Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling.
Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ "cancer stem cells," such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000-50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-beta-receptor type II (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. elf(+/-) mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-beta signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in elf(+/-) mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGF-beta signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting IL-6 in HCCs lacking a functional TGF-beta pathway.
Tang
Yi
Y
Cancer Genetics, Digestive Diseases and Developmental Molecular Biology, Institute of Transplant Surgery, Department of Surgery, Lombardi Comprehensive Cancer Center, Georgetown University, Medical/Dental Building, Washington, DC 20007, USA.
Kitisin
Krit
K
Jogunoori
Wilma
W
Li
Cuiling
C
Deng
Chu-Xia
CX
Mueller
Susette C
SC
Ressom
Habtom W
HW
Rashid
Asif
A
He
Aiwu Ruth
AR
Mendelson
Jonathan S
JS
Jessup
John M
JM
Shetty
Kirti
K
Zasloff
Michael
M
Mishra
Bibhuti
B
Reddy
E P
EP
Johnson
Lynt
L
Mishra
Lopa
L
D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002469:Cell Separation; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053491:Proteinase Inhibitory Proteins, Secretory; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D006023:Glycoproteins; D015850:Interleukin-6; C112970:Itih4 protein, mouse; D053491:Proteinase Inhibitory Proteins, Secretory; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta