Molecular pathology of hemangiopericytomas accompanied by severe hypoglycemia: oncogenes, tumor-suppressor genes and the insulin-like growth factor family

Abstract

Relatively little is known about molecular genetic events that participate in the genesis and progression of hemangiopericytoma. In this study, we describe two cases of hemangiopericytoma accompanied by severe hypoglycemia. Tumor cells from patient 1 exhibited insulin-growth factor I (IGF I) and insulin-like growth factor I receptor (IGF IR) mRNA transcripts. Tumor cells from patient 2 exhibited IGF II, IGF IR and IGF binding proteins 1-3 mRNA. Serum from patient 2 contained IGF II, mostly in a large molecular form ("big" IGF II); the IGF II level did not change after the tumor removal. The presence of IGF IR in tumor cells was confirmed by immunoprecipitation with antibodies that recognize human IGF IR subunit (visualized as a 460-kDa band). The hemangiopericytoma cells derived from patient 1 expressed 210000 IGF I receptors/cell. Specific binding of IGF I to the tumor cell membrane fraction was higher in tissue from patient 1, while the tissue of patient 2 showed relatively low IGF I binding. In contrast, IGF II binding was much higher in tissue from patient 2. Both tumor tissues showed positive immunostaining for c-Jun; one tumor showed strong immunostaining for c-Myc, H-Ras and p53, while the other exhibited strong reaction with H-Ras antibodies only. No loss of the heterozygosity at the genes APC, NFI and nm23-H1 loci in tumor tissue obtained from patient 1 was found. In effect, our results suggest multiple molecular genetic changes in hemangiopericytoma -- activation of some oncogenes and the IGF growth factor family. IGF ligands together with IGF IR could be responsible for hypoglycemia and perhaps the transformed phenotype.

Hypoglycemia Associated with the Production of Insulin-like Growth Factor II in Adrenocortical Carcinoma.

“…At first, the elevation of non-suppressible insulin-like activity (NSILA) in acid-ethanol was detected in the cases of NICTH (15), and then increased levels of IGF-II were proven in the serum (16)(17)(18)(19)(20)(21)(22) and the tumor extracts (23)(24)(25). Moreover, immunohistochemical staining method using IGF-II antiserum allowed the detection of IGF-II localization in the tumor (23)(24)(25). In the present case, the serum level of IGF-II before the operation waselevated and the tumor tissue stained positively for IGF-II immunohistochemically.…”

Insulin-like growth factor II-producing intra-abdominal hemangiopericytoma associated with hypoglycemia

“…IGF-I was within the normal range in 2 patients, 26,29 but was low in the other 10, while the IGF-II level was elevated in 2 patients, 26,32 and within the normal range in the other 10. The molecular weight of the IGF-II was determined in only 8 of these patients, 22,23,[25][26][27]32,33 but increased "big" IGF-II was reported in all of them. The tissue concentration of IGF-II in our patient was much higher than that of IGF-I, and Hoekman et al 23 also reported a low IGF-I level and a very high IGF-II level in tissue.…”

“…Serum IGF-I and IGF-II levels were measured in 12 15,[21][22][23][24][25][26][27]29,32,33 of the 33 reported patients 3-33 with hemangiopericytoma associated with hypoglycemia, including our patient. IGF-I was within the normal range in 2 patients, 26,29 but was low in the other 10, while the IGF-II level was elevated in 2 patients, 26,32 and within the normal range in the other 10.…”

A case of haemangiopericytoma-associated hypoglycaemia: beneficial effect of treatment with radiotherapy

“…The association of hypoglycaemia with non‐islet cell tumours was first reported in 1930 (1). Since then, many tumour types have been shown to be associated with hypoglycaemia (2–5). These tumours are often large, slow growing, well differentiated, and they can be benign or malignant (3,6).…”