Elevated serum levels of IGF-binding protein 2 in patients with non-seminomatous germ cell cancer: correlation with tumor markers α-fetoprotein and human chorionic gonadotropin

Abstract

Background/aims: Alterations of the IGF system have been described in several different types of cancer. However, no information is available about the role of the IGF system in patients with nonseminomatous germ cell cancer. Methods: Free IGF-I, IGF-II, acid-labile subunit, and IGF-binding proteins (IGFBPs) 1-4 were analyzed by specific RIAs in 32 patients with untreated non-seminomas and compared with IGFBP levels of 38 healthy controls. Serum IGFBPs were analyzed by western ligand blotting (WLB) and immunoblotting. In 16 patients, IGFBP profiles were measured before, during, and after treatment. Results: In patients with testicular cancer, IGF-II levels were on average 1.44-fold higher than in the healthy control group (1027G48 ng/ml versus 711G30 ng/ml, P!0.0001). IGFBP-2 levels were on average 2.6-fold higher (586G58 ng/ml versus 226G17 ng/ml, P!0.001). During follow-up, a decrease in IGFBP-2 levels was observed in all successfully treated patients, which correlated closely with a decrease in the tumor markers a-fetoprotein and human chorionic gonadotropin. Additionally, in all patients with recurrent disease, a significant further increase in IGFBP-2 levels (from 358G97 to 976G 260 ng/ml) was detected. IGFBP-3 levels, as measured by RIA, were not different in patients with testicular cancer compared with controls. However, WLB analysis demonstrated markedly decreased intact IGFBP-3 bands in untreated patients and a significant increase after successful therapy. Conclusion: Our results demonstrate that markedly elevated IGF-II and IGFBP-2 serum levels in patients with non-seminomatous germ cell cancer, showing a significant decrease after successful therapy and an increase in recurrent disease. Additionally, indirect evidence points to an increased proteolytic activity for IGFBP-3 in untreated testicular cancer patients.

IGF1R signalling in testicular germ cell tumour cells impacts on cell survival and acquired cisplatin resistance

“…Here, we have identified active IGF1R signalling and have demonstrated that this plays a key role in maintaining nonseminoma cell viability and can also contribute to cisplatin resistance. Our finding of phosphorylated IGF1R in nonseminoma cells and high IGF1R expression levels in patient samples fits with previous observations noting high serum levels of IGF-2 and IGFBP2 in nonseminoma patients that reduced after treatment [42]. Similarly, the proportion of cleaved IGFBP3 (which promotes proliferation in breast cancer [43]) is greater in nonseminoma patients and declines upon response to treatment.…”

Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma

“…55,56 The inverse relationship between IGFBP-2 and IGFBP-3 expression at tissue and serum levels in a variety of cancers, including prostate, 31,55,57 ovarian, 58 and testicular cancer, has been well recognized. 59 We also found a relatively inverse relationship between secreted levels of IGFBP-2 and IGFBP-3 in lung adenocarcinoma cell lines (unpublished data). Remarkably, IGFBP-2 is predominantly expressed in cytoplasm and nucleus of lung epithelium when exposed to hyperoxia, whereas IGFBP-3 is localized in the extracellular compartment.…”

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

“…TGCTs frequently retain this loss of imprinting, expressing IGF2 biallelically (Van Gurp et al ., ), which has been linked to increased tumour aggressiveness in other cancer types (Damaschke et al ., ). Increased serum levels of IGF2 and IGFBP2 have been found in non‐seminomatous TGCT, decreasing upon successful therapy and increasing again in cases of recurrence (Fottner et al ., ). Our group has recently shown that IGF1R is expressed in approximately half of non‐seminomas and influences survival of non‐seminoma cells in vitro (Selfe et al ., ).…”