TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma
Open Access
- 20 September 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (41), 16618-16623
- https://doi.org/10.1073/pnas.1117610109
Abstract
Although the role of TGF-β 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-β blockade on the delivery and efficacy of conventional therapeutics and nanotherapeutics in orthotopic mammary carcinoma mouse models. We used both genetic (overexpression of sTβRII, a soluble TGF-β type II receptor) and pharmacologic (1D11, a TGF-β neutralizing antibody) approaches to block TGF-β signaling. In two orthotopic mammary carcinoma models (human MDA-MB-231 and murine 4T1 cell lines), TGF-β blockade significantly decreased tumor growth and metastasis. TGF-β blockade also increased the recruitment and incorporation of perivascular cells into tumor blood vessels and increased the fraction of perfused vessels. Moreover, TGF-β blockade normalized the tumor interstitial matrix by decreasing collagen I content. As a result of this vessel and interstitial matrix normalization, TGF-β 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.This publication has 53 references indexed in Scilit:
- Causes, consequences, and remedies for growth-induced solid stress in murine and human tumorsProceedings of the National Academy of Sciences of the United States of America, 2012
- Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent mannerNature Nanotechnology, 2012
- Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumorsProceedings of the National Academy of Sciences of the United States of America, 2011
- Delivering nanomedicine to solid tumorsNature Reviews Clinical Oncology, 2010
- TGF- Biology in Mammary Development and Breast CancerCold Spring Harbor Perspectives in Biology, 2010
- Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signalingProceedings of the National Academy of Sciences of the United States of America, 2007
- Ki26894, a novel transforming growth factor‐β type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell lineCancer Science, 2006
- Transforming growth factor-β in cancer and metastasisCancer and Metastasis Reviews, 2006
- Molecular regulation of vessel maturationNature Medicine, 2003
- Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generationNature Medicine, 2003