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

Abstract

The 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.

Endosteal-like extracellular matrix expression on melt electrospun written scaffolds

“…Our group has already demonstrated that melt electrospun PCL scaffolds are suitable to engineer bone constructs to study species-specific mechanisms in vivo [24,25]. However, the endosteallike ECM deposition by hOBs on melt electrospun PCL scaffolds has not been characterised [47,48].…”

“…Melt electrospun written scaffolds made of medical grade poly(ɛ-caprolactone) (PCL) have supported de novo formation of bone in vivo [24,25]. Thus, melt electrospun PCL scaffolds represent a 3D testing platform to tailor characteristic components of the endosteal niche in a highly controlled fashion.…”

Knockdown of Bone Morphogenetic Proteins Type 1a Receptor (BMPR1a) in Breast Cancer Cells Protects Bone from Breast Cancer-Induced Osteolysis by Suppressing RANKL Expression

“…To explore the role of BMPR1a in tumor-stromal interaction in bone metastasis, human breast cancer MDA-MB-231-luc cells were injected intratibially into nude mice to construct a breast cancer bone metastasis model [23]. Immunofluorescent analysis for BMPR1a of tumor-bearing bone sections obtained from different metastatic mice demonstrated a stronger staining of BMPR1a of breast cancer cells at the tumor-bone interface, compared with cancer cells distant from the interface (Fig.…”

Humanized mice models for primary bone tumor and bone metastasis research

“…We and others have described the development of large volume bone implants with a physiologically relevant morphology and which include a high number of human stromal cells. 5,6 Different research groups utilize hBMSCs to engineer ectopic humanized bone tissues. However, most of them do not demonstrate the retention of the human cells after transplantation, nor do they characterize the degree of humanization of the newly formed tissue.…”

“…Another key aspect which is largely missing in most studies is evidence not only of the presence of human cells in the engineered tissues but also of the incorporation of humanderived extracellular matrix (ECM). 6 In fact the bone niche regulates the behavior of normal and malignant cells via various chemo-attractive and adhesive pathways, which include cell-cell as well as cell-ECM interactions. In our recently published paper we have shown that the b1 integrin cell-ECM adhesion molecules expressed by breast cancer cells play a significant role in the development of metastases within a humanized bone microenvironment.…”