Divergent Anabolic Deficits and Pro-inflammatory Effectors of Muscle Wasting in Xenograft and Metastatic Tumor Models of Colorectal Cancer.

Colorectal cancer (CRC) is the second deadliest cancer in the United States, with ~70% of CRC cases developing liver metastases and cachexia. Here we investigated two tumor types (HCT116 and C26) as xenograft (x) or metastatic (m) models. Male Nod SCID gamma and CD2F1 mice were injected subcutaneously or intrasplenically with HCT116 or C26 tumor cells, respectively. CRC tumor growth was investigated at 30 days (xHCT116), 24 days (mHCT116), and 14 days (xC26 and mC26), and resulted in a significant gastrocnemius muscle depletion regardless of tumor model or type (xHCT116: 14.2%, mHCT116: 29.0%, xC26: 20.4%, mC26: 17.1%; P < 0.05). mHCT116 tumors caused a reduction in ribosomal (r)RNA content (21.2%, P < 0.05) and rDNA transcription (40%, P < 0.001), but the mC26 tumor showed no loss of rRNA and the upregulation of rDNA transcription (>2-fold, P < 0.001). All tumor-bearing mice experienced a reduction in γ4E-BP1 phosphorylation (xHCT116: 57.8%, mHCT116: 73.4%, xC26: 50.9%, mC26: 99.2%; P < 0.05) suggesting impaired translational control. Muscle IL-6 mRNA was elevated in all tumor-bearing mice except xHCT116 (mHCT116: 1.8-fold, xC26: 3.6-fold, mC26: 4.1-fold; P < 0.05). TNF-α mRNA was lower in xHCT116 (52.9%, P < 0.05) and was not induced in the other tumor-bearing mice. Expression of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) was elevated only in mC26 muscle (5-fold, P < 0.0001). Neither IL-18 nor IL-1β mRNA levels were consistent with changes in NLRP3, however IL-1β mRNA increased in both tumor models and types (xHCT116: 5.5-fold, mHCT116: 10-fold, xC26: 2.5-fold, mC26: 3.5-fold; P < 0.05) with a greater expression in each metastatic relative to the xenograft model within each type of tumor. Our findings indicate that the mHCT116 tumor results in more drastic muscle depletion and anabolic deficits, while the mC26 exhibited a divergent pro-inflammatory phenotype than the xenograft model. Our data highlight potentially important divergence in the pathogenesis of muscle wasting among the HCT116 and C26 pre-clinical models of CRC.