Human Soluble TRAIL Secreted by Modified Lactococcus lactis Bacteria Promotes Tumor Growth in the Orthotopic Mouse Model of Colorectal Cancer
Archivum Immunologiae et Therapiae Experimentalis, vol. 72
Abstract
Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of sensitive cancer cells, including colorectal cancer (CRC). Due to its short biological half-life after intravenous administration and related clinical ineffectiveness, novel formulations of TRAIL need to be developed. Here we propose Lactococcus lactis bacteria as a vehicle for local delivery of human soluble TRAIL (hsTRAIL) in CRC. The use of common probiotics targeting guts as carriers for TRAIL could ensure its sustained release at the tumor site and extend the duration of its activity. We have already engineered hsTRAIL-secreting L.lactis bacteria and showed their effectiveness in elimination of human CRC cells in vitro and in vivo in a mouse subcutaneous model. Here, L.lactis (hsTRAIL+) were administered by gastric gavage to SCID mice with orthotopically developed HCT116 tumor in cecum, in monotherapy or in combination with metformin (MetF), already shown to enhance the hsTRAIL anti-tumor activity in subcutaneous CRC model. Oral administration of L.lactis (hsTRAIL+) resulted in significant progression of HCT116 tumors and shortening of the colon crypts. Secretion of hsTRAIL in the colon was accompanied by infiltration of the primary tumor with M2-macrophages, while MetF promoted transient colonization of the gut by L.lactis . Our study indicates that L.lactis bacteria after oral administration enable delivery of biologically active hsTRAIL to colon, however its potential therapeutic effect in CRC treatment is abolished by its pro-tumorigenic signalling, leading to the recruitment of M2-macrophages and tumor growth promotion.
Authors 5
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Affiliation as printed
Department of Clinical Immunology, Institute of Pediatrics , Jagiellonian University Medical College , Kraków , Poland
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Ivo Que Aachen Translational Nanobiomaterials and Imaging Department of Radiology, Leiden University Medical Center
Leiden University Medical Center · Erasmus MC · Erasmus University Rotterdam
Affiliation as printed
Currently: Department of Radiology and Nuclear Medicine, Department of Molecular Genetics , Erasmus University Medical Center , Dr. Molewaterplein 40 , Rotterdam , The Netherlands
Translational Nanobiomaterials and Imaging, Department of Radiology , Leiden University Medical Center , Albinusdreef 2 , Leiden , The Netherlands
Currently: Department of Radiology and Nuclear Medicine, Department of Molecular Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands
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Affiliation as printed
Department of Clinical Immunology, Institute of Pediatrics , Jagiellonian University Medical College , Kraków , Poland
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Affiliation as printed
Percuros B.V. , Zernikedreef 8 , Leiden , The Netherlands
Percuros B.V., Zernikedreef 8, 2333 CL Leiden, The Netherlands
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Affiliation as printed
Department of Clinical Immunology, Institute of Pediatrics , Jagiellonian University Medical College , Kraków , Poland
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