Tryptophan Modulation in Cancer-Associated Cachexia Mouse Models

Area of Science:

• Biochemistry
• Oncology
• Immunology

Background:

• Cancer cachexia is a complex syndrome impacting patient survival and quality of life, with no effective treatments or clear pathophysiology.
• Previous research indicated altered tryptophan metabolites in cachectic patients, suggesting a role for tryptophan in the syndrome.

Purpose of the Study:

• To investigate the role of tryptophan metabolism in cancer-associated cachexia using syngeneic murine models (B16F10 melanoma and KPC pancreatic adenocarcinoma).
• To evaluate the therapeutic potential of inhibiting tryptophan degradation in cancer cachexia.

Main Methods:

• Established B16F10 and KPC murine models to induce cancer cachexia.
• Assessed physiological and molecular markers of cachexia, including body weight, spleen weight, plasma proteins (MCP1, carbonylated proteins, CRP), myostatin, and skeletal muscle atrophy genes (Atrogin1).
• Measured plasma tryptophan levels and analyzed immune cell populations (monocytes, lymphocytes, Tregs, CD8+ T cells) and their activation markers before and after treatment with 1-methyl-tryptophan (1-MT).

Main Results:

• Murine models exhibited cachexia signs: reduced body weight, increased spleen weight, elevated MCP1 and carbonylated proteins. Skeletal muscle showed decreased weight and cross-sectional area, with increased atrophy gene expression.
• Plasma tryptophan levels were significantly reduced in tumor-bearing mice and cachectic patients.
• 1-MT treatment restored plasma tryptophan, improved splenomegaly and carbonylated protein levels, and modulated immune responses by reducing CCR2 expression on monocytes and activating lymphocytes, Tregs, and CD8+ T cells, indicating reduced systemic inflammation.
• While 1-MT did not reverse muscle wasting, it preserved muscle functionality and promoted regeneration features.

Conclusions:

• Tryptophan metabolism is dysregulated in cancer cachexia and contributes to systemic inflammation.
• Inhibiting tryptophan degradation via 1-MT shows potential for modulating inflammation and improving immune status in cancer cachexia.
• The tryptophan metabolic pathway represents a promising therapeutic target for managing inflammation associated with cancer cachexia.