> Research & Grants
> Grants Program
> Research Grants
> Research Grants Awarded
Endothelin-1 Effects on the Development of Breast Cancer Bone Metastases
Background: Breast cancer remains a leading cause of death in women. The development of breast cancer bone metastases involves a vicious cycle of interactions between tumor cells, bone cells and the immune system resulting in osteolytic lesions. Currently, no in vivo immuno-competent model allows the study of early events of bone metastases. Antagonists to vascular endothelial growth factor (VEGF) delayed the development of bones metastases stressing the key role of angiogenesis in the disease. Other angiogenic molecules including endothelin-1, which regulates the expression of VEGF may also play a crucial role in the occurrence of bone metastases. Whether altering endothelin-1 effects would durably prevent the development of breast cancer metastases to the bone remains to be elucidated.
Objective/Hypothesis: Our preliminary studies indicate that both the mammary tumor cells 4T1 and bone fragments grew without immune rejection in skin-fold chambers (SFC) implanted on immuno-competent mice. Furthermore, the changes in vascularization could be monitored using intravital microscopy. Therefore, we propose to develop a SFC murine model of breast cancer bone metastases. Additionally, we propose to determine the effects of endothelin-1 on the development of breast cancer bone metastases.
Specific Aims: (1) To determine whether concurrent implantations of bone fragments and tumor cells within the SFC of immuno-competent mice result in the development of bone metastases (2) to identify early changes in vascularization associated with bone metastases and (3) to determine if endothelin-1 is critical to the development of bone metastases.
Study design: To address the issue of a relevant model mimicking the development of breast cancer bone metastases, both bone fragments and tumor cells will be implanted within the SFC, and the development of osteolytic metastases will be monitored using stably fluorescent- labeled tumor cells and intravital microscopy. Similar techniques will be used to determine the changes in vascularization. The role of endothelin-1 will be assessed using different receptor antagonists.
Cancer relevance: These studies will contribute to our understanding of the mechanism underlying the early development of breast cancer bone metastases. In the long-term, the proposed in vivo immuno-competent model will be invaluable for the testing of new drugs and other promising therapies to prevent the development of breast cancer bone metastases.
The development of bone metastases in breast cancer patients is common. Bone metastases develop following the migration of breast tumor cells through the blood vessels, the anchoring within the bone tissue, and the multiplication of the tumor cells in the absence of a response from the body defense system. Developing an animal model with a functional defense system is the only way to mimic the development of bone metastases observed in breast cancer patients. Additionally, because the bone is not easily accessible, the implantation within the skin of bone and tumor cells will allow intra-vital microscopy imaging. Such a model is crucial for a clear understanding of the early steps associated with the development of breast cancer bone metastases. Among the steps associated with metastases of breast cancer cells to the bone, the vascularization changes associated with tumor growth within the bone are critical. Indeed, preventing tumor growth by preventing the development of new vessels (therefore starving the tumor cells) may become a clinical option for patients with solid tumor including breast cancer bone metastases. Towards this aim we have started to develop an experimental mouse model system for breast cancer bone metastases. Lessons we learn from this model should aid us in understanding the steps associated with the development of breast cancer bone metastases. Already, the limitation of vessel growth has been shown to delay tumor metastases. This proposal aims to develop a model closely related to the development of breast cancer metastases to the bone and to understand the effect of endothelin-1, a key protein associated with the development of new vessels, a critical step for tumor growth. Eventually, we hope to find a way to inhibit the development of vessels associated with breast cancer bone metastases. If successful in clinical trials, such an approach will limit the mortality associated with the development of bone metastases in breast cancer patients.