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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Dietary Prevention of Obesity-related Disease Research » Research » Publications at this Location » Publication #335513

Research Project: Health Roles of Dietary Selenium in Obesity

Location: Dietary Prevention of Obesity-related Disease Research

Title: Monocyte chemotactic protein-1 attenuates and high-fat diet exacerbates bone loss in mice with pulmonary metastasis of Lewis lung carcinoma

item Yan, Lin
item NIELSEN, FORREST - Former ARS Employee
item Sundaram, Sneha
item Cao, Jay

Submitted to: Oncotarget
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/26/2016
Publication Date: 2/3/2017
Publication URL:
Citation: Yan, L., Nielsen, F.H., Sundaram, S., Cao, J.J. 2017. Monocyte chemotactic protein-1 attenuates and high-fat diet exacerbates bone loss in mice with pulmonary metastasis of Lewis lung carcinoma. Oncotarget. doi:10.18632/oncotarget.15055.

Interpretive Summary: Cancer spread or metastasis is the most devastating aspect of cancer. Its occurrence is accompanied with wasting continuously throughout the course of malignant progression, which eventually leads to wasting syndrome characterized by a significant weight loss and multi-organ functional failures including bone deterioration. Prevention and treatment of cancer spread and its associated wasting remain great challenges to cancer research and clinical practice. Obesity is a risk factor for cancer. Excessive body fat produces many chemicals (for example, monocyte chemotactic protein-1 (MCP-1)) that contribute to cancer progression. We investigated the effects of a high-fat diet and MCP-1 deficiency (by knocking out MCP-1 genes) on bone structural changes in mice with cancer spread to lungs. We found that cancer spread caused bone loss and that feeding mice a high-fat diet enhanced whereas MCP-1 deficiency attenuated metastasis-mediated bone loss. Our findings show that cancer spread is accompanied with bone loss and that the high-fat diet-induced obesity and its production of MCP-1 contribute to bone loss of metastasis-associated wasting. These data suggest that reductions in body fat mass and its production of cancer-promoting chemicals are useful for attenuating not only cancer spread but also the bone deterioration of metastasis-related wasting.

Technical Abstract: Bone can be adversely affected by obesity and cancer-associated complications including wasting. The objective of this study was to determine whether a high-fat diet and a deficiency in monocyte chemotactic protein-1 (MCP-1) altered bone structural defects found in male C57BL/6 mice with Lewis lung carcinoma (LLC) metastases in lungs. Compared to non-tumor-bearing mice, LLC reduced bone volume fraction (BV/TV), connectivity density (Conn.D), trabecular number (Tb.N), trabecular thickness (Tb.Th) and bone mineral density (BMD) and increased trabecular separation (Tb.Sp) in femurs; similar changes occurred in vertebrae. The high-fat diet compared to the AIN93G diet exacerbated LLC-induced detrimental structural changes; the exacerbation was greater in femurs than in vertebrae. Mice deficient in MCP-1 exhibited decreased LLC-induced bone structural changes. The deficiency improved BV/TV, Conn.D, Tb.N and Tb.Sp in both femurs and vertebrae, and Tb.Th, BMD and structure model index in vertebrae. Lewis lung carcinoma significantly decreased the concentration of osteocalcin but increased the concentration of tartrate-resistant acid phosphatase 5b (TRAP 5b) in plasma. In LLC-bearing mice, the high-fat diet exacerbated plasma TRAP 5b and deficiency in MCP-1 decreased TRAP 5b; neither the high-fat diet nor MCP-1 deficiency affected plasma concentration of osteocalcin. We conclude that pulmonary metastasis of LLC is accompanied by detrimental bone structural changes and that the high-fat diet exacerbates and MCP-1 deficiency attenuates the metastasis-associated bone wasting.