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Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2223-8. doi: 10.1073/pnas.1525697113. Epub 2016 Feb 8.

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

Author information

1
David H. Koch Center for Applied Research of Genitourinary Cancers, MD Anderson Cancer Center, University of Texas, Houston, TX 77030;
2
University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
3
University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; Department of Oncology, University of Torino, Candiolo 10060, Italy;
4
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8656, Japan; The University of Tokyo Hospital, Tokyo 113-8656, Japan;
5
Department of Surgery and Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461;
6
Division of Molecular Oncology, San Raffaele Scientific Institute and VIta Salute San Raffaele University, Milan 20132, Italy;
7
Harvard Medical School and Department of Neurology, Beth Israel-Deaconess Medical Center, Boston, MA 02215; richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
8
University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131 richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
9
University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.

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.

KEYWORDS:

apoptosis; endothelial cells; engineered tumor cells; tumor necrosis factor; vascular damaging agent

PMID:
26858439
PMCID:
PMC4776485
DOI:
10.1073/pnas.1525697113
[Indexed for MEDLINE]
Free PMC Article

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