Insulin-like growth factor-I receptor activity is essential for Kaposi's sarcoma growth and survival

Abstract

Kaposi's sarcoma (KS) is a highly vascular tumour and is the most common neoplasm associated with human immunodeficiency virus (HIV-1) infection. Growth factors, in particular vascular endothelial growth factor (VEGF), have been shown to play an important role in its development. The role of insulin-like growth factors (IGFs) in the pathophysiology of different tumours led us to evaluate the role of IGF system in KS. The IGF-I receptors (IGF-IR) were identified by immunohistochemistry in biopsies taken from patients with different AIDS/HIV-related KS stages and on KSIMM cells (an established KS-derived cell line). Insulin-like growth factor-I is a growth factor for KSIMM cells with a maximum increase of 3 H-thymidine incorporation of 130±27.6% ( P <0.05) similar to that induced by VEGF and with which it is additive (281±13%) ( P <0.05). Moreover, specific blockade of the receptor (either by α IR3 antibody or by picropodophyllin, a recently described selective IGF-IR tyrosine phosphorylation inhibitor) induced KSIMM apoptosis, suggesting that IGF-IR agonists (IGF-I and -II) mediate antiapoptotic signals for these cells. We were able to identify an autocrine loop essential for KSIMM cell survival in which IGF-II is the IGF-IR agonist secreted by the cells. In conclusion, IGF-I pathway inhibition is a promising therapeutical approach for KS tumours.

The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

“…In contrast, similar treatments targeting the IGF-IR had no effect. The latter finding is different from a recent report that demonstrated that autocrine stimulation of the IGF-IR by IGF-II was essential for growth and survival of the KS-derived cell line KSIMM (Catrina et al, 2005). Although originally derived from KS tumors, KSIMM are negative for KSHV (Flamand et al, 1996).…”

“…IGF-IR was detected by immunohistochemistry in tumor spindle cells (Catrina et al, 2005). Overexpression of the IR in KS tissue compared to normal skin was reported by Wang et al (2004) in a comprehensive microarray study, and we have independently shown that IR gene expression is induced in KSHV-infected primary DMVEC, AIDS-KS tissue and TIME cells.…”

“…A recent report showed that autocrine stimulation of the insulin-like growth factor I receptor (IGF-IR) by IGF-II is required for continued growth and protection against apoptosis of KS-derived KSIMM cells (Catrina et al, 2005). IGFs are part of a complex system of growth factors, growth factor receptors, and IGF-binding proteins and deregulation of IGF action has been implicated in tumorigenesis in many cancers (LeRoith and Roberts, 2003).…”

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

“…Moreover, PPP reduced phosphorylation of Akt, induced caspase 3 activation and apoptosis and caused tumor regression in grafted mice Vasilcanu et al, 2004;Catrina et al, 2005;Ulfarsson et al, 2005;Conti et al, 2007;Menu et al, 2006;Stromberg et al, 2006;Tomizawa and Saisho, 2006;Vasilcanu et al, 2006;Colon et al, 2007;Razuvaev et al, 2007). PPP did, however, not affect growth of established R-vsrc (IGF-1RÀ/À) tumor grafts , suggesting selectivity for IGF-1R regarding tumor growth.…”

The insulin-like growth factor-1 receptor inhibitor PPP produces only very limited resistance in tumor cells exposed to long-term selection

“…We recently demonstrated that the cyclolignan PPP specifically inhibits the IGF-1R activity , where it did not inhibit the highly homologous insulin receptor . In IGF-1R-positive tumor cells, PPP induced apoptosis and reduced cell survival with IC 50 values in the range of 0.05-0.5 mM Vasilcanu et al, 2004;Catrina et al, 2005;Menu et al, 2005;Stromberg et al, 2005;Ulfarsson et al, 2005). Furthermore, PPP caused complete regression of solid tumors in xenografted mice as well it strongly decreased the tumor burden and significantly prolonged survival of mice in multiple myeloma 5T33MM mouse model (Menu et al, 2005).…”