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

JAWORSKI, FELIPE M; GENTILINI, LUCAS; GUERON, GERALDINE; MEISS, ROBERTO P; ORTIZ, EMILIANO G; BERGUER, PAULA M; AHMED, ASIF; NAVONE, NORA M.; RABINOVICH, GABRIEL A; COMPAGNO, DANIEL; LADERACH, DIEGO J; VAZQUEZ, ELBA S

CLINICAL CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Año: 2017

1078-0432

Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shapetumor fate by targeting the tumor microenvironment. In this study we assessed how hemin, apharmacological inducer of Heme Oxygenase-1 (HO-1), impacts upon prostate cancer (PCa)development in an in vivo conditioning model.Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administrationof hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays wereperformed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinicalinsight, we used PCa patient-derived samples in our studies to assess the expression of HO-1 andother relevant genes.Results: Conditioning resulted in increased tumor latency and decreased initial growth rate.Histological analysis of tumors grown in conditioned mice revealed impaired vascularization. HemintreatedHUVEC exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neo-vascularization inan in vivo Matrigel plug assay. Additionally, hemin boosted CD8+ T-cell proliferation and degranulationin vitro and antigen-specific cytotoxicity in vivo. A significant systemic increase in CD8+ T-cell frequencywas observed in pre-conditioned tumor-bearing mice. Tumors from hemin-conditioned mice showedreduced 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 PCa patientderivedxenografts and PCa patient samples with mild HO-1 and low Gal-1 expression levels.