| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Dondossola, Eleonora Dobroff, Andrey S. Hosoya, Hitomi Libutti, Steven K. Marchiò, Serena Sidman, Richard L. Arap, Wadih Corti, Angelo Pasqualini, Renata Cardó-vila, Marina |
| Description |
Author Affiliation: Dondossola E ( David H. Koch Center for Applied Research of Genitourinary Cancers, MD Anderson Cancer Center, University of Texas, Houston, TX 77030); Dobroff AS ( University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131); Marchiò S ( University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131); Cardó-Vila M ( University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131); Hosoya H ( Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8656, Japan); Libutti SK ( Department of Surgery and Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461); Corti A ( Division of Molecular Oncology, San Raffaele Scientific Institute and VIta Salute San Raffaele University, Milan 20132, Italy); Sidman RL ( Harvard Medical School and Department of Neurology, Beth Israel-Deaconess Medical Center, Boston, MA 02215); Arap W ( University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131); Pasqualini R ( University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131); |
| 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. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
8 |
| Volume Number |
113 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2016-02-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Neoplasms, Experimental Therapy Tumor Necrosis Factor-alpha Biosynthesis Animals Apoptosis Carcinoma, Lewis Lung Pathology Cell Engineering Cell Line, Tumor Cell- And Tissue-Based Therapy Drug Delivery Systems Endothelium, Vascular Mammary Neoplasms, Experimental Melanoma, Experimental Mice Mice, Inbred BALB C Mice, Inbred C57BL Recombinant Proteins Genetics Therapeutic Use Transduction, Genetic Xenograft Model Antitumor Assays Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
