The Expression Of Insulin-like Growth Factor System In Gastrointestinal Stromal Tumors

The advent of imatinib mesylate has significantly prolonged the survival of patients with recurrent or metastatic gastrointestinal stromal tumor (GIST). Imatinib is a selective inhibitor of KIT and PDGFRA receptor tyrosine kinases. However, as the wide use of imatinib, some tumors become resistant to it. Researchers have found that imatinib response depends on KIT/PDGFRA mutational status. Patients with KIT exon 11 mutant GIST show better clinical benefit than KIT exon 9 mutant and wild-type GIST. What's more, some studies suggested that there were other mechanism in the oncogenesis of GIST except KIT and PDGFRA gene mutation, which could be studied as a new target for GIST therapy.Insulin-like growth factor system (IGF) plays an important role in the oncogenesis of many malignancies. AVE1642 is a monoclonal antibody against IGF1R. In vitro, AVE1642 was found to inhibit the proliferation of non-small cell lung cancer cells. Furthermore, pretreatment with paclitaxel for 24h followed by AVE1642 for 72h significantly enhanced the inhibition of cell proliferation, compared with sequence versus, and paclitaxel alone, AVE1642 alone for 96h respectively. NVP-AEW541 is a small molecular tyrosine kinase inhibitor of IGF1R. NVP-AE2541 could inhibit activation of PI3K in colon cancer cell. In GIST, NVP-AEW541 could also inhibit proliferation of GIST cells. Therefore, IGF system can be studied as a new theraputic target.IGF system includes two ligands IGF1 and IGF2, two receptors IGF1R and IGF2R, six IGF binding proteins IGFBP1-6. IGF2R does not transducer any signals. IGF1R plays an important role in signal transduction through activation by IGF1 or IGF2. So far, there were a few pieces of research about IGF system in GIST. But these studies all had small samples and some only experiment in vitro.Our study collected 65 GISTs, including 10 CD117-negtive cases. All pathology slides have been reviewed and classified into four groups according to risk stratification of GIST. KIT and PDGFRA gene mutations were detected with all cases. Meanwhile, expression of IGF 1, IGF2, IGF1R and IGFBP3 was performed in all GISTs. At last, we evaluated the expression of the four antibodies in GISTs with different pathologic features and gene mutation status. We found that the number of patients with KIT exon 9, exon11, PDGFRA mutation GIST and wild-type GIST were 4,36,1 and 24, respectively. The positive expression of IGF1R in wild-type GIST was significantly higher than mutant GIST (P=0.01), which implicated that IGF1R played a role in wild-type GIST and might be studied as a new theraputic target. The expression of IGF1R (P=0.031) and IGFBP3 (P<0.001) significantly increased accompanied with the elevation of GIST risk stratification. There were no significantly differences in the expression of IGF 1 and IGF2 between different risk stratifications and gene mutant-types. However, IGF1 and IGF2 were expressed in normal gastric glands besides tumors, and their expression was much stronger in normal gastric glands than in tumor. This suggested that IGF1 and IGF2 might activate IGF1R by the way of paracrine.