A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone

Laure Thibaudeau,Carl A Power,Parisa Hesami,Dietmar W Hutmacher,Toby D Brown,Brett G Hollier,Tobias Fuehrmann,Verena M Quent,Paul D Dalton,Anna V Taubenberger,Boris M Holzapfel

doi:10.1242/dmm.014076

Abstract

ABSTRACTThe skeleton is a preferred homing site for breast cancer metastasis. To date, treatment options for patients with bone metastases are mostly palliative and the disease is still incurable. Indeed, key mechanisms involved in breast cancer osteotropism are still only partially understood due to the lack of suitable animal models to mimic metastasis of human tumor cells to a human bone microenvironment. In the presented study, we investigate the use of a human tissue-engineered bone construct to develop a humanized xenograft model of breast cancer-induced bone metastasis in a murine host. Primary human osteoblastic cell-seeded melt electrospun scaffolds in combination with recombinant human bone morphogenetic protein 7 were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. The tissue-engineered constructs led to the formation of a morphologically intact ‘organ’ bone incorporating a high amount of mineralized tissue, live osteocytes and bone marrow spaces. The newly formed bone was largely humanized, as indicated by the incorporation of human bone cells and human-derived matrix proteins. After intracardiac injection, the dissemination of luciferase-expressing human breast cancer cell lines to the humanized bone ossicles was detected by bioluminescent imaging. Histological analysis revealed the presence of metastases with clear osteolysis in the newly formed bone. Thus, human tissue-engineered bone constructs can be applied efficiently as a target tissue for human breast cancer cells injected into the blood circulation and replicate the osteolytic phenotype associated with breast cancer-induced bone lesions. In conclusion, we have developed an appropriate model for investigation of species-specific mechanisms of human breast cancer-related bone metastasis in vivo.

Highlights

Bone metastasis is one of the most frequent complications of breast cancer (BC), occurring in 80% of patients with advanced disease (Kozlow and Guise, 2005)
The authors show that human breast cancer cell lines with different affinity for bone metastasize to the human tissueengineered bone construct after intracardiac injection
The metastases detected in the human tissueengineered bone construct (hTEBC) replicate the osteolytic phenotype of the bone lesions typically induced by metastasis of breast cancer cells

Summary

Introduction

Bone metastasis is one of the most frequent complications of breast cancer (BC), occurring in 80% of patients with advanced disease (Kozlow and Guise, 2005). The preferential homing of circulating cancer cells to the skeleton has been attributed to mechanical factors, such as blood-flow pathways, as well as favorable molecular interactions between the tumor cells and the target bone site (Chambers et al, 2002). For example it has been shown that metastatic cancer cells have the ability to usurp hematopoietic stem cell (HSC) homing pathways to reach the bone microenvironment (Kaplan et al, 2005; Psaila and Lyden, 2009; Shiozawa et al, 2011). Skeletal metastases from BC are usually associated with an increased osteoclast activity in response to multiple growth factors and cytokines produced by the cancer cells. There are only palliative treatment options available to prevent further disease progression and reduce the associated pain and symptoms (Suva et al, 2011)

Methods

Results

Conclusion