E-cadherin expression in human breast cancer cells suppresses the development of osteolytic bone metastases in an experimental metastasis model
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G Mbalaviele1, C R Dunstan, A Sasaki
1University of Texas Health Science Center, Department of Medicine, San Antonio 78284-7877, USA.
Abstract:
The molecular mechanisms by which human cancer cells spread to bone are largely unexplored. The process likely involves cell adhesion molecules (CAMs) that are responsible for homophilic and heterophilic cell-cell interactions. One relevant CAM may be the calcium-dependent transmembrane glycoprotein E-cadherin. To investigate the involvement of E-cadherin in breast cancer metastasis to bone, we used an in vivo model in which osteolytic bone metastases preferentially occur after injections of cancer cells directly into the arterial circulation through the left ventricle of the hearts of nude mice. We have found that E-cadherin-negative human breast cancer cells MDA-MB-231 (MDA-231) develop radiographically detectable multiple osteolytic bone metastases and cachexia in this model. However, MDA-231 breast cancer cells that were transfected with E-cadherin cDNA showed a dramatically impaired capacity to form osteolytic metastases and induce cachexia. Histological and histomorphometrical analyses of bones of mice bearing mock-transfected MDA-231 revealed aggressive metastatic tumor, whereas metastatic tumor burden was significantly decreased in the bones of mice bearing E-cadherin-expressing MDA-231. Nude mice bearing E-cadherin-transfected MDA-231 breast cancer cells survived longer than mice bearing mock-transfected MDA-231 breast cancer cells. Anchorage-dependent and -independent growth in culture and tumor enlargement in the mammary fat pad of nude mice were unchanged between mock-transfected and E-cadherin-expressing MDA-231, suggesting that these differences in metastatic behavior are not due to an impairment of cell growth and tumor-igenicity. Our results show the suppressive effects of E-cadherin expression on bone metastasis by circulating breast cancer cells and suggest that the modulation of expression of this CAM may reduce the destructive effects of breast cancer cells on bone.
Insights
E-cadherin expression suppresses breast cancer cell spread to bone. Introducing E-cadherin to cancer cells reduced bone metastasis and cachexia, improving survival in mice.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Bone metastasis is a significant challenge in breast cancer treatment.
- The molecular mechanisms driving cancer cell spread to bone are not fully understood.
- Cell adhesion molecules (CAMs) mediate cell-cell interactions crucial for metastasis.
Purpose of the Study:
- To investigate the role of E-cadherin in breast cancer metastasis to bone.
- To determine if E-cadherin expression affects the development of osteolytic bone metastases and cachexia.
Main Methods:
- Utilized an in vivo model of breast cancer bone metastasis in nude mice.
- Injected E-cadherin-negative MDA-MB-231 (MDA-231) and E-cadherin-transfected MDA-231 cells into the arterial circulation.
- Assessed metastasis, cachexia, tumor burden, and survival rates.
Main Results:
- E-cadherin-negative MDA-231 cells formed multiple osteolytic bone metastases and induced cachexia.
- E-cadherin-transfected MDA-231 cells showed significantly impaired metastasis and cachexia development.
- Histological analysis confirmed reduced tumor burden in bones of mice with E-cadherin-expressing cells.
- Mice bearing E-cadherin-transfected cells survived longer than those with mock-transfected cells.
- E-cadherin expression did not affect cell growth or tumorigenicity in vitro or in vivo.
Conclusions:
- E-cadherin expression suppresses the bone metastatic potential of circulating breast cancer cells.
- Modulating E-cadherin expression may offer a therapeutic strategy to reduce bone metastasis and its complications.