, a high tumour epithelial FAAH-IR was associated with a poor disease-specific survival. Multivariate Cox proportional-hazards regression analyses indicated that FAAH-IR gave additional prognostic information to that provided by CB(1)IR when a midrange, but not a high CB(1)IR cutoff value was used. Interleukin-4 (IL-4) receptor IR was found on tumour epithelial cells and incubation of prostate cancer PC-3 and R3327 AT1 cells with IL-4 increased their FAAH activity.


CONCLUSIONS
Tumour epithelial FAAH-IR is associated with prostate cancer severity and outcome at mid-range, but not high, CB(1)IR scores. The correlation with CB(1)IR in the tumour tissue may be related to a common local dysregulation by a component of the tumour microenvironment.
Thors
Lina
L
Pharmacology Unit, Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Bergh
Anders
A
Persson
Emma
E
Hammarsten
Peter
P
Stattin
Pär
P
Egevad
Lars
L
Granfors
Torvald
T
Fowler
Christopher J
CJ
D000581:Amidohydrolases / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008297:Male; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D011467:Prostate / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D066246:ErbB Receptors; D015847:Interleukin-4; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases
Br J Cancer. 2005 Mar 14;92(5):921-8
15714203
Acta Paediatr. 2007 May;96(5):644-7
17376185
Cell. 2010 Jan 8;140(1):49-61
20079333
FASEB J. 2004 Oct;18(13):1606-8
15289448
Nat Med. 2000 Mar;6(3):313-9
10700234
J Biol Chem. 2003 Apr 11;278(15):13318-24
12556536
Cancer Genet Cytogenet. 2006 Nov;171(1):31-8
17074588
Int J Cancer. 2008 Feb 15;122(4):742-50
17943729
Cancer Res. 2005 Mar 1;65(5):1635-41
15753356
Curr Top Med Chem. 2010;10(8):814-27
20370711
Genomics. 1998 Dec 15;54(3):408-14
9878243
Cell Stem Cell. 2007 Oct 11;1(4):389-402
18371377
Pharmacol Res. 2009 Aug;60(2):107-16
19559362
J Immunol. 2004 May 1;172(9):5467-77
15100288
J Pharmacol Exp Ther. 2010 Feb;332(2):336-44
19889794
Pharmacol Res. 2008 Jul;58(1):72-6
18675915
J Immunol. 2001 Jun 15;166(12):7183-9
11390466
Prostate. 2008 Jan 1;68(1):85-91
18008330
Mol Pharmacol. 2008 Mar;73(3):1013-9
18156315
Prostate. 2003 Jun 15;56(1):1-12
12746841
J Neurosci. 2006 Dec 20;26(51):13318-27
17182782
Gene. 2007 Aug 1;397(1-2):126-35
17537592
Eur J Cancer. 2009 Jan;45(1):174-82
19056257
Anal Biochem. 1990 May 1;186(2):285-7
2363501
Cancer Res. 2008 Aug 1;68(15):6468-76
18676872
J Leukoc Biol. 2007 Jan;81(1):336-43
17041005
Cancer Res. 2004 Mar 15;64(6):1943-50
15026328
J Biol Chem. 2000 Oct 13;275(41):31938-45
10913156
Mol Cancer Ther. 2003 Mar;2(3):245-54
12657719
Proc Biol Sci. 1998 Nov 7;265(1410):2081-5
9842734
Endocrinology. 2000 Jan;141(1):118-26
10614630
Cancer Res. 2004 Dec 15;64(24):8826-30
15604240
PLoS One. 2010 Jan 14;5(1):e8702
20090845
Eur J Neurosci. 2003 Oct;18(7):1979-92
14622230
New Biol. 1991 Sep;3(9):880-5
1931832
Eur J Pharmacol. 2005 May 16;515(1-3):20-7
15913603
Am J Epidemiol. 2006 Apr 1;163(7):670-5
16410346
Cancer Res. 2008 Nov 1;68(21):8687-94
18974110
J Biol Chem. 2006 Dec 22;281(51):39480-91
17068343
Endocrinology. 2007 Mar;148(3):1431-9
17110429
FEBS Lett. 1999 Sep 24;458(3):400-4
10570948
Prostate. 2009 Jun 1;69(8):799-809
19189305
FEBS Lett. 1998 Jan 23;422(1):69-73
9475172
Neurosci Lett. 1998 Oct 2;254(3):137-40
10214976
Tissue Antigens. 2007 Apr;69(4):293-8
17389011
J Urol. 2000 Sep;164(3 Pt 1):722-5
10953133
Glia. 2009 Oct;57(13):1374-85
19229996
Int J Cancer. 2008 Sep 15;123(6):1318-26
18566995
Clin Chem. 1993 Apr;39(4):561-77
8472349
Clin Cancer Res. 2010 Feb 15;16(4):1245-55
20145160
Nat Med. 2003 Jan;9(1):76-81
12461523
Gastroenterology. 2003 Sep;125(3):677-87
12949714
J Biochem Biophys Methods. 2004 Aug 31;60(2):171-7
15262451
J Cancer Res Clin Oncol. 2009 Apr;135(4):507-14
18830626
Virchows Arch A Pathol Anat Histopathol. 1992;421(2):157-61
1381129
Carcinogenesis. 2006 Jan;27(1):1-22
16195239
Br J Cancer. 2009 Sep 15;101(6):940-50
19690545
J Urol. 1974 Jan;111(1):58-64
4813554
Int J Cancer. 2007 Sep 1;121(5):984-91
17443494
J Pharmacol Exp Ther. 1999 Feb;288(2):478-83
9918548
Gene. 2002 May 29;291(1-2):203-10
12095693
BJU Int. 2002 Apr;89(6):538-42
11942960
J Urol. 2005 Jan;173(1):10-20
15592017