Role of Tumor-Associated Macrophages in The Heximl and TGF Beta/SMAD Pathway, and Their Influence on Progression of Prostatic Adenocarcinoma

Abstract

Background: Hexamethylene bisacetamide-inducible protein 1 (Heximl) regulates transforming growth factor-beta (TGF beta) activity and turnover of SMAD proteins in a cyclin-dependent kinase 9-dependent way. It does so specifically through inhibiting function of this enzyme and by inhibiting the transcriptional activity of positive transcription elongation factor b (P-TEFb). Tumor-associated macrophages (TAMs) play a role in the progression of prostate adenocarcinomas. We investigated the clinicopathological significance of Heximl, TGF beta, SMAD2, and SMAD7 expression in prostate adenocarcinoma cells, and assessed associations between TAMs density and these proteins.

Methods: The cases of 100 patients diagnosed with prostate acinar adenocarcinoma who had undergone radical prostatectomy were retrospectively examined. Each was reviewed for Gleason score, cancer stage, and specific histopathological features. Original slides were re-examined, and new slides were prepared and immunostained with Heximl, TGF beta, SMAD2, SMAD7 and CD68.

Results: Heximi expression was positively correlated with Gleason score, cancer stage, lymphovascular invasion, perineural invasion, extracapsular extension, and positive surgical margin. TAMs density was positively correlated with Gleason score, cancer stage, perineural invasion, extracapsular extension, and positive surgical margin. TAMs density was positively correlated with Heximl expression and TGF beta expression. More advanced cancer stage, lymphovascular invasion, perineural invasion, and extracapsular extension were correlated with strong Heximl expression, strong SMAD2 expression, and mild SMAD7 expression, respectively. Strong Heximl expression, strong TGF beta expression, and mild SMAD7 expression were associated with higher Gleason score. Strong Heximl expression was correlated with strong TGF beta expression and mild SMAD7 expression. Strong Heximi expression, strong SMAD2 expression, and mild expression of SMAD7 were associated with disease progression. Strong SMAD2 expression was associated with shorter disease-free survival.

Conclusion: The results suggest that greater TAMs density, strong Heximl expression, strong SMAD2 expression, and mild SMAD7 expression play important roles in the progression of prostate adenocarcinoma. Further investigation of these proteins will help facilitate the definitive prognosis of prostate adenocarcinomas. Ultimately, these proteins may be therapeutic targets for patients with prostate cancer. (C) 2015 Elsevier GmbH. All rights reserved.