Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases
Year: 2017
Type: article
Abstract: Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, β3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGFβ signaling through SMAD2/SMAD3 was necessary for breast cancer induction of β3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvβ3 (αvβ3-MPs of ∼12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with αvβ3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvβ3 at that metastatic site. Cancer Res; 77(22); 6299–312. ©2017 AACR.
Source: Cancer Research
Authors: Michael H. Ross, Alison K. Esser, Gregory C. Fox, Anne H. Schmieder, Xiaoxia Yang, Grace Hu, Dipanjan Pan, Xinming Su, Yalin Xu, Deborah V. Novack, Thomas Walsh, Graham A. Colditz, Gabriel H. Lukaszewicz, Elizabeth Cordell, Joshua Novack, James A. J. Fitzpatrick, David L. Waning, Khalid S. Mohammad, Theresa A. Guise, Gregory M. Lanza, Katherine N. Weilbaecher
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
Funders: National Institutes of Health, Musculoskeletal Research Center, Washington University in St. Louis, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources
Awards: G1220868724, G1234843147, G1383854014, Center for Multiple Myeloma Nanotherapy, TGFbeta IN THE BONE MICROENVIRONMENT: ROLE IN TUMOR METASTASIS, G2100007707, G304139194, G3117263138, WU-MDACC Inter-Institutional Molecular Imaging Center, G3401557599, Core Center for Musculoskeletal Biology and Medicine, G4500330726, BREAST CANCER METASTASES TO BONE--ROLE OF PTHRP &TGFB, Differential TGF-Beta Signaling in Bone Microenviroment: Impact on Tumor Growth, G500294632, G5165247642, Training Program in Cellular and Molecular Biology, Expanding Access to Planar Illumination Microscopy in a Neuroimaging Core, G6811495677, G709588784, G7196538893, National Research Service Award-Medical Scientist, Retrovirus Models of Cancer, Cancer Center Support Grant, Skeletal Disorders Training Program, G921849644, G964580632
OpenAlex ID: W2750781621