MOLECULAR PATHOLOGY OF HEMANGIOPERICYTOMAS ACCOMPANIED BY SEVERE HYPOGLYCEMIA - ONCOGENES, TUMOR-SUPPRESSOR GENES AND THE INSULIN-LIKE-GROWTH-FACTOR FAMILY

Relatively little is known about molecular genetic events that partici pate in the genesis and progression of hemangiopericytoma. In this stu dy, we describe two cases of hemangiopericytoma accompanied by severe hypoglycemia. Tumor cells from patient I exhibited insulin-growth fact or I (IGF I) and insulin-like growth factor I receptor (IGF IR) mRNA t ranscripts. Tumor cells from patient 2 exhibited IGF II, IGF IR and IG F binding proteins 1-3 mRNA. Serum from patient 2 contained IGF II, mo stly in a large molecular form (''big'' IGF II); the IGF II level did not change after the tumor removal. The presence of ICF IR in tumor ce lls was confirmed by immunoprecipitation with antibodies that recogniz e human IGF IR subunit (visualized as a 460-kDa band). The hemangioper icytoma cells derived from patient 1 expressed 210 000 IGF I receptors /cell. Specific binding of IGF I to the tumor cell membrane fraction w as higher in tissue from patient I, while the tissue of patient 2 show ed relatively low IGF I binding. In contrast, IGF II binding was much higher in tissue from patient 2. Both tumor tissues showed positive im munostaining for c-Jun; one tumor showed strong immunostaining for c-M yc, H-Ras and p53, while the other exhibited strong reaction with H-Ra s antibodies only. No loss of the heterozygosity at the genes APC, NFI and nm23-H1 loci in tumor tissue obtained from patient I was found. I n effect, our results suggest multiple molecular genetic changes in he mangiopericytoma - activation of some oncogenes and the IGF growth fac tor family. IGF ligands together with IGF IR could be responsible for hypoglycemia and perhaps the transformed phenotype.