Insulin-like growth factor-I regulates the liver microenvironment in obese mice and promotes liver metastasis.
Among the mechanisms implicated in the tumor-promoting effects of obesity, signaling by insulin-like growth factor-I (IGF-I) and insulin has received considerable attention. However, the emerging realization that obesity is associated with chronic inflammation has prompted other consideration of how the IGF-I axis may participate in cancer progression. In the present study, we used two mouse models of chronic (LID) and inducible (iLID) igf-1 gene deficiency in the liver to investigate the role of IGF-I in regulating the host microenvironment and colorectal carcinoma growth and metastasis in obese mice. Obese mice had a heightened inflammatory response in the liver, which was abolished in mice with chronic IGF-I deficiency (LID). In control animals changes to the hepatic microenvironment associated with obesity sustained the presence of tumor cells in the liver and increased the incidence of hepatic metastases after intrasplenic/portal inoculation of colon carcinoma cells. These changes did not occur in LID mice with chronic IGF-1 deficiency. In contrast, these changes occurred in iLID mice with acute IGF-1 deficiency, in the same manner as the control animals, revealing a fundamental difference in the nature of the requirement for IGF-1 on tumor growth and metastasis. In the setting of obesity, our findings imply that IGF-1 is critical to activate and sustain an inflammatory response in the liver that is needed for hepatic metastasis, not only through direct, paracrine effect on tumor cell growth, but also through indirect effects involving the tumor microenvironment.
Wu
Yingjie
Y
Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
Brodt
Pnina
P
Sun
Hui
H
Mejia
Wilson
W
Novosyadlyy
Ruslan
R
Nunez
Nomeli
N
Chen
Xiaoli
X
Mendoza
Arnulfo
A
Hong
Sung-Hyeok
SH
Khanna
Chand
C
Yakar
Shoshana
S
D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D015870:Gene Expression; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D007334:Insulin-Like Growth Factor I