Involvement of insulin‐like growth factor‐insulin receptor signal pathway in the transgenic mouse model of medulloblastoma

Abstract

M edulloblastoma is an invasive embryonic tumor of the cerebellum with predominant neuronal differentiation. It is the most common malignant brain tumor of childhood, which mainly occurs between 5 and 10 years of age.(1) Despite recent advances in understanding the pathogenesis of medulloblastoma, the specific genetic alterations and molecular mechanisms involved in the brain tumor are not well defined.(2) It is generally accepted that medulloblastoma, like other cancers, represents a genetic disease of somatic cell alterations, such as gene mutations, deletions, translocations, or amplifications. The etiology and risk factors that contribute to the genetic aberrations for the tumors remain to be elucidated. It has been reported that aberrant activations of several cell signal pathways, such as Shh (3,4) Wnt (5,6) ErbB2 (7,8) and insulin-like growth factor 1-R (IGF1-R) pathways (9,10) were implicated in the pathological processes of brain tumors.Simian virus 40 (SV40) has been detected in medulloblastoma. (11,12) Several lines of evidence indicated that the viral early protein T antigen could be involved in the tumorigenesis process. SV40 T antigen (SV40Tag) is a multifunctional regulatory protein that binds to the tumor suppressor genes, including p53 (13) and the retinoblastoma (Rb) family of proteins.Furthermore, the antigen could interact with insulin receptor substrate I (IRS-1), which plays a critical role in transforming R-cells. (15,16) It is known that the interactions between SV40 Tantigen (SV40Tag) and tumor suppressor proteins stimulate DNA duplication, facilitate cell proliferation and induce cell transformation. (17,18) However, the molecular mechanism of the SV40 induction of tumors is not completely clear.Transgenic technology has provided a way to determine whether a particular gene product could contribute to the neoplastic process.Furthermore, the transgenic animal models could be used for studies on tumor development, progression and therapeutic targets identification and evaluation. Recently, a number of SV40Tag transgenic animal models have been reported, in which the transgene was constitutively expressed. (19)(20)(21)(22)(23)(24) These animal models were used for the studies of neoplastic development, as well as the equilibrium between proliferation and cell death. (25)(26)(27) However, the constitutive expression of SV40Tag may affect the development of the animal and therefore, hamper the analysis of critical steps of tumorigenesis. In an attempt to circumvent these limitations, we generated inducible transgenic mice expressing SV40Tag under the control of tetracycline. In this report, we have described the generation and molecular characterization of the tetracyclineresponsive SV40Tag transgenic mouse model for medulloblastoma. Materials and MethodsGeneration of the inducible SV40Tag transgenic mice. A 2.5-kb fragment containing the SV40Tag gene from pBC-SV40Tag (28) was generated with Xho I digestion and cloned into the Sal I site of pTRE-2 DNA vector (pTRE-SV40Tag). Linearized pTRE-S...

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

“…The cerebellum is also believed to be highly sensitive to IR‐mediated processes at various stages of its development that may underlie the association between a very frequent and highly malignant oncological condition in children, that is, medulloblastoma, constituting about 25% of all pediatric intracranial neoplasms, and abnormal functions of insulin receptor substrate‐1 (IRS‐1), a major signaling molecule of IR‐related cascades …”

A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report

“…Deregulated insulin-like growth-factor signaling through the type 1 receptor is common to many childhood solid tumors(1) including Ewing sarcoma,(2) rhabdomyosarcoma,(3) osteosarcoma,(4, 5) neuroblastoma,(6–8) brain tumors,(9–13) Wilms tumor(14) and hepatoblastoma. (15) Similarly, the cell signaling pathways that activate the mammalian target of rapamycin (mTOR) are altered in many pediatric cancers, making them susceptible to mTOR inhibition by sirolimus and its analogs.…”

Η Συμβολή Των Ρυθμιστών Του Κυτταρικού Κύκλου, Της Απόπτωσης Και Των Διαβιβαστών Μηνύματος Στην Εκτίμηση Της Έκβασης Παιδιατρικών Εμβρυονικών Νεοπλασμάτων Του Κεντρικού Νευρικού Συστήματος

“…ε πεηξακαηφδσα, φπσο ράκζηεξ θαη αξνπξαίνπο, έρνπλ πξνθιεζεί παξεγθεθαιηδηθά λενπιάζκαηα κε θαηλφηππν φκνην κε ην αλζξψπηλν κπεινβιάζησκα, κεηά απφ ελδνεγθεθαιηθή έγρπζε ηψλ 147,148. Δπίζεο αξθεηέο αλνζντζηνρεκηθέο κειέηεο έρνπλ απνδείμεη πςειή ζπρλφηεηα αλίρλεπζεο ηνπ ηνχ JC θαη ηνπ SV40, πνπ φκσο δελ έρνπλ ηεθκεξησζεί πιήξσο [149][150][151]. Απμεκέλνο θίλδπλνο εκθάληζεο ηνπ λενπιάζκαηνο έρεη αλαθεξζεί, επίζεο, ζε πξφσξα παηδηά 152.…”