Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors

Eleonora Dondossola, Andrey S. Dobroff, Serena Marchiò, Marina Cardó-Vila, Hitomi Hosoya, Steven K. Libutti, Angelo Corti, Richard L. Sidman, Wadih Arap, Renata Pasqualini

Research output: Contribution to journalArticle

Abstract

Circulating cancer cells can putatively colonize distant organs to form metastases or to reinfiltrate primary tumors themselves through a process termed "tumor self-seeding." Here we exploit this biological attribute to deliver tumor necrosis factor alpha (TNF), a potent antitumor cytokine, directly to primary and metastatic tumors in a mechanism that we have defined as "tumor self-targeting." For this purpose, we genetically engineered mouse mammary adenocarcinoma (TSA), melanoma (B16-F10), and Lewis lung carcinoma cells to produce and release murine TNF. In a series of intervention trials, systemic administration of TNF-expressing tumor cells was associated with reduced growth of both primary tumors and metastatic colonies in immunocompetent mice. We show that these malignant cells home to tumors, locally release TNF, damage neovascular endothelium, and induce massive cancer cell apoptosis. We also demonstrate that such tumor-cell-mediated delivery avoids or minimizes common side effects often associated with TNF-based therapy, such as acute inflammation and weight loss. Our study provides proof of concept that genetically modified circulating tumor cells may serve as targeted vectors to deliver anticancer agents. In a clinical context, this unique paradigm represents a personalized approach to be translated into applications potentially using patient-derived circulating tumor cells as self-targeted vectors for drug delivery.

Original languageEnglish
Pages (from-to)2223-2228
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number8
DOIs
Publication statusPublished - Feb 23 2016

Keywords

  • Apoptosis
  • Endothelial cells
  • Engineered tumor cells
  • Tumor necrosis factor
  • Vascular damaging agent

ASJC Scopus subject areas

  • General

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