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The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
Published on: November 30, 2016
Characterization of the male ApcMin/+ mouse as a hypogonadism model related to cancer cachexia
James P White1, Melissa J Puppa, Aditi Narsale
1Integrative Muscle Biology Laboratory, Department of Exercise Science, Public Health Research Center, University of South Carolina, Columbia, SC 29208, USA.
Abstract:
Cancer cachexia, the unintentional loss of lean body mass, is associated with decreased quality of life and poor patient survival. Hypogonadism, involving a reduction in circulating testosterone, is associated with the cachectic condition. At this time there is a very limited understanding of the role of hypogonadism in cancer cachexia progression. This gap in our knowledge is related to a lack of functional hypogonadal models associated with cancer cachexia. The Apc(Min/+) mouse is an established colorectal cancer model that develops an IL-6 dependent cachexia which is physiologically related to human disease due to the gradual progression of tumor development and cachexia. The purpose of this study was to assess the utility of the Apc(Min/+) mouse for the examination of hypogonadism during cancer cachexia and to investigate if IL-6 has a role in this process. We report that Apc(Min/+) mice that are weight stable have comparable testosterone levels and gonad size compared to wild type mice. Cachectic Apc(Min/+) mice exhibit a reduction in circulating testosterone and gonad size, which has a significant association with the degree of muscle mass and functional strength loss. Circulating testosterone levels were also significantly associated with the suppression of myofibrillar protein synthesis. Skeletal muscle and testes androgen receptor expression were decreased with severe cachexia. Although testes STAT3 phosphorylation increased with severe cachexia, systemic IL-6 over-expression for 2 weeks was not sufficient to reduce either testes weight or circulating testosterone. Inhibition of systemic IL-6 signaling by an IL-6 receptor antibody to Apc(Min/+) mice that had already initiated weight loss was sufficient to attenuate a reduction in testes size and circulating testosterone. In summary, the Apc(Min/+) mouse becomes hypogonadal with the progression of cachexia severity and elevated circulating IL-6 levels may have a role in the development of hypogonadism during cancer cachexia.
Insights
Cancer cachexia causes unintentional weight loss. This study shows that hypogonadism (low testosterone) develops as cachexia worsens in Apc(Min/+) mice, and Interleukin-6 (IL-6) may play a role.
Area of Science:
- Oncology
- Endocrinology
- Physiology
Background:
- Cancer cachexia, characterized by lean body mass loss, significantly impacts patient quality of life and survival.
- Hypogonadism, a state of reduced testosterone, is frequently observed in cachectic patients, but its precise role in cancer cachexia progression remains poorly understood.
- A lack of suitable animal models hinders the investigation of hypogonadism within the context of cancer cachexia.
Purpose of the Study:
- To evaluate the Apc(Min/+) mouse model for studying hypogonadism during cancer cachexia.
- To investigate the potential role of Interleukin-6 (IL-6) in the development of hypogonadism associated with cancer cachexia.
Main Methods:
- Utilized the Apc(Min/+) mouse model, which develops IL-6-dependent cachexia mirroring human disease progression.
- Assessed testosterone levels, gonad size, muscle mass, and functional strength in Apc(Min/+) mice at different stages of cachexia.
- Investigated the effects of IL-6 overexpression and IL-6 receptor inhibition on hypogonadism markers in cachectic Apc(Min/+) mice.
Main Results:
- Cachectic Apc(Min/+) mice exhibited reduced circulating testosterone and gonad size, correlating with muscle mass and strength loss.
- Decreased androgen receptor expression in skeletal muscle and testes was observed in severe cachexia.
- While IL-6 overexpression did not induce hypogonadism, IL-6 receptor inhibition in already weight-losing mice attenuated the reduction in testes size and testosterone levels.
Conclusions:
- The Apc(Min/+) mouse model effectively recapitulates hypogonadism development alongside progressive cancer cachexia.
- Elevated circulating IL-6 levels appear to contribute to the development of hypogonadism during cancer cachexia progression.
- These findings highlight a potential therapeutic target for managing hypogonadism in cancer cachexia.
