In vivo hemin conditioning targets the vascular and immunologic compartments and restrains prostate tumor development


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.

Publication DOI:
Divisions: College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Additional Information: © 2017 American Association for Cancer Research
Uncontrolled Keywords: prostate-cancer,eme-Oxygenase-1,conditioning,inflammation,Galectin-1,Oncology,Cancer Research
Publication ISSN: 1557-3265
Last Modified: 06 May 2024 07:21
Date Deposited: 11 Oct 2017 15:30
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2017-09-01
Accepted Date: 2017-05-10
Authors: Jaworski, Felipe M.
Gentilini, Lucas D.
Gueron, Geraldine
Meiss, Roberto P.
Ortiz, Emiliano G.
Berguer, Paula M.
Ahmed, Asif (ORCID Profile 0000-0002-8755-8546)
Navone, Nora
Rabinovich, Gabriel A.
Compagno, Daniel
Laderach, Diego J.
Vazquez, Elba S.



Version: Accepted Version

| Preview

Export / Share Citation


Additional statistics for this record