Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 41, Pages 16618-16623Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1117610109
Keywords
breast cancer; vessel normalization; drug delivery
Categories
Funding
- Dyax
- MedImmune
- Roche
- Enlight
- Noxxon
- SynDevRx
- American Cancer Society [ACS122839-RSG-12-199-01]
- National Institutes of Health [R01-CA85140, R01-CA115767, R01-CA126642]
- Department of Defense Breast Cancer Research Innovator Award [W81XWH-10-1-0016]
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Although the role of TGF-beta in tumor progression has been studied extensively, its impact on drug delivery in tumors remains far from understood. In this study, we examined the effect of TGF-beta blockade on the delivery and efficacy of conventional therapeutics and nanotherapeutics in orthotopic mammary carcinoma mouse models. We used both genetic (overexpression of sT beta RII, a soluble TGF-beta type II receptor) and pharmacologic (1D11, a TGF-beta neutralizing antibody) approaches to block TGF-beta signaling. In two orthotopic mammary carcinoma models (human MDA-MB-231 and murine 4T1 cell lines), TGF-beta blockade significantly decreased tumor growth and metastasis. TGF-beta blockade also increased the recruitment and incorporation of perivascular cells into tumor blood vessels and increased the fraction of perfused vessels. Moreover, TGF-beta blockade normalized the tumor interstitial matrix by decreasing collagen I content. As a result of this vessel and interstitial matrix normalization, TGF-beta blockade improved the intratumoral penetration of both a low-molecular-weight conventional chemotherapeutic drug and a nanotherapeutic agent, leading to better control of tumor growth.
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