Preclinical Orthotopic and Intracardiac Injection Models of Human Breast Cancer Metastasis to Bone and Their Use in Drug Discovery

Scepansky, Ellen M.; Goldstein, Robert H.; Rosenblatt, Michael

doi:10.1002/0471141755.ph1418s52

Cited by 3 publications

(2 citation statements)

References 49 publications

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“…Compared to bone chips, the hTEBCs have a distinct advantage in allowing control of the shape, size and surface properties of the implant as well as the opportunity to characterize the cell viability prior to implantation. The hTEBCs integrated well under the skin and did not result in wound problems or dehiscence that are common after implantation of sharp-edged bone pieces ( Scepansky et al, 2001 ). The hTEBCs led to the formation of mineralized tissue in all implants, indicating a high reproducibility for this procedure.…”

Section: Discussionmentioning

confidence: 99%

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

Thibaudeau

Taubenberger

Holzapfel

et al. 2014

Disease Models &Amp; Mechanisms

113

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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.

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Section: Discussionmentioning

confidence: 99%

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

Thibaudeau

Taubenberger

Holzapfel

et al. 2014

Disease Models &Amp; Mechanisms

113

View full text Add to dashboard Cite

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“…The 4T1 intra-cardiac model is an interesting experimental animal model for human mammary metastatic cancer, as it produces reliable bone metastases that are common in human cancer patients 38 . Such a model provides a good means for evaluating imaging agents 13 and drug/biologic therapies 39 . However, metastatic cancer is particularly difficult to analyze, as tumors can be small and scattered over various types of tissue in cryo-images, thus making the human annotation time consuming and prone to error.…”

Section: Discussionmentioning

confidence: 99%

Quantitative analysis of metastatic breast cancer in mice using deep learning on cryo-image data

Liu

Gargesha

Qutaish

et al. 2021

Sci Rep

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Cryo-imaging sections and images a whole mouse and provides ~ 120-GBytes of microscopic 3D color anatomy and fluorescence images, making fully manual analysis of metastases an onerous task. A convolutional neural network (CNN)-based metastases segmentation algorithm included three steps: candidate segmentation, candidate classification, and semi-automatic correction of the classification result. The candidate segmentation generated > 5000 candidates in each of the breast cancer-bearing mice. Random forest classifier with multi-scale CNN features and hand-crafted intensity and morphology features achieved 0.8645 ± 0.0858, 0.9738 ± 0.0074, and 0.9709 ± 0.0182 sensitivity, specificity, and area under the curve (AUC) of the receiver operating characteristic (ROC), with fourfold cross validation. Classification results guided manual correction by an expert with our in-house MATLAB software. Finally, 225, 148, 165, and 344 metastases were identified in the four cancer mice. With CNN-based segmentation, the human intervention time was reduced from > 12 to ~ 2 h. We demonstrated that 4T1 breast cancer metastases spread to the lung, liver, bone, and brain. Assessing the size and distribution of metastases proves the usefulness and robustness of cryo-imaging and our software for evaluating new cancer imaging and therapeutics technologies. Application of the method with only minor modification to a pancreatic metastatic cancer model demonstrated generalizability to other tumor models.

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Engineering a humanized bone organ model in mice to study bone metastases

et al. 2017

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Current in vivo models for investigating human primary bone tumors and cancer metastasis to the bone rely on the injection of human cancer cells into the mouse skeleton. This approach does not mimic species-specific mechanisms occurring in human diseases and may preclude successful clinical translation. We have developed a protocol to engineer humanized bone within immunodeficient hosts, which can be adapted to study the interactions between human cancer cells and a humanized bone microenvironment in vivo. A researcher trained in the principles of tissue engineering will be able to execute the protocol and yield study results within 4-6 months. Additive biomanufactured scaffolds seeded and cultured with human bone-forming cells are implanted ectopically in combination with osteogenic factors into mice to generate a physiological bone 'organ', which is partially humanized. The model comprises human bone cells and secreted extracellular matrix (ECM); however, other components of the engineered tissue, such as the vasculature, are of murine origin. The model can be further humanized through the engraftment of human hematopoietic stem cells (HSCs) that can lead to human hematopoiesis within the murine host. The humanized organ bone model has been well characterized and validated and allows dissection of some of the mechanisms of the bone metastatic processes in prostate and breast cancer.

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Preclinical Orthotopic and Intracardiac Injection Models of Human Breast Cancer Metastasis to Bone and Their Use in Drug Discovery

Cited by 3 publications

References 49 publications

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

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

Quantitative analysis of metastatic breast cancer in mice using deep learning on cryo-image data

Engineering a humanized bone organ model in mice to study bone metastases

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