Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice
- Hyun-Seuk Moon1,
- Xiaowen Liu1,
- Jutta M Nagel1,
- John P Chamberland1,
- Kalliope N Diakopoulos1,
- Mary T Brinkoetter1,
- Maria Hatziapostolou2,3,
- Yan Wu4,
- Simon C Robson4,
- Dimitrios Iliopoulos2,3,
- Christos S Mantzoros1,5
- 1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
- 2Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- 3Department of Microbiology & Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
- 4Department of Medicine, Gastroenterology and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
- 5Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
- Correspondence to Dr Christos S Mantzoros, Professor of Medicine, Harvard Medical School, JP9B52A, 150 S. Huntington Ave, Boston, MA 02130, USA;
Contributors HSM, XL, JMN and JPC contributed equally to this work. HSM, XL, JMN, JPC, KND, MH, YW, MTB, SCR, DI and CSM participated in the study design, performance and coordination. HSM, XL, JMN, JPC, DI and CSM wrote this manuscript. CSM planned and conceived the study. All authors read and approved the final manuscript.
- Revised 16 May 2012
- Accepted 3 June 2012
- Published Online First 26 June 2012
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.
Conclusion 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.
- colon cancer
- adiponectin-insufficient heterozygous mice
- high-fat diet
- metabolic/inflammatory/cell cycle signalling pathways
- endocrine hormones
- colon carcinogenesis
- pancreatic cancer
H-SM, XL, JMN and JPC contributed equally to this work.
Funding This study was supported by a joint California Walnut Commission and AICR grant. The Mantzoros Laboratory is supported by DK79929-02, DK058785-08 and DK081913-02 grants from the National Institute of Diabetes and Digestive and Kidney Diseases. The Robson laboratory acknowledges support from NIH via HL076540 and HL094400. The Mantzoros Laboratory is also supported by a discretionary grant from Beth Israel Deaconess Medical Center and a VA Merit award (grant 10684957).
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.