<abstract xmlns="http://www.w3.org/1999/xhtml">

<p>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 <italic>Lactococcus lactis</italic> 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 <italic>L.lactis</italic> bacteria and showed their effectiveness in elimination of human CRC cells in vitro and in vivo in a mouse subcutaneous model. Here, <italic>L.lactis</italic>(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 <italic>L.lactis</italic>(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 <italic>L.lactis</italic>. Our study indicates that <italic>L.lactis</italic> 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.</p>
</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.

Human Soluble TRAIL Secreted by Modified <italic>Lactococcus lactis</italic> Bacteria Promotes Tumor Growth in the Orthotopic Mouse Model of Colorectal Cancer

Department of Clinical Immunology, Institute of Pediatrics

Translational Nanobiomaterials and Imaging, Department of Radiology

Department of Radiology and Nuclear Medicine, Department of Molecular Genetics

Archivum Immunologiae et Therapiae Experimentalis

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Human Soluble TRAIL Secreted by Modified  Bacteria Promotes Tumor Growth in the Orthotopic Mouse Model of Colorectal Cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of sensitive cancer cells, including colorectal cancer (CRC). Due...

Human Soluble TRAIL Secreted by Modified Lactococcus lactis Bacteria Promotes Tumor Growth in the Orthotopic Mouse Model of Colorectal Cancer

Article Category: Original

Published Online: Jan 06, 2024

Page range: -

Received: Jul 05, 2023

Accepted: Nov 30, 2023

DOI: https://doi.org/10.2478/aite-2024-0002

Keywords
Colorectal cancer, TRAIL, Metformin, Orthotopic mice model of CRC

© 2023 Katarzyna Kaczmarek et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Human Soluble TRAIL Secreted by Modified Lactococcus lactis Bacteria Promotes Tumor Growth in the Orthotopic Mouse Model of Colorectal Cancer

Article Category: Original

Published Online: Jan 06, 2024

Page range: -

Received: Jul 05, 2023

Accepted: Nov 30, 2023

DOI: https://doi.org/10.2478/aite-2024-0002

KeywordsColorectal cancer, TRAIL, Metformin, Orthotopic mice model of CRC

© 2023 Katarzyna Kaczmarek et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
Colorectal cancer, TRAIL, Metformin, Orthotopic mice model of CRC