High levels of fatty acid synthase expression in esophageal cancers represent a potential target for therapy.
Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. To investigate the expression of this candidate target in esophageal cancer, we evaluated expression of FAS protein in 22 cases of esophageal squamous cancer, 79 cases of esophageal adenocarcinoma and 16 cases of Barrett's esophagus with high-grade dysplasia--a lesion thought to represent a pre-invasive precursor to esophageal cancer. Using immunohistochemistry, we found significantly higher levels of FAS expression in 77% of the squamous cancers, 96% of the adenocarcinomas and 94% of the Barrett's lesions with high-grade dysplasia, when compared to levels in normal esophageal epithelium and non-dysplastic Barrett mucosa. To evaluate the potential for inhibiting this enzyme as a treatment of esophageal cancer, we treated mice bearing xenografts of the Colo680N esophageal squamous cell carcinoma cell line using C93, a rationally designed molecule that inhibits FAS activity. In these experiments, C93 significantly inhibited the growth of orthotopic xenograft tumors without causing anorexia and weight loss in the treated animals. We conclude that, similar to several other common types of human cancer, FAS is expressed at very high levels in esophageal cancer and growth of these cancers can be inhibited by pharmacological agents that target this enzyme. Moreover, this high expression of FAS is also seen in high-risk, pre-invasive lesions of the esophagus, leading us to propose considering FAS-inhibitors for purposes of esophageal cancer chemoprevention.
Orita
Hajime
H
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. hajimeorita@gmail.com
Coulter
Jonathan
J
Tully
Ellen
E
Abe
Masaaki
M
Montgomery
Elizabeth
E
Alvarez
Hector
H
Sato
Koichi
K
Hino
Okio
O
Kajiyama
Yoshiaki
Y
Tsurumaru
Masahiko
M
Gabrielson
Edward
E
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D004947:Esophagus / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D064429:Fatty Acid Synthases