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Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2023

Open Access 01-12-2023 | Medulloblastoma | Research

IGFBP2 promotes proliferation and cell migration through STAT3 signaling in Sonic hedgehog medulloblastoma

Authors: Haritha Kunhiraman, Leon McSwain, Shubin W. Shahab, Timothy R. Gershon, Tobey J. MacDonald, Anna Marie Kenney

Published in: Acta Neuropathologica Communications | Issue 1/2023

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Abstract

Medulloblastoma (MB) is the most common pediatric brain malignancy and is divided into four molecularly distinct subgroups: WNT, Sonic Hedgehog (SHHp53mut and SHHp53wt), Group 3, and Group 4. Previous reports suggest that SHH MB features a unique tumor microenvironment compared with other MB groups. To better understand how SHH MB tumor cells interact with and potentially modify their microenvironment, we performed cytokine array analysis of culture media from freshly isolated MB patient tumor cells, spontaneous SHH MB mouse tumor cells and mouse and human MB cell lines. We found that the SHH MB cells produced elevated levels of IGFBP2 compared to non-SHH MBs. We confirmed these results using ELISA, western blotting, and immunofluorescence staining. IGFBP2 is a pleiotropic member of the IGFBP super-family with secreted and intracellular functions that can modulate tumor cell proliferation, metastasis, and drug resistance, but has been understudied in medulloblastoma. We found that IGFBP2 is required for SHH MB cell proliferation, colony formation, and cell migration, through promoting STAT3 activation and upregulation of epithelial to mesenchymal transition markers; indeed, ectopic STAT3 expression fully compensated for IGFBP2 knockdown in wound healing assays. Taken together, our findings reveal novel roles for IGFBP2 in SHH medulloblastoma growth and metastasis, which is associated with very poor prognosis, and they indicate an IGFBP2-STAT3 axis that could represent a novel therapeutic target in medulloblastoma.
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Literature
1.
Ansari D, Aronsson L, Sasor A, Welinder C, Rezeli M, Marko-Varga G, Andersson R (2014) The role of quantitative mass spectrometry in the discovery of pancreatic cancer biomarkers for translational science. J Transl Med 12(1):1–15CrossRef
2.
3.
Azar W, Zivkovic S, Werther G, Russo V (2014) IGFBP-2 nuclear translocation is mediated by a functional NLS sequence and is essential for its pro-tumorigenic actions in cancer cells. Oncogene 33(5):578–588PubMedCrossRef
4.
Baron-Hay S, Boyle F, Ferrier A, Scott C (2004) Elevated serum insulin-like growth factor binding protein-2 as a prognostic marker in patients with ovarian cancer. Clin Cancer Res 10(5):1796–1806PubMedCrossRef
5.
Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Olson JM (2002) Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297(5586):1559–1561PubMedCrossRef
6.
Cavalli FM, Remke M, Rampasek L, Peacock J, Shih DJ, Luu B, Morrissy AS (2017) Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 31(6):737–754PubMedPubMedCentralCrossRef
7.
Chua CY, Liu Y, Granberg KJ, Hu L, Haapasalo H, Annala MJ, Fuller GN (2016) IGFBP2 potentiates nuclear EGFR–STAT3 signaling. Oncogene 35(6):738–747PubMedCrossRef
8.
Dahmane N, Ruiz-i-Altaba AJD (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126(14):3089–3100PubMedCrossRef
9.
Das SK, Pradhan AK, Bhoopathi P, Talukdar S, Shen X-N, Sarkar D, Fisher PB (2018) The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer InvasionMDA-9 Mediates Prostate Cancer Invasion. Cancer Res 78(11):2852–2863PubMedPubMedCentralCrossRef
10.
de Bont JM, van Doorn J, Reddingius RE, Graat GH, Passier MM, den Boer ML, Pieters R (2008) Various components of the insulin-like growth factor system in tumor tissue, cerebrospinal fluid and peripheral blood of pediatric medulloblastoma and ependymoma patients. Int J Cancer 123(3):594–600PubMedCrossRef
11.
Del Valle L, Enam S, Lassak A, Wang JY, Croul S, Khalili K, Reiss KJCCR (2002) Insulin-like growth factor I receptor activity in human medulloblastomas. Clin Cancer Res 8(6):1822–1830PubMed
12.
Dongre A, Weinberg RA (2019) New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 20(2):69–84PubMedCrossRef
13.
Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN, Zhang W (2007) Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci 104(28):11736–11741PubMedPubMedCentralCrossRef
14.
Fernandez-L A, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S (2009) YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev 23(23):2729–2741PubMedPubMedCentralCrossRef
15.
Flyvbjerg A, Mogensen O, Mogensen B, Nielsen OS (1997) Elevated serum insulin-like growth factor-binding protein 2 (IGFBP-2) and decreased IGFBP-3 in epithelial ovarian cancer: correlation with cancer antigen 125 and tumor-associated trypsin inhibitor. J Clin Endocrinol Metab 82(7):2308–2313PubMed
16.
Fukushima, T., & Kataoka, H. (2011). Insulin-Like growth factor binding protein-2: a possible regulator of invasive growth in glioblastoma. Mol Targets CNS Tumors 395
17.
Gao S, Sun Y, Zhang X, Hu L, Liu Y, Chua CY, Wang H (2016) IGFBP2 activates the NF-κB pathway to drive epithelial–mesenchymal transition and invasive character in pancreatic ductal adenocarcinoma. Cancer Res 76(22):6543–6554PubMedPubMedCentralCrossRef
18.
Garzia L, Kijima N, Morrissy AS, De Antonellis P, Guerreiro-Stucklin A, Holgado BL, Zayne K (2018) A hematogenous route for medulloblastoma leptomeningeal metastases. Cell 172(5):1050–1062PubMedPubMedCentralCrossRef
19.
Guo D, Wang Y, Cheng Y, Liao S, Hu J, Du F, Cheung M (2021) Tumor cells generate astrocyte-like cells that contribute to SHH-driven medulloblastoma relapse. J Exp Med 218(9):e20202350PubMedPubMedCentralCrossRef
20.
Hallahan AR, Pritchard JI, Hansen S, Benson M, Stoeck J, Hatton BA, Beachy PA (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64(21):7794–7800PubMedCrossRef
21.
Hatton BA, Villavicencio EH, Tsuchiya KD, Pritchard JI, Ditzler S, Pullar B, Eberhart CG (2008) The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res 68(6):1768–1776PubMedCrossRef
22.
He Y, Pei J-H, Li X-Q, Chi G (2021) IL-35 promotes EMT through STAT3 activation and induces MET by promoting M2 macrophage polarization in HCC. Biochem Biophys Res Commun 559:35–41PubMedCrossRef
23.
Holmes KM, Annala M, Chua CY, Dunlap SM, Liu Y, Hugen N, Nykter M (2012) Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-κB network. Proc Natl Acad Sci 109(9):3475–3480PubMedPubMedCentralCrossRef
24.
Hough CD, Cho KR, Zonderman AB, Schwartz DR, Morin PJ (2001) Coordinately up-regulated genes in ovarian cancer. Cancer Res 61(10):3869–3876PubMed
25.
Huang G, Yan H, Ye S, Tong C, Ying QL (2014) STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates. Stem Cells 32(5):1149–1160PubMedCrossRef
26.
Iser IC, Pereira MB, Lenz G, Wink MR (2017) The epithelial-to-mesenchymal transition-like process in glioblastoma: an updated systematic review and in silico investigation. Med Res Rev 37(2):271–313PubMedCrossRef
27.
Kanety H, Madjar Y, Dagan Y, Levi J, Papa MZ, Pariente C (1993) Serum insulin-like growth factor-binding protein-2 (IGFBP-2) is increased and IGFBP-3 is decreased in patients with prostate cancer: correlation with serum prostate-specific antigen. J Clin Endocrinol Metab 77(1):229–233PubMed
28.
Kendrick ZW, Firpo MA, Repko RC, Scaife CL, Adler DG, Boucher KM, Mulvihill S (2014) Serum IGFBP2 and MSLN as diagnostic and prognostic biomarkers for pancreatic cancer. HPB 16(7):670–676PubMedCrossRef
29.
Kenney AM, Cole MD, Rowitch DH (2003) Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors
30.
Kenney AM, Rowitch DH (2000) Sonic hedgehog promotes G1 cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 20(23):9055–9067PubMedPubMedCentralCrossRef
31.
Kramer N, Walzl A, Unger C, Rosner M, Krupitza G, Hengstschläger M, Dolznig H (2013) In vitro cell migration and invasion assays. Mutat Res/Rev Mutat Res 752(1):10–24CrossRef
32.
33.
Li T, Forbes ME, Fuller GN, Li J, Yang X, Zhang W (2020) IGFBP2: integrative hub of developmental and oncogenic signaling network. Oncogene 39(11):2243–2257PubMedPubMedCentralCrossRef
34.
Li T, Zhang C, Zhao G, Zhang X, Hao M, Hassan S, Liu L (2020) IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma. Oncogene 477:19–30
35.
Lin Y, Jiang T, Zhou K, Xu L, Chen B, Li G, Song SW (2009) Plasma IGFBP-2 levels predict clinical outcomes of patients with high-grade gliomas. Neuro Oncol 11(5):468–476PubMedPubMedCentralCrossRef
36.
Liu H, Le Li HC, Kong R, Pan S, Hu J, Wang Y, Sun B (2017) Silencing IGFBP-2 decreases pancreatic cancer metastasis and enhances chemotherapeutic sensitivity. Oncotarget 8(37):61674PubMedPubMedCentralCrossRef
37.
Liu Y, Song C, Shen F, Zhang J, Song SW (2019) IGFBP2 promotes immunosuppression associated with its mesenchymal induction and FcγRIIB phosphorylation in glioblastoma. PLoS ONE 14(9):e0222999PubMedPubMedCentralCrossRef
38.
Liu Y, Yuelling LW, Wang Y, Du F, Gordon RE, O’Brien JA, Liu H (2017) Astrocytes promote medulloblastoma progression through hedgehog secretionastrocytes support medulloblastoma growth. Cancer Res 77(23):6692–6703PubMedPubMedCentralCrossRef
39.
Malawsky DS, Weir SJ, Ocasio JK, Babcock B, Dismuke T, Cleveland AH, Gershon TR (2021) Cryptic developmental events determine medulloblastoma radiosensitivity and cellular heterogeneity without altering transcriptomic profile. Commun Biol 4(1):1–16CrossRef
40.
Maximov V, Chen Z, Wei Y, Robinson MH, Herting CJ, Shanmugam NS, Northcott PA (2019) Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma. Nat Commun 10(1):1–11CrossRef
41.
McCaffery I, Tudor Y, Deng H, Tang R, Suzuki S, Badola S, Patterson SD (2013) Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor. Clin Cancer Res 19(15):4282–4289PubMedCrossRef
42.
McDonald KL, O’Sullivan MG, Parkinson JF, Shaw JM, Payne CA, Brewer JM (2007) IQGAP1 and IGFBP2: valuable biomarkers for determining prognosis in glioma patients. J Neuropathol Exp Neurol 66(5):405–417PubMedCrossRef
43.
Narayan R, Shastry AH, Thota B, Sampath S, Thennarasu K, Arivazhagan A, Santosh V (2013) Expression patterns of insulin-like growth factor binding protein isoforms in medulloblastoma subtypes and clinical correlation. Pediatr Neurosurg 49(6):325–330PubMedCrossRef
44.
Northcott PA, Hielscher T, Dubuc A, Mack S, Shih D, Remke M, Eberhart CG (2011) Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol 122(2):231–240PubMedPubMedCentralCrossRef
45.
Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, French P (2011) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29(11):1408PubMedCrossRef
46.
Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Schumacher SE (2012) Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488(7409):49–56PubMedPubMedCentralCrossRef
47.
Ocrant I, Fay CT, Parmelee JT (1990) Characterization of insulin-like growth factor binding proteins produced in the rat central nervous system. Endocrinology 127(3):1260–1267PubMedCrossRef
48.
Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM, Wechsler-Reya R (2003) Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci 100(12):7331–7336PubMedPubMedCentralCrossRef
49.
Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Marymont MH (2006) Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24(25):4202–4208PubMedCrossRef
50.
51.
Pfeifer TL, Chegini N (1994) Immunohistochemical localization of insulin-like growth factor (IGF-I), IGF-I receptor, and IGF binding proteins 1–4 in human fallopian tube at various reproductive stages. Biol Reprod 50(2):281–289PubMedCrossRef
52.
Phillips LM, Zhou X, Cogdell DE, Chua CY, Huisinga A, Hess R, K., Zhang, W. (2016) Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies. J Pathol 239(3):355–364PubMedPubMedCentralCrossRef
53.
Ramaswamy V, Remke M, Bouffet E, Bailey S, Clifford SC, Doz F, Milde T (2016) Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol 131:821–831PubMedPubMedCentralCrossRef
54.
Ramaswamy V, Remke M, Bouffet E, Faria CC, Perreault S, Cho Y-J, Northcott PA (2013) Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol 14(12):1200–1207PubMedPubMedCentralCrossRef
55.
Russo V, Schutt B, Andaloro E, Ymer S, Hoeflich A, Ranke M, Werther G (2005) Insulin-like growth factor binding protein-2 binding to extracellular matrix plays a critical role in neuroblastoma cell proliferation, migration, and invasion. Endocrinology 146(10):4445–4455PubMedCrossRef
56.
Schutt B, Langkamp M, Rauschnabel U, Ranke M, Elmlinger M (2004) Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells. J Mol Endocrinol 32(3):859–868PubMedCrossRef
57.
Scrideli CA, Carlotti CG, Mata JF, Neder L, Machado HR, Oba-Sinjo SM, Tone LG (2007) Prognostic significance of co-overexpression of the EGFR/IGFBP-2/HIF-2A genes in astrocytomas. J Neuro-oncology 83(3):233–239CrossRef
58.
Sengupta S, Krummel DP, Pomeroy SJF (2017) The evolution of medulloblastoma therapy to personalized medicine. F1000research 6
59.
Shariat SF, Lamb DJ, Kattan MW, Nguyen C, Kim J, Beck J, Slawin KM (2002) Association of preoperative plasma levels of insulin-like growth factor I and insulin-like growth factor binding proteins-2 and-3 with prostate cancer invasion, progression, and metastasis. J Clin Oncol 20(3):833–841PubMedCrossRef
60.
Smoll NR, Drummond KJ (2012) The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children. J Clin Neurosci 19(11):1541–1544PubMedCrossRef
61.
Sun L, Zhang X, Song Q, Liu L, Forbes E, Tian W, Fleming JB (2021) IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma through the STAT3 pathway. Cancer lett 500:132–146PubMedCrossRef
62.
Tarbell NJ, Friedman H, Polkinghorn WR, Yock T, Zhou T, Chen Z, Kun L (2013) High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031). J Clin Oncol 31(23):2936PubMedPubMedCentralCrossRef
63.
Tennant MK, Thrasher JB, Twomey PA, Birnbaum RS, Plymate SR (1996) Insulin-like growth factor-binding protein-2 and-3 expression in benign human prostate epithelium, prostate intraepithelial neoplasia, and adenocarcinoma of the prostate. J Clin Endocrinol Metab 81(1):411–420PubMed
64.
Tombolan L, Orso F, Guzzardo V, Casara S, Zin A, Bonora M, Alaggio R (2011) High IGFBP2 expression correlates with tumor severity in pediatric rhabdomyosarcoma. Am J Pathol 179(5):2611–2624PubMedPubMedCentralCrossRef
65.
von Bueren AO, Kortmann R-D, von Hoff K, Friedrich C, Mynarek M, Müller K, Warmuth-Metz M (2016) Treatment of children and adolescents with metastatic medulloblastoma and prognostic relevance of clinical and biologic parameters. J Clin Oncol 34(34):4151–4160CrossRef
66.
Wallace VA (1999) Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 9(8):445–448PubMedCrossRef
67.
Wang GK, Hu L, Fuller GN, Zhang W (2006) An interaction between insulin-like growth factor-binding protein 2 (IGFBP2) and integrin α5 is essential for IGFBP2-induced cell mobility. J Biol Chem 281(20):14085–14091PubMedCrossRef
68.
Wang H, Arun BK, Wang H, Fuller GN, Zhang W, Middleton LP, Sahin AA (2008) IGFBP2 and IGFBP5 overexpression correlates with the lymph node metastasis in T1 breast carcinomas. The Breast J 14(3):261–267PubMedCrossRef
69.
Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22(1):103–114PubMedCrossRef
70.
71.
Yuan L, Zhang H, Liu J, Malhotra A, Dey A, Yu B, MacDonald TJ (2022) STAT3 is required for Smo-dependent signaling and mediates Smo-targeted treatment resistance and tumorigenesis in Shh medulloblastoma. Mol Oncol 16(4):1009–1025PubMedCrossRef
72.
Zhao Q, Kho A, Kenney AM, Yuk D-I, Kohane I, Rowitch DH (2002) Identification of genes expressed with temporal-spatial restriction to developing cerebellar neuron precursors by a functional genomic approach. Proc Natl Acad Sci 99(8):5704–5709PubMedPubMedCentralCrossRef
Metadata
Title
IGFBP2 promotes proliferation and cell migration through STAT3 signaling in Sonic hedgehog medulloblastoma
Authors
Haritha Kunhiraman
Leon McSwain
Shubin W. Shahab
Timothy R. Gershon
Tobey J. MacDonald
Anna Marie Kenney
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/s40478-023-01557-2

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