Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma

Abstract

The online version of this article has a Supplementary Appendix. BackgroundType I insulin-like growth factor receptor (IGF-IR) tyrosine kinase induces significant oncogenic effects. Strategies to block IGF-IR signaling are being tested in clinical trials that include patients with aggressive solid malignancies. Mantle cell lymphoma is a B-cell neoplasm with poor prognosis and a tendency to develop resistance. The expression and potential significance of IGF-IR in mantle cell lymphoma are not known. Design and MethodsWe used reverse transcriptase polymerase chain reaction, quantitative real-time polymerase chain reaction, immunoprecipitation, western blotting, flow cytometry, and immunohistochemistry to analyze the expression of IGF-IR mRNA, and IGF-IR and pIGF-IR proteins in mantle cell lymphoma cell lines and patients' specimens. Selective and specific blockade of IGF-IR was achieved using picropodophyllin and short-interfering RNA, respectively. Cell viability, apoptosis, cell cycle, cellular morphology, cell proliferation, and target proteins were then analyzed. ResultsWe detected the expression of IGF-IR and pIGF-IR in mantle cell lymphoma cell lines. Notably, IGF-IR molecules/cell were markedly increased in mantle cell lymphoma cell lines compared with human B-lymphocytes. IGF-IR and pIGF-IR were also detected in 78% and 74%, respectively, of 23 primary mantle cell lymphoma specimens. Treatment of serum-deprived mantle cell lymphoma cell lines with IGF-I salvaged these cells from apoptosis. Selective inhibition of IGF-IR by picropodophyllin decreased the viability and proliferation of mantle cell lymphoma cell lines, and induced apoptosis and cell cycle arrest. Selective inhibition of IGF-IR was associated with caspase-3, caspase-8, caspase-9, and PARP cleavage, cytochrome c release, up-regulation of cyclin B1, and down-regulation of cyclin D1, pCdc2, pIRS-1, pAkt, and pJnk. Similar results were obtained by using IGF-IR short-interfering RNA. In addition, picropodophyllin decreased the viability and proliferation of primary mantle cell lymphoma cells that expressed IGF-IR. ConclusionsIGF-IR is up-regulated and frequently activated in mantle cell lymphoma. Our data suggest that IGF-IR could be a molecular target for the treatment of mantle cell lymphoma. Haematologica 2011;96(6):871-880. doi:10.3324/haematol.2010 Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma

Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression

“…It became evident that the majority of mantle cell lymphoma cell lines and primary tumors show increased IGF2BP3 mRNA expression, in line with IGF2BP3 belonging to the 'mantle cell lymphoma gene expression signature' as reported in a global gene expression profiling study. 6 To a lesser extent and more pronounced in some mantle cell lymphoma cell lines, we found that the IGF 1 and 2 receptors are also expressed on the mRNA level, in concordance with a recent study by Vishwamitra et al 26 These authors demonstrated elegantly that inhibiting the IGF1 receptor by picropodophyllin or short interfering RNA led to decreased viability and proliferation of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells by inducing apoptosis and cell cycle arrest. 26 The rate of tumor cell proliferation has been established as a key biological feature of clinical aggressiveness in mantle cell lymphoma, and several genetic events occurring during the progression of the disease appear to enhance proliferation leading to decreased survival times.…”

“…6 To a lesser extent and more pronounced in some mantle cell lymphoma cell lines, we found that the IGF 1 and 2 receptors are also expressed on the mRNA level, in concordance with a recent study by Vishwamitra et al 26 These authors demonstrated elegantly that inhibiting the IGF1 receptor by picropodophyllin or short interfering RNA led to decreased viability and proliferation of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells by inducing apoptosis and cell cycle arrest. 26 The rate of tumor cell proliferation has been established as a key biological feature of clinical aggressiveness in mantle cell lymphoma, and several genetic events occurring during the progression of the disease appear to enhance proliferation leading to decreased survival times. 1 Despite the strong statistical association in our cohort between IGF2BP3 protein expression and an increased Ki-67 index of the tumor cells, the major prognostic marker for survival in previous studies, 22,23 IGF2BP3 expression itself did not correlate with clinical outcome in our analysis reinforcing the idea that the quantitative measurement of tumor cell proliferation in mantle cell lymphoma serves as an integrator of various unfavorable molecular events.…”

“…Therefore, therapeutic intervention with this pathway, eg, by inhibiting the IGF1 receptor, may represent a viable future treatment option in mantle cell lymphoma. 26 In this context, it is worthwhile to note that IGF2BP3 protein expression and, hypothetically, the level of IGF signaling appear to be relatively constant in mantle cell lymphoma cells over time, as IGF2BP3 expression was not markedly different in paired mantle cell lymphoma specimens investigated at primary diagnosis and at the time of relapse.…”

Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells

“…In contrast, the cyclolignan PPP, launched as a selective IGF-1R inhibitor [14], has been well tolerated in a phase I/II clinical study and possibly contributed to disease stabilization in four squamous non-small cell lung cancer patients [22]. Although PPP has been suggested as a potential therapy for the B-cell neoplasm multiple myeloma [5,6] and for different classes of lymphoma [7][8][9][10], there are no reports investigating the potential benefits of using PPP against DLBCL.…”

“…Among the lymphohematopoietic cancers, the IGF-1R has been suggested to represent a therapeutic target in multiple myeloma [4][5][6], T cell ALK? anaplastic largecell lymphoma [7], T lymphoblastic leukemia/lymphoma [8], mantle cell lymphoma [9] and classical Hodgkin lymphoma [10].…”