The Regulating Function Of IGFBP-2 In Chemically Induced Colorectal Carcinogenesis

Background:The insulin-like growth factors (IGFs) are part of a complex system that cells use to communicate with their physiologic environment. This complex system consists of two cell-surface receptors (IGF1R and IGF2R), two ligands (Insulin-like growth factor 1 (IGF-I) and Insulin-like growth factor 2 (IGF-2), a family of six high-affinity IGF-binding proteins (IGFBP-1 to IGFBP-6), as well as associated IGFBP degradingenzymes, referred to collectively as proteases.IGFBPs Due to their high affinity towards IGFs, IGFBPs act not only as carriers that prolong IGFs’half-lives, but also regulate the bioavailability of the growth factors to their cellular targets.With IGFs-mediated and IGFBPs regulation, through endocrine, autocrine, paracrine on the target organ, not only played roles of mitogenic effect, stimulate DNA synthesis, promotes cell proliferation and differentiation in tissue cell growth and development, functional behavior development, but also with tumor development. Continued growth of tumors is dependent on the cell cycle of the conversion regulation, growth factors and their receptors regulate the interaction of the signal operation. IGF family is attracting increasing attention in the occurrence, development and transformation of tumor cells.IGFBPs were proposed in the early 1960s, research on growth factors, the initial studies on the regulation of IGFBPs effect of IGF. But gradually found that some IGFBPs independent of IGF function, biological effects of IGFBPs, which include:① Limit the level of free IGFs and the biological activity of IGFs by forming complexes with IGFs;②IGFBP-1, IGFBP-2, IGFBP-4 IGFs can be adjusted in the transport vessel and outside;③IGFBP-1, IGFBP-2 can prevent IGFs induced hypoglycemia;④ IGFBP-1, IGFBP-3, IGFBP-5 could facilitate performance of IGFs active in some circumtance except limiting the free activity of IGFs function.⑤Prolong the half-life in the circulation. ⑥IGFBP-1, IGFBP-3, IGFBP-5, IGFBP-2 has independ role in regulating cell proliferation and apoptosis.IGFBP-2 plays a vital role as a key target if multiple signaling pathways in cancer occurrence, development, invasion and metastasis. Expression of IGFBP-2 by tumors has often been demonstrated, and a positive correlation between the tumor grade and level of IGFBP-2 expression has been described in colon tumors, adrenal cancer, mammary tumors, ovarian cancer, prostate cancerColorectal cancer (CRC) is the third most prevalent cancer in the world. The mortality rate accounts for 8% of all malignant tumors International Agency for Research on Cancer in 2008. In China, CRC now ranks the fourth in cancer of mortality, and in recent years, the morbidity and mortality of CRC in China presents a ring tendency. A large number of clinical trials and epidemiological studies analyzed the relationship between IGFBP-2 and colorectal cancer.Objectives:Most of the current knowledge about the IGF system is derived from in vitro experiments. To date no experimental studies have been published to investigate whether and during which stages IGFBP-2 over abundance might have an influence on colorectal carcinogenesis in vivo. Clarify the mechanism action of IGFBP-2 in the pathogenesis of colorectal cancer may rich etiology and molecular pathology theories of Colorectal cancer.Methods:In 1986, Bird firstly discovered aberrant crypt foci (ACF) in animal models. Studies have shown that prevalence and number of normal colon, adenomas and colorectal cancer patients gradually increased. ACF may be used as a surrogate marker of colorectal cancer.To address this question we have induced colorectal carcinogenesis by injection of 1,2-dimethylhydrazine (DMH) leading to the development of aberrant crypt foci (ACF) and adenomas using a transgenic mouse line in which IGFBP-2 is strongly overexpressed. Firstly, we have evaluated the effect of IGFBP-2 overexpression on the development and growth of adenomas in these animals. Secondly, we have analyzed the impact of IGFBP-2 on the appearance of early hyperplastic and dysplastic ACF. Finally, we have explored potential mechanisms which could influence adenoma growth by determination of parameters of cell proliferation and apoptosis.Results:While tumor incidence was comparable in transgenic and control mice, the volume of adenomas in IGFBP-2 transgenic mice was reduced more than 2-fold. Furthermore, serum IGFBP-2 levels negatively correlated with tumor volume in the IGFBP-2 transgenic group. Histological examination showed that IGFBP-2 transgenic mice developed significantly less dysplastic ACF with a high potential to progress to advanced stages. The reduced tumor volume in IGFBP-2 transgenic animals was due to significantly reduced proliferative capacity, evidenced by a lower proportion of cells positive for Ki67.Conclusions:We have shown for the first time in an animal model of chemical carcinogenesis that IGFBP-2 reduces the appearance of dysplastic ACF which are known to have a high potential to progress to advanced stages of colon cancer. In addition, IGFBP-2 strongly inhibited the growth of developing adenomas by triggering a pronounced reduction of the proliferation rate. As the localization and histology of the induced tumors are similar to human colon cancers, our findings are also of relevance for the biology of clinical cancers.