TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 41; pp. 16618 - 16623
• Main Authors: Liu, Jieqiong, Liao, Shan, Diop-Frimpong, Benjamin, Chen, Wei, Goel, Shom, Naxerova, Kamila, Ancukiewicz, Marek, Boucher, Yves, Jain, Rakesh K., Xu, Lei
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.10.2012; National Acad Sciences
• Subjects: animal models; Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - immunology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antineoplastics; Apoptosis; Apoptosis - drug effects; Biological Sciences; Blood vessels; Blotting, Western; breast neoplasms; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; collagen; Collagen Type I - metabolism; Collagens; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; drug therapy; drugs; Female; gene overexpression; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Metastasis; Mice; Mice, Nude; neoplasm cells; neutralizing antibodies; Perfusion; Physical Sciences; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Tissue Distribution; transforming growth factor beta; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - metabolism; Treatment Outcome; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1117610109

Although the role of TGF-ß 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-ß blockade on the delivery and efficacy of conventional therapeutics and nanotherapeutics in orthotopic mammary carcinoma mouse models. We used both genetic (overexpression of sTßRII, a soluble TGF-ß type II receptor) and pharmacologie (1D11, a TGF-ß neutralizing antibody) approaches to block TGF-ß signaling. In two orthotopic mammary carcinoma models (human MDA-MB-231 and murine 4T1 cell lines), TGF-ß blockade significantly decreased tumor growth and metastasis. TGF-ß blockade also increased the recruitment and incorporation of perivascular cells into tumor blood vessels and increased the fraction of perfused vessels. Moreover, TGF-ß blockade normalized the tumor interstitial matrix by decreasing collagen I content. As a result of this vessel and interstitial matrix normalization, TGF-ß 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.