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Tumour epithelial expression levels of endocannabinoid markers modulate the value of endoglin-positive vascular density as a prognostic marker in prostate cancer.

By July 23, 2013November 1st, 2023No Comments

pm2Tumour epithelial expression levels of endocannabinoid markers modulate the value of endoglin-positive vascular density as a prognostic marker in prostate cancer.

Source

Pharmacology Unit, Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden. Electronic address: cf@pharm.umu.se.

Abstract

Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of the endogenous cannabinoid (CB) receptor ligand anandamide. Here we have investigated whether the expression levels of FAAH and CB(1) receptors influence the prognostic value of markers of angiogenesis in prostate cancer. Data from a cohort of 419 patients who were diagnosed with prostate cancer at transurethral resection for lower urinary tract symptoms, of whom approximately 2/3 had been followed by expectancy, were used. Scores for the angiogenesis markers endoglin and von Willebrand factor (vWf), the endocannabinoid markers fatty acid amide hydrolase (FAAH) and cannabinoid CB(1) receptors and the cell proliferation marker Ki-67 were available in the database. For the cases followed by expectancy, the prognostic value of endoglin was dependent upon the tumour epithelial FAAH immunoreactivity (FAAH-IR) and CB(1)IR scores, and the non-malignant epithelial FAAH-IR scores, but not the non-malignant CB(1)IR scores or the tumour blood vessel FAAH-IR scores. This dependency upon the tumour epithelial FAAH-IR or CB(1)IR scores was less apparent for vWf, and was not seen for Ki-67. Using an endoglin cut-off value of 10 positively stained vessels per core and a median split of tumour FAAH-IR, four groups could be generated, with 15year of disease-specific survival (%) of 68±7 (low endoglin, low FAAH), 45±11 (high endoglin, low FAAH), 77±6 (low endoglin, high FAAH) and 21±10 (high endoglin, high FAAH). Thus, the cases with high endoglin and high FAAH scores have the poorest rate of disease-specific survival. At diagnosis, the number of cases with tumour stages 1a-1b relative to stages 2-4 was sensitive to the endoglin score in a manner dependent upon the tumour FAAH-IR. It is concluded that the prognostic value of endoglin as a marker of neovascularisation in prostate cancer can be influenced by the expression level of markers of the endocannabinoid system. This article is part of a Special Issue entitled Dysregulated Lipid Metabolism in Cancer.
Copyright © 2012 Elsevier B.V. All rights reserved.
PMID:

23262399
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Highlights

► Angiogenesis and endocannabinoid markers show associations in prostate cancer. ► The markers studied were endoglin, von Willebrand factor, CB1 receptors and FAAH. ► At high CB1 or FAAH tumour expression levels, endoglin was a prognostic biomarker. ► At low CB1 or FAAH tumour expression levels, this property of endoglin was lost.

Abbreviations

  • bv, blood vessel;
  • CB, cannabinoid;
  • FAAH, fatty acid amide hydrolase;
  • GS, Gleason score;
  • IR,immunoreactivity;
  • LT, tumour stage;
  • †Pca, death due to prostate cancer (Pca);
  • ROC, receiver-operated characteristic;
  • vWf, von Willebrand factor

Keywords

  • Cannabinoid CB1 receptor;
  • Fatty acid amide hydrolase;
  • Angiogenesis;
  • Endoglin;
  • von Willebrand factor;
  • Prostate cancer

Figures and tables from this article:

Full-size image (46 K)
Fig 1. Frequency distribution of FAAH-IR scores in the tumour tissues. The insert shows an example of the immunoreactive staining for part of a core from a case with a Gleason score of 7. The dotted lines represent the tranches used in the present study: the turquoise lines show the tertiary split, and the red line shows the median split.
Full-size image (90 K)
Fig. 2. ROC analyses for tumour endoglin scores and different cut-off ranges of endocannabinoid markers. The ROC curves for tumour endoglin were divided on the basis of A, tumour epithelial FAAH-IR; B, tumour epithelial CB1IR; C, tumour blood vessel FAAH-IR; D, non-malignant luminal epithelial FAAH-IR; E, non-malignant basal epithelial FAAH; F, non-malignant epithelial CB1IR scores. A 15 year cut-off was used for the patients who were followed with expectancy following diagnosis. The tranches used were chosen to divide the data into three approximately equal sample sizes. The exception to this rule was in Panel C, where the dataset did not allow this to be done. In this case, the samples sizes were 96, 105 and 36 for the bvFAAH-IR tranches 0–2.375, 2.5 and 2.75–3, respectively. The dotted lines indicate the ROC curve that would be found if the biomarker in question has absolutely no prognostic value (AUC = 0.5). Significance levels of the ROC curves are shown in the figures: ***P < 0.001, **P < 0.01, *P < 0.05, NSnot significant.
Full-size image (85 K)
Fig. 3. Prognostic significance of tumour endoglin scores for cases followed by expectancy: relationship with tumour epithelial FAAH-IR. Panels A and B show data for cases with FAAH-scores below the median (0–2) and Panels C and D for cases with FAAH scores above the median (2.05–3). Panels A and C show Exp(B) values (± 95% confidence intervals), obtained from Cox proportional-hazards regression analyses for different cut-offs of endoglin. Exp(B) is defined as the increase in risk for death due to prostate cancer for a score above the cut-off value relative to a score below the cut-off value. The beige dotted lines indicate Exp(B) = 1. When both confidence limits are above unity (filled symbols in the figure), the cut-off value provides significant prognostic information. The filled symbols are coloured according to significance levels: grey, P < 0.05; blue, P < 0.01; red, P < 0.001; turquoise squares, P < 0.0001. Values with a significance level 0.05 < P < 0.1 are shown as open triangles, whilst those with P values > 0.05 are shown as unfilled circles. The blue dotted lines indicate the % of cases in the dataset above the cut-off value. Panels B and D show Kaplan–Meier plots for the cases using endoglin cut-offs of < 10 and ≥ 10 (i.e. cut-off values in the area of highest significance shown in Panels A and C. †Pca refers to the number of patients who died as a result of their prostate cancer during the follow-up period. The ϗ2 values are for the log-rank (Mantel–Cox) tests, with the P values shown: ***P < 0.001, *P < 0.05.
Full-size image (94 K)
Fig. 4. Tumour stages (LT, Panels A to C) and Gleason scores (GS, Panels D to F) for the cases in the database scored for endoglin and tumour endocannabinoid markers. Panels A and D, epithelial FAAH-IR (tranches 0–2 and 2.05–3); Panels B and E, CB1IR (tranches 0–2 and 2.01–3); Panels C and F, blood vessel FAAH-IR (tranches 0–2.375 and 2.5–3). a and A refer to cases with an endoglin score < 10; b and B refer to cases with an endoglin score ≥ 10. Lower case letters (a,b) refer to the endocannabinoid marker score below the median, and upper case letters (A,B) are for the endocannabinoid marker score above the median. The numbers within the columns refer to the total number of cases for that column. The capped lines show significance levels for Chi-squared tests for the columns in question: the capped lines above the graph are for comparisons for low to high endoglin at a fixed endocannabinoid marker; the capped lines below the graph are for comparisons for low to high endocannabinoid marker for the given endoglin range. For the entire data set, the significance levels were Panel A, 0.002; Panels B, D and E, < 0.0001; Panel C, 0.015 and Panel F, 0.009 (Chi-squared test). Note that for bvFAAH, the number of cases with tumour stage 4 was too low for the Chi-squared test to be valid, so in this case, the tests were performed with tumour stages 3 and 4 combined.
Table 1. Spearman’s rho correlation coefficients between tumour epithelial and blood vessel FAAH-IR and CB1IR scores and the corresponding tumour endoglin and vWf scores for the cases scored for these markers.
Abbreviations: n, number of cases analysed; r, rho correlation coefficients; P, significance value.
View Within Article
Table 2. ROC analyses with a 15 year cut-off for endoglin, vWf and Ki67 index for cases followed by expectancy: influence of the tumour FAAH-IR score using different data tranches.
Abbreviations: AUC, area under the ROC curves; n, number of cases analysed, †Pca, number of cases who died due to prostate cancer. #1–210 and #211–419 designate the random split of the data (see Experimental for details). Note that not all cases scored for endoglin (or vWf or Ki67) were scored for FAAH. Thus, the number of cases in the first row (“all cases”) is slightly higher than the combined number of cases is for the FAAH subdivisions.
View Within Article
Table 3. Univariate and multivariate Cox proportional-hazards regression analyses of cancer-specific survival for endoglin as a prognostic marker: effect of FAAH-IR.
n end < 10 and n end ≥ 10 refer to the number of cases with endoglin scores < 10 and ≥ 10, respectively. GS, Gleason score, grouped into two groups: 4–7 and 8–10. LT, tumour stage, grouped into three groups, 1a–1b, 2, and 3–4.
View Within Article
☆
This article is part of a Special Issue entitled Dysregulated Lipid Metabolism in Cancer.
Corresponding author contact information
Corresponding author at: Pharmacology Unit, Department of Pharmacology and Clinical Neuroscience, Umeå University, SE901 87 Umeå, Sweden. Tel.: + 46 907851510.
1
Present address: Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.

Copyright © 2012 Elsevier B.V. All rights reserved.
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