Details

Autor(en) / Beteiligte

• Catarinella, Mario
• Monestiroli, Andrea
• Escobar, Giulia
• Fiocchi, Amleto
• Tran, Ngoc Lan
• Aiolfi, Roberto
• Marra, Paolo
• Esposito, Antonio
• Cipriani, Federica
• Aldrighetti, Luca
• Iannacone, Matteo
• Naldini, Luigi
• Guidotti, Luca G
• Sitia, Giovanni

Titel

IFNα gene/cell therapy curbs colorectal cancer colonization of the liver by acting on the hepatic microenvironment

Ist Teil von

• EMBO molecular medicine, 2016-02, Vol.8 (2), p.155-170

Ort / Verlag

England: John Wiley & Sons, Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Colorectal cancer (CRC) metastatic dissemination to the liver is one of the most life‐threatening malignancies in humans and represents the leading cause of CRC‐related mortality. Herein, we adopted a gene transfer strategy into mouse hematopoietic stem/progenitor cells to generate immune‐competent mice in which TEMs—a subset of Tie2+ monocytes/macrophages found at peritumoral sites—express interferon‐alpha (IFNα), a pleiotropic cytokine with anti‐tumor effects. Utilizing this strategy in mouse models of CRC liver metastasis, we show that TEMs accumulate in the proximity of hepatic metastatic areas and that TEM‐mediated delivery of IFNα inhibits tumor growth when administered prior to metastasis challenge as well as on established hepatic lesions, improving overall survival. Further analyses unveiled that local delivery of IFNα does not inhibit homing but limits the early phases of hepatic CRC cell expansion by acting on the radio‐resistant hepatic microenvironment. TEM‐mediated IFNα expression was not associated with systemic side effects, hematopoietic toxicity, or inability to respond to a virus challenge. Along with the notion that TEMs were detected in the proximity of CRC metastases in human livers, these results raise the possibility to employ similar gene/cell therapies as tumor site‐specific drug‐delivery strategies in patients with CRC. Synopsis Despite recent improvements in the treatment of CRC, a significant number of patients still succumb to CRC metastatic disease, especially of the liver. This study suggests that targeted IFNα gene/cell therapy of hepatic lesions may improve therapeutic outcomes. In preclinical CRC liver metastasis mouse models, Tie2+ monocytes/macrophages (TEMs) accumulate in the proximity of hepatic lesions; TEM‐mediated delivery of IFNα inhibits tumor growth and improves overall survival. By acting on the radio‐resistant hepatic microenvironment, IFNα primarily limits the early phases of hepatic CRC cell expansion. Further containment of cancer growth may result from IFNα‐induced anti‐tumor immune responses. Targeted gene/cell therapy of IFNα causes neither detectable side effects nor hematopoietic toxicity and does not inhibit the host response to a virus challenge. TEMs localize near human CRC liver metastases, suggesting that that this targeted gene/cell therapy approach could be employed as an additional adjuvant therapy for patients with, or at high risk of developing, CRC liver metastases. Despite recent improvements in the treatment of CRC, a significant number of patients still succumb to CRC metastatic disease, especially of the liver. This study suggests that targeted IFNα gene/cell therapy of hepatic lesions may improve therapeutic outcomes.