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. 2021 Aug;39(8):495.e7-495.e15.
doi: 10.1016/j.urolonc.2021.01.010. Epub 2021 Feb 7.

Exploration of biomarkers from a pilot weight management study for men undergoing radical prostatectomy

Mohamad Dave Dimachkie  1 , Misty D Bechtel  1 , Hilary L Robertson  1 , Carrie Michel  1 , Eugene K Lee  1 , Debra K Sullivan  2 , Prabhakar Chalise  3 , J Brantley Thrasher  1 , William P Parker  1 , Andrew K Godwin  4 , Harsh B Pathak  4 , John DiGiovanni  5 , Nitin Shivappa  6 , James R Hébert  6 , Jill M Hamilton-Reeves  7
Affiliations

Exploration of biomarkers from a pilot weight management study for men undergoing radical prostatectomy

Mohamad Dave Dimachkie et al. Urol Oncol. 2021 Aug.

Abstract

Background: Several biologic mechanisms, including inflammation and immune changes, have been proposed to explain the role of obesity in prostate cancer (CaP) progression. Compared to men of a healthy weight, overweight and obese men are more likely to have CaP recurrence post-prostatectomy. Obesity is related to inflammation and immune dysregulation; thus, weight loss may be an avenue to reduce inflammation and reverse these immune processes.

Objectives: This study explores the reversibility of the biological mechanisms through intentional weight loss using a comprehensive weight management program in men undergoing prostatectomy. Outcomes include blood and tissue biomarkers, microtumor environment gene expression, inflammation markers and Dietary Inflammatory Index (DII) scores.

Methods: Twenty overweight men undergoing prostatectomy participated in this study. Fifteen men chose the intervention and 5 men chose the nonintervention group. The intervention consisted of a comprehensive weight loss program prior to prostatectomy and a weight maintenance program following surgery. Prostate tissue samples were obtained from diagnostic biopsies before the intervention and prostatectomy samples after weight loss. Blood samples and diet records were collected at baseline, pre-surgery after weight loss and at study end after weight maintenance. Immunohistochemistry and NanoString analysis were used to analyze the tissue samples. Flow cytometry was used to assess circulating immune markers. Inflammation markers were measured using Luminex panels.

Results: The intervention group lost >5% body weight prior to surgery. DII scores improved during the weight loss intervention from baseline to pre-surgery (P = 0.002); and between group differences were significant (P = 0.02). DII scores were not associated with IL-6 nor hsCRP. In the intervention, CXCL12, CXCR7, and CXCR4 (C-X-C motif chemokine ligand/receptor) and Ki67 expression decreased in the prostate tissue from biopsy to surgery (P = 0.06), yet plasma CXCL12 increased during the same timeframe (P = 0.009). The downregulation of several genes (FDR<0.001) was observed in the intervention compared to the non-intervention. Changes in immune cells were not significant in either group.

Conclusion: This feasibility study demonstrates that in overweight men with localized CaP, weight loss alters blood, and tissue biomarkers, as well as tumor gene expression. More research is needed to determine the biological and clinical significance of these findings.

Keywords: Biomarkers; Gene expression; Inflammation; Overweight/obese; Prostate cancer; Weight loss/maintenance.

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Conflict of interest statement

Conflict of interest None of the authors had conflicts of interests to report.

Figures

Figure 1.
Figure 1.. CXCR4, CXCR7 and CXCL12 Intensity & Ki-67% Positive Staining –
A) Immunohistochemistry images showing the representative change in CXCR4, CXCR7 and CXCL12 stain intensity from biopsy to surgery in both intervention and non-intervention participants. B) Immunohistochemistry images showing the representative change in Ki-67 staining in men from biopsy to surgery in both intervention and non-intervention participants.
Figure 2.
Figure 2.. Cancer Signaling Genes Heat map, Immune Signaling Genes Heatmap and Differential Expression of Genes Intervention vs Non-intervention Volcano Plot –
A) Heatmap showing expression of cancer signaling genes of men in intervention and non-intervention arms. HGNC Database Identifier Numbers: PIN1, HGNC:8988; ITGAE, HGNC:6147; CXCR7, HGNC:23692; FCGR3A, HGNC:3619; TFEB, HGNC:11753; CXCL12, HGNC:10672; STAT5B, HGNC:11367; TBK1, HGNC:11584; CTSL, HGNC:2537; IL4R, HGNC:6015; CXCR4, HGNC:2561; IL8, HGNC:6025; CXCL3, HGNC:4604; CXCL1, HGNC:4602; CXCL5, HGNC:10642; CXCL2, HGNC:4603; C3, HGNC:1318; LCN2, HGNC:6526; SAA1, HGNC:10513; CXCL14, HGNC:10640; ULBP2, HGNC:14894; SPINK5, HGNC:15464; IL11RA, HGNC:5967; IL15RA, HGNC:5978; MRC1L1, HGNC:7228; IL17RB, HGNC:18015; LYN, HGNC:6735; TLR2, GNC:11848; IFNA1, HGNC:5417; IL13, HGNC:5973; CD86, HGNC:1705; CCR3, HGNC:1604; IFNA2, HGNC:5423; IL2, HGNC:6001; IL21, HGNC:6005; IFNB1, HGNC:5434; S100A8, HGNC:10498; NOS2A, HGNC:7873; HLA-DPB1, HGNC:4940; C1QBP, HGNC:1243; MAF, HGNC:6776; TMEFF2, HGNC:11867; ARG2, HGNC:664; CD44, HGNC:1681; HLA-DRA, HGNC:4947; LTF, HGNC:6720. B) Heatmap showing expression of immune signaling genes of men in intervention and non-intervention arms. HGNC Database Identifier Numbers: STAT5B, HGNC:11367; TBK1, HGNC:11584; CTSL, HGNC:2537; IL4R, HGNC:6015; TNFAIP3, HGNC:11896; CXCR4, HGNC:2561; C7, HGNC:1346; CXCL12, HGNC:10672; PIN1, HGNC:8988; ITGAE, HGNC:6147; CXCR7, HGNC:23692; COLEC12, HGNC:16016; FCGR3A, HGNC:3619; TFEB, HGNC:11753; IFNA17, HGNC:5422; CT45A1, HGNC:33267; SPINK5, HGNC:15464; CXCL14, HGNC:10640; ULBP2, HGNC:14894; CYBB, HGNC:2578; CXCL3, HGNC:4604; CXCL6, HGNC:10643; TLR2, HGNC:11848; CXCL5, HGNC:10642; CXCL2, HGNC:4603; C3, HGNC:1318; LCN2, HGNC:6526; CXCL1, HGNC:4602; IL8, HGNC:6025; SAA1, HGNC:10513; IFNA2, HGNC:5423; IL2, HGNC:6001; BTLA, HGNC:21087; LRRN3, HGNC:17200; IFNA8, HGNC:5429; ITK, HGNC:6171; IL21, HGNC:6005; PMCH, HGNC:9109; IL11RA, HGNC:5967; IL15RA, HGNC:5978; MRC1, HGNC:7228; IL17RB, HGNC:18015; LYN, HGNC:6735; IFNA1, HGNC:5417; IL13, HGNC:5973; CD86, HGNC:1705; CCR3, HGNC:1604; CCL15, HGNC:10613; IFNB1, HGNC:5434; SPO11, HGNC:11250; GNLY, HGNC:4414; CSF3R, HGNC:2439; S100A8, HGNC:10498; IL1R2, HGNC:5994; CLEC5A, HGNC:2054; TNFSF14, HGNC:11930; NOS2A, HGNC:7873; CD44, HGNC:1681; HLA-DPB1, HGNC:4940; ARG2, HGNC:664; HLA-B, HGNC:4932; HLA-DRA, HGNC:4947; C1QBP, HGNC:1243; PSMB8, HGNC:9545; MAF, HGNC:6776; TMEFF2, HGNC:11867; LTF, HGNC:6720. C) Volcano plot showing the differential expression of immune and cancer signaling genes of men in intervention versus non-intervention arms. HGNC Database Identifier Numbers: CXCL5, HGNC:10642; SAA1, HGNC:10513; TNFSF14, HGNC:11930; IL8, HGNC:6025; S100A8, HGNC:10498; GNLY, HGNC:4414; LCN2, HGNC:6526; CSF3R, HGNC:2439; CXCL3, HGNC:4604; CXCL1, HGNC:4602; CXCL2, HGNC:4603; TLR2, HGNC:11848; C3, HGNC:1318; CXCL6, HGNC:10643; CCL15, HGNC:10613; SPO11, HGNC:11250; IFNA2, HGNC:5423; IFNA17, HGNC:5422; IFNA8, HGNC:5429; ULBP2, HGNC:14894; CT45A1, HGNC:33267.
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