Tumor-protective effects of IGFBP-2: reduced tumor incidence in IGFBP-2 transgenic mice

Elevated expression of IGFBP-2 is often found under malignant conditions in vivo. However, to date it is unknown if high levels of IGFBP-2 exert positive or negative effects during development or progression of tumors. In vitro, conditional effects of IGFBP-2 have been demonstrated: in non-malignant cells an inhibitory effect on cell proliferation was found while in tumor cell lines IGFBP-2 clearly was found further to increase different malignant features of the cell. We therefore have used our IGFBP-2 transgenic mouse model in to two different approaches: fist we have analyzed spontaneous tumor development in senescent IGFBP-2 transgenic mice and controls. We were surprised to find dramatically reduced tumor incidence in IGFBP-2 transgenic mice. While in non transgenic mice tumor incidence amounted to about 31% (6/19), in IGFBP-2 transgenic mice tumor incidence was reduced by almost 50% (17%, 4/24). Most severely, the amount of liver tumors was reduced in IGFBP-2 transgenic mice: 4/19 senescent control mice but merely 1/24 senescent IGBP-2 transgenic mouse had one or more tumors in the liver. In order to test if IGFBP-2 might enhance tumor development or progression under malignant conditions in vivo we have then started a carcinogenesis study in the colon by using the colon-specific carcinogen 1,2-dimethyl-hydrazine (DMH). While a consistent effect of IGFBP-2 on the amount of aberrant crypt foci (ACF) can not be found at different timepoints, preliminary results indicate inhibitory effects of IGFBP-2 on the transition of ACF to microadenoma in the colon: both in male and female mice the amount of microadenoma was reduced by more than 50%. We thus clearly found protective effects of IGFBP-2 under normal conditions in vivo but also during a distinct stage of early colon carcinogenesis.