Thalidomide attenuates tumor growth and preserves fast-twitch skeletal muscle fibers in cholangiocarcinoma rats.
BACKGROUND
The prognosis for cholangiocarcinoma remains dismal due to a low resection rate and early recurrence. Cancer cachexia is associated with decreased survival and poor quality of life. Herein, we present a rat model of cholangiocarcinoma and demonstrate that thalidomide attenuates tumor growth and improves cachexia.


METHODS
A cholangiocarcinoma model was established using Sprague-Dawley rats that were fed thioacetamide for 40 weeks. Cholangiocarcinoma rats were treated using either thalidomide or saline for 8 weeks. Tumor growth and body weight were recorded for all animals. The expression of CD31, VEGF, and eIF4E of cholangiocarcinoma were determined using immunohistochemistry. Level of apoptosis and Fas-mediated apoptosis genes of cholangiocarcinoma were determined using TUNEL assay and ribonuclease protection assay, respectively. The distribution of fast-twitch soleus skeletal muscle fibers was determined as was the expression of TNFalpha and TGFbeta1 within soleus muscle.


RESULTS
After an 8-week treatment, the mean weight of saline- and thalidomide-treated rats was 24% and 19%, respectively, less than that of control (ANOVA, P < .05). The tumor volume (x +/-SD) of thalidomide-treated rats was less than saline-treated rats (1.9 +/- 0.4 vs 4.6 +/- 1.3 cm3, P < .01). The expression of CD31, eIF4E, and VEGF of cholangiocarcinoma was less than thalidomide-treated rats than for saline-treated rats, while the level of apoptosis of tumor cells was greater for thalidomide- treated rats than for saline-treated rats. The expression of mRNA for Fas, caspase-3, and Bax of cholangiocarcinoma in the thalidomide-treated rats was greater than for saline-treated rats. The number of fast-twitch skeletal muscle fibers per 500 mm2 of control, saline-, and thalidomide-treated rats was 43 +/- 6, 14 +/- 3, and 41 +/- 8 (ANOVA, P < .001). The expression of TNFalpha and TGFbeta1 of soleus muscles for thalidomide-treated rats was less than for saline-treated rats.


CONCLUSIONS
Using our rat cholangiocarcinoma model, we demonstrated that thalidomide inhibited tumor growth and was associated with a decrease in expression of reduced eIF4E and VEGF expression; in addition, thalidomide preserved fast-twitch skeletal muscle fibers and was associated with decreased expression of TNFalpha and TGFbeta1.
Liu
Keng-Hao
KH
Department of Surgery, Xiamen Chang Gung and Hospital Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan.
Liao
Li-Min
LM
Ro
Long-Sun
LS
Wu
Yu-Lien
YL
Yeh
Ta-Sen
TS
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D002100:Cachexia / Q000188:drug therapy / Q000209:etiology; D018281:Cholangiocarcinoma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D018656:Muscle Fibers, Fast-Twitch / Q000166:cytology*; D018482:Muscle, Skeletal / Q000166:cytology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013792:Thalidomide / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D013792:Thalidomide