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Updated: Oct 30, 2025
The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
Published on: November 30, 2016
Skeletal muscle-specific over-expression of the nuclear sirtuin SIRT6 blocks cancer-associated cachexia by regulating
Sadhana A Samant1, Vinodkumar B Pillai1, Mahesh P Gupta1,2
1Department of Surgery University of Chicago 5841 South Maryland Avenue Chicago IL 60637 USA.
Background:
During cancer cachexia, cytokines released from tumour cells can alter body's metabolism, which can lead to onset of this disease process. Biological basis of cachexia is multifactorial; hence, it is important to identify and modulate multiple targets to curtail the process of cachexia. Previously, we reported that the nuclear sirtuin, SIRT6, blocks expression of myostatin, a negative regulator of muscle growth, through modulation of the NF-κB signalling. This study was undertaken to test whether muscle-specific over-expression of SIRT6 can block the cancer-associated muscle wasting in vivo and to identify additional relevant targets of SIRT6, which can explain its ability to maintain muscle health.
Methods:
We generated a skeletal muscle-specific SIRT6 over-expressing transgenic mouse line (Sk.T6Tg) expressing SIRT6 at a moderate (two-fold to four-fold) level, compared with its control littermates. To generate a cancer-cachexia model, B16F10 mouse melanoma cells were injected subcutaneously in the flanks of mice. Gastrocnemius muscle tissues from non-tumour and tumour controls and Sk.T6Tg mice (n = 5-20) were analysed by histology, immunoblotting, and RT-qPCR. Plasma samples of mice were evaluated using cytokine arrays and ELISA in both non-tumour and tumour conditions.
Results:
Our results demonstrate dual benefits of muscle-specific moderate over-expression of SIRT6 in a mouse model of cancer-cachexia. In tumour-bearing mice, SIRT6 over-expression preserved muscle weight (P < 0.001) and fibre size (P < 0.005) as well as suppressed tumour growth (P < 0.05). SIRT6 over-expression significantly reduced myostatin expression and plasma free fatty acids levels but maintained plasma insulin levels in tumour-bearing mice. These positive effects of SIRT6 were associated with downregulation of the circulatory chemokine, CXCL10, and the myokine, WNT4. SIRT6 also upregulated expression of GLUT4, the major glucose transporter in the skeletal muscle. These results for the first time demonstrate that SIRT6 regulates multiple targets to limit tumour growth and cancer-associated muscle atrophy.
Conclusion:
Given the multifactorial nature of cachexia, SIRT6, which concurrently controls multiple pathways, can be a valuable therapeutic target to overcome this debilitating syndrome.
Insights
SIRT6 over-expression in muscle combats cancer cachexia by preserving muscle mass and reducing tumor growth. This nuclear sirtuin (SIRT6) modulates multiple targets, offering a promising therapeutic strategy for this debilitating syndrome.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cancer cachexia involves complex metabolic alterations driven by tumor-released cytokines.
- Identifying and targeting multiple pathways is crucial for effective cachexia intervention.
- Nuclear sirtuin 6 (SIRT6) previously shown to inhibit myostatin expression via NF-κB signaling.
Purpose of the Study:
- To investigate the efficacy of muscle-specific SIRT6 overexpression in preventing cancer-associated muscle wasting in vivo.
- To identify additional molecular targets regulated by SIRT6 that contribute to maintaining muscle health during cancer cachexia.
Main Methods:
- Generation of a skeletal muscle-specific SIRT6 transgenic mouse line (Sk.T6Tg).
- Induction of cancer cachexia by subcutaneous injection of B16F10 melanoma cells.
- Analysis of muscle tissue (histology, immunoblotting, RT-qPCR) and plasma (cytokine arrays, ELISA) in control and transgenic mice.
Main Results:
- Muscle-specific SIRT6 overexpression preserved muscle weight and fiber size in tumor-bearing mice.
- SIRT6 overexpression suppressed tumor growth and reduced myostatin expression.
- SIRT6 modulated key targets including CXCL10, WNT4, and GLUT4, while maintaining insulin levels.
Conclusions:
- SIRT6 exhibits dual benefits by limiting tumor growth and preventing muscle atrophy in cancer cachexia.
- SIRT6's ability to concurrently regulate multiple pathways makes it a potent therapeutic target for cachexia.
- Targeting SIRT6 offers a promising strategy to combat the multifaceted nature of cancer cachexia.
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