title: Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors.
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.
authors: David H. Koch Center for Applied Research of Genitourinary Cancers, MD Anderson Cancer Center, University of Texas, Houston, TX 77030;
authors: Eleonora
authors: E
authors: Dondossola
authors: 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;
authors: Andrey S
authors: AS
authors: Dobroff
authors: 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;
authors: Serena
authors: S
authors: Marchiò
authors: 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;
authors: Marina
authors: M
authors: Cardó-Vila
authors: 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;
authors: Hitomi
authors: H
authors: Hosoya
authors: Department of Surgery and Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461;
authors: Steven K
authors: SK
authors: Libutti
authors: Division of Molecular Oncology, San Raffaele Scientific Institute and VIta Salute San Raffaele University, Milan 20132, Italy;
authors: Angelo
authors: A
authors: Corti
authors: 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.
authors: Richard L
authors: RL
authors: Sidman
authors: 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.
authors: Wadih
authors: W
authors: Arap
authors: 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.
authors: Renata
authors: R
authors: Pasqualini
mesh_terms: D000818:Animals; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000556:secondary / Q000628:therapy; D060846:Cell Engineering; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000556:secondary / Q000628:therapy; D008546:Melanoma, Experimental / Q000473:pathology / Q000556:secondary / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha
keywords: apoptosis; endothelial cells; engineered tumor cells; tumor necrosis factor; vascular damaging agent