Format

Send to

Choose Destination
Cancer Res. 2017 Nov 15;77(22):6299-6312. doi: 10.1158/0008-5472.CAN-17-1225. Epub 2017 Aug 30.

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases.

Author information

1
Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.
2
Department of Medicine, Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri.
3
Department of Bioengineering, University of Illinois at Urbana-Champaign, Champaign, Illinois.
4
Department of Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri.
5
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri.
6
Department of Surgery, Division of Public Health Sciences, St. Louis Breast Tissue Registry, Washington University School of Medicine, St. Louis, Missouri.
7
Departments of Cell Biology & Physiology and Neuroscience, Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, Missouri.
8
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
9
Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana.
10
Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri. kweilbae@wustl.edu.

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.

PMID:
28855208
PMCID:
PMC5841166
DOI:
10.1158/0008-5472.CAN-17-1225
[Indexed for MEDLINE]
Free PMC Article

MeSH terms, Substances, Grant support

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center