Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice.
BACKGROUND
Obesity and a high-fat diet are associated with the risk and progression of colon cancer. Low adiponectin levels may play an important role in the development of colon and other obesity-related malignancies. No previous studies have directly investigated the mechanistic effects of adiponectin on colon cancer in the settings of obesity, a high-fat diet and/or adiponectin deficiency.


OBJECTIVE
To investigate the effects of adiponectin on the growth of colorectal cancer in adiponectin-deficient or wild-type-C57BL/6 mice fed a low-fat or high-fat diet.


RESULTS
Mice fed a high-fat-diet gained more weight and had larger tumours than mice fed a low-fat-diet. Adiponectin administration suppressed implanted tumour growth, causing larger central necrotic areas. Adiponectin treatment also suppressed angiogenesis assessed by CD31 staining and VEGFb and VEGFd mRNA expression in tumours obtained from mice fed a high-fat-diet and from adiponectin-deficient mice. Adiponectin treatment decreased serum insulin levels in mice on a high-fat-diet and increased serum-interleukin (IL)-12 levels in adiponectin-deficient mice. In vitro, it was found that adiponectin directly controls malignant potential (cell proliferation, adhesion, invasion and colony formation) and regulates metabolic (AMPK/S6), inflammatory (STAT3/VEGF) and cell cycle (p21/p27/p53/cyclins) signalling pathways in both mouse MCA38 and human HT29, HCT116 and LoVo colon cancer cell lines in a LKB1-dependent way.


CONCLUSIONS
These new mechanistic and pathophysiology studies provide evidence for an important role of adiponectin in colon cancer. The data indicate that adiponectin or analogues might be useful agents in the management or chemoprevention of colon cancer.
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02130, USA.
Hyun-Seuk
HS
Moon
Xiaowen
X
Liu
Jutta M
JM
Nagel
John P
JP
Chamberland
Kalliope N
KN
Diakopoulos
Mary T
MT
Brinkoetter
Maria
M
Hatziapostolou
Yan
Y
Wu
Simon C
SC
Robson
Dimitrios
D
Iliopoulos
Christos S
CS
Mantzoros
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology*; D016213:Cyclins / Q000378:metabolism; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D052242:Adiponectin; D015415:Biomarkers; D016213:Cyclins; D007328:Insulin; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D018664:Interleukin-12; D019893:Ribosomal Protein S6 Kinases; D055372:AMP-Activated Protein Kinases