Submitted to: Anticancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/7/2015
Publication Date: 7/1/2015
Publication URL: http://handle.nal.usda.gov/10113/61052
Citation: Yan, L., Nielsen, F.H., Sundaram, S., Cao, J.J. 2015. High-fat diet enhances and plasminogen activator inhibitor-1 deficiency attenuates bone loss in mice with Lewis Lung carcinoma. Anticancer Research. 35(7):3839-3847.
Interpretive Summary: Cancer spread or metastasis is the most devastating aspect of cancer. It occurrence is accompanied by wasting, including bone deterioration, continuously throughout the course of malignant progression. Obesity is a risk factor for cancer, and excessive body fat produces inflammatory factors (for example, plasminogen activator inhibitor-1 (PAI-1)) that contribute to cancer. We studied the effects of a high-fat diet and PAI-1 deficiency on bone structural changes in mice with cancer metastases in the lungs. We found bone loss in mice bearing lung metastases, and consumption of a high-fat diet enhanced this bone loss. However, PAI-1 deficiency attenuated this bone loss. Our findings indicate that cancer spread is accompanied by bone loss and that obesity, through production of PAI-1, enhances this bone loss. It suggests that prevention of obesity is important to improve the quality life of cancer survivors by reducing the risk of metastasis-associated bone loss.
Technical Abstract: This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (PAI-1-/-) on bone structure in mice bearing Lewis lung carcinoma (LLC) in lungs. Reduction in bone volume fraction (BV/TV) by 22% and 21%, trabecular number (Tb.N) by 8% and 4% and bone mineral density (BMD) by 17% and 15% in right femurs and vertebrae, respectively, were found in LLC-bearing mice compared to non-tumor-bearing mice (p<0.01 for each comparison). In LLC-bearing mice, the high-fat diet compared to the AIN93G control diet further reduced BV/TV by 18% , Tb.N by 8% and BMD by 14% in femurs and reduced BV/TV by 9% in vertebrae. The high-fat diet decreased BMD by 12% in vertebrae in wild-type mice but not in PAI-1-/- mice. Compared to wild-type mice, PAI-1-/- mice exhibited a 19% increase in BV/TV and a 5% increase in Tb.N in femurs. The plasma concentration of osteocalcin was 24% lower and TRAP 5b was 80% higher in LLC-bearing mice than in non-tumor-bearing mice. The high-fat diet compared to the AIN93G diet further decreased plasma osteocalcin by 33% and increased TRAP 5b by 67%. Deficiency in PAI-1 did not affect plasma concentration of osteocalcin but completely prevented the high-fat diet-induced increase in plasma TRAP 5b in wild-type mice. These findings indicate that LLC metastasis is accompanied by bone loss. A high-fat diet enhances this bone loss, however, PAI-1 deficiency attenuates this loss. It indicates that a high-fat diet and PAI-1 contribute positively to metastasis-associated bone deterioration.