ABSTRACT
Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may also have the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoid receptor (GR). Given the association between inflammation and PCa, and the anti-inflammatory role of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by the interaction between HO-1 and GR. PCa-derived cell lines were treated with Hemin, Dexamethasone (Dex), or both. We studied GR gene expression by RTqPCR, protein expression by Western Blot, transcriptional activity using reporter assays, and nuclear translocation by confocal microscopy. We also evaluated the expression of HO-1, FKBP51, and FKBP52 by Western Blot. Hemin pre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmic GR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possibly accounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumors growing as xenografts. We found non-significant differences in tumor growth among treatments. Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We did not observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltrating macrophages. Our results suggest an association and crossed modulation between HO-1 and GR pathways.
Subject(s)
Heme Oxygenase-1/metabolism , Prostatic Neoplasms/metabolism , Receptors, Glucocorticoid/metabolism , Animals , Cell Line, Tumor , Dexamethasone/pharmacology , Disease-Free Survival , Heme Oxygenase-1/genetics , Hemin/pharmacology , Humans , Male , Mice , Promoter Regions, Genetic/genetics , Response Elements/genetics , Signal Transduction , Tacrolimus Binding Proteins/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study, we assessed how hemin, a pharmacologic inducer of heme oxygenase-1 (HO-1), has an impact on prostate cancer development in an in vivo conditioning model.Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinical insight, we used prostate cancer patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes.Results: Conditioning resulted in increased tumor latency and decreased initial growth rate. Histologic analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated human umbilical vein endothelial cells (HUVEC) exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1-conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neovascularization in an in vivo Matrigel plug assay. In addition, hemin boosted CD8+ T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo A significant systemic increase in CD8+ T-cell frequency was observed in preconditioned tumor-bearing mice. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment. We also found a subset of prostate cancer patient-derived xenografts and prostate cancer patient samples with mild HO-1 and low Gal-1 expression levels.Conclusions: These results highlight a novel function of a human-used drug as a means of boosting the antitumor response. Clin Cancer Res; 23(17); 5135-48. ©2017 AACR.
Subject(s)
Galectin 1/genetics , Heme Oxygenase-1/genetics , Hemin/administration & dosage , Prostatic Neoplasms/drug therapy , Animals , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/pathology , Cell Proliferation/drug effects , Disease Models, Animal , Galectin 1/antagonists & inhibitors , Gene Expression Regulation, Neoplastic/drug effects , Heme Oxygenase-1/antagonists & inhibitors , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Male , Mice , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer death among men worldwide. While localized prostate cancer can be cured, advanced and metastatic prostate cancer remains a significant therapeutic challenge. Malignant transformation is associated with important modifications of the cellular glycosylation profile, and it is postulated that these changes have a considerable relevance for tumor biology. Metastasis is a multiphasic process that encompasses angiogenesis, the spread of tumor cells and their growth at distant sites from the primary tumor location. Recognition of glycoconjugates by galectins, among other lectins, plays a fundamental role in the metastatic spread, tumor immune escape and the neovascularization process. Particularly in prostate cancer, both carbohydrates and galectins have been implicated in many cellular processes such as proliferation, apoptosis, migration and invasion. However, a limited number of studies assessed their potential implications in the induction of metastasis in prostate cancer patients or in animal models. Moreover, the role of galectin-glycan interactions in vivo still remains poorly understood; concerted effort should thus be made in order to shed some light on this question. This review summarizes current evidence on both the expression and role of glycans and galectins in prostate cancer, particularly turning our attention to the angiogenic and metastatic processes.
Subject(s)
Galectins/genetics , Neovascularization, Pathologic/genetics , Polysaccharides/genetics , Prostatic Neoplasms/genetics , Apoptosis/genetics , Cell Movement/genetics , Cell Proliferation/genetics , Galectins/metabolism , Gene Expression Regulation, Neoplastic , Humans , Male , Neoplasm Metastasis , Polysaccharides/metabolism , Prostatic Neoplasms/pathologyABSTRACT
A better understanding of multimolecular interactions involved in tumor dissemination is required to identify new effective therapies for advanced prostate cancer (PCa). Several groups investigated protein-glycan interactions as critical factors for crosstalk between prostate tumors and their microenvironment. This review both discusses whether the "galectin-signature" might serve as a reliable biomarker for the identification of patients with high risk of metastasis and assesses the galectin-glycan lattices as potential novel targets for anticancer therapies. The ultimate goal of this review is to convey how basic findings related to galectins could be in turn translated into clinical settings for patients with advanced PCa.
ABSTRACT
Galectins, a family of glycan-binding proteins, can control tumor progression by promoting transformation, angiogenesis and immune escape. We identified a dynamically regulated 'galectin signature', which delineates the progression of prostate cancer, highlighting galectin-1 as an attractive target for anti-angiogenic therapy in advanced stages of the disease.
