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Journal of Hematology & Oncology

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Open Access 01-12-2013 | Research

IGF binding protein 2 is a cell-autonomous factor supporting survival and migration of acute leukemia cells

Authors: Xiaoli Chen, Junke Zheng, Yizhou Zou, Chun Song, Xuemei Hu, Cheng Cheng Zhang

Published in: Journal of Hematology & Oncology | Issue 1/2013

Abstract

Background

The role of IGF binding protein 2 (IGFBP2) in cancer development is intriguing. Previously we identified IGFBP2 as an extrinsic factor that supports the activity of hematopoietic stem cells (HSCs).

Methods and results

Here we investigated the role of IGFBP2 in in human leukemia cells and in the retroviral AML1-ETO9a transplantation acute myeloid leukemia (AML) mouse model.

Results

IGFBP2 is highly expressed in certain human AML and acute lymphoblastic leukemia (ALL) cells. Inhibition of expression of endogenous IGFBP2 in human leukemia cells led to elevated apoptosis and decreased migration and, consistently, to decreased activation of AKT and other signaling molecules. We also studied the effects of IGFBP2 knockout in the retroviral AML1-ETO9a transplantation AML mouse model. The deletion of IGFBP2 in donor AML cells significantly decreased leukemia development in transplanted mice. Lack of IGFBP2 resulted in upregulation of PTEN expression and downregulation of AKT activation, in the mouse AML cells. The treatment of IGFBP2 deficient AML cells with a PTEN inhibitor restored the wild-type colony forming ability. The deletion of IGFBP2 also led to decreased AML infiltration into peripheral organs and tissues, suggesting that IGFBP2 is required for the migration of AML cells out of bone marrow.

Conclusion

IGFBP2 is a critical cell-autonomous factor that promotes the survival and migration of acute leukemia cells.

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Appelbaum FR, Rowe JM, Radich J, Dick JE: Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2001, 62-86.

Ranke MB, Elmlinger M: Functional role of insulin-like growth factor binding proteins. Horm Res. 1997, 48 (Suppl 4): 9-15.CrossRefPubMed

Kibbey MM, Jameson MJ, Eaton EM, Rosenzweig SA: Insulin-like growth factor binding protein-2: contributions of the C-terminal domain to insulin-like growth factor-1 binding. Mol Pharmacol. 2006, 69: 833-845.PubMed

Rajaram S, Baylink DJ, Mohan S: Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev. 1997, 18: 801-831. 10.1210/er.18.6.801.PubMed

Russo VC, Bach LA, Werther GA: Cell membrane association of insulin-like growth factor binding protein-2 (IGFBP-2) in the rat brain olfactory bulb. Prog Growth Factor Res. 1995, 6: 329-336. 10.1016/0955-2235(95)00018-6.CrossRefPubMed

Schutt BS, Langkamp M, Rauschnabel U, Ranke MB, Elmlinger MW: Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells. J Mol Endocrinol. 2004, 32: 859-868. 10.1677/jme.0.0320859.CrossRefPubMed

Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN, Zhang W: Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci U S A. 2007, 104: 11736-11741. 10.1073/pnas.0703145104.PubMedCentralCrossRefPubMed

Wang GK, Hu L, Fuller GN, Zhang W: An interaction between insulin-like growth factor-binding protein 2 (IGFBP2) and integrin alpha5 is essential for IGFBP2-induced cell mobility. J Biol Chem. 2006, 281: 14085-14091. 10.1074/jbc.M513686200.CrossRefPubMed

Pereira JJ, Meyer T, Docherty SE, Reid HH, Marshall J, Thompson EW, Rossjohn J, Price JT: Bimolecular interaction of insulin-like growth factor (IGF) binding protein-2 with alphavbeta3 negatively modulates IGF-I-mediated migration and tumor growth. Cancer Res. 2004, 64: 977-984. 10.1158/0008-5472.CAN-03-3056.CrossRefPubMed

10.

Moore MG, Wetterau LA, Francis MJ, Peehl DM, Cohen P: Novel stimulatory role for insulin-like growth factor binding protein-2 in prostate cancer cells. Int J Cancer. 2003, 105: 14-19. 10.1002/ijc.11015.CrossRefPubMed

11.

Wang H, Shen W, Huang H, Hu L, Ramdas L, Zhou YH, Liao WS, Fuller GN, Zhang W: Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res. 2003, 63: 4315-4321.PubMed

12.

Hoeflich A, Reisinger R, Lahm H, Kiess W, Blum WF, Kolb HJ, Weber MM, Wolf E: Insulin-like growth factor-binding protein 2 in tumorigenesis: protector or promoter?. Cancer Res. 2001, 61: 8601-8610.PubMed

13.

Migita T, Narita T, Asaka R, Miyagi E, Nagano H, Nomura K, Matsuura M, Satoh Y, Okumura S, Nakagawa K: Role of insulin-like growth factor binding protein 2 in lung adenocarcinoma: IGF-independent antiapoptotic effect via caspase-3. Am J Pathol. 2010, 176: 1756-1766. 10.2353/ajpath.2010.090500.PubMedCentralCrossRefPubMed

14.

Kim DS, Cho HJ, Yang SK, Shin JW, Huh CH, Park KC: Insulin-like growth factor-binding protein contributes to the proliferation of less proliferative cells in forming skin equivalents. Tissue Eng Part A. 2009, 15: 1075-1080. 10.1089/ten.tea.2008.0236.CrossRefPubMed

15.

Hsieh D, Hsieh A, Stea B, Ellsworth R: IGFBP2 promotes glioma tumor stem cell expansion and survival. Biochem Biophys Res Commun. 2010, 397: 367-372. 10.1016/j.bbrc.2010.05.145.CrossRefPubMed

16.

Chakrabarty S, Kondratick L: Insulin-like growth factor binding protein-2 stimulates proliferation and activates multiple cascades of the mitogen-activated protein kinase pathways in NIH-OVCAR3 human epithelial ovarian cancer cells. Cancer Biol Ther. 2006, 5: 189-197. 10.4161/cbt.5.2.2333.CrossRefPubMed

17.

Bartling B, Koch A, Simm A, Scheubel R, Silber RE, Santos AN: Insulin-like growth factor binding proteins-2 and −4 enhance the migration of human CD34-/CD133+ hematopoietic stem and progenitor cells. Int J Mol Med. 2010, 25: 89-96.PubMed

18.

Russo VC, Schutt BS, Andaloro E, Ymer SI, Hoeflich A, Ranke MB, Bach LA, Werther GA: Insulin-like growth factor binding protein-2 binding to extracellular matrix plays a critical role in neuroblastoma cell proliferation, migration, and invasion. Endocrinology. 2005, 146: 4445-4455. 10.1210/en.2005-0467.CrossRefPubMed

19.

Huynh H, Zheng J, Umikawa M, Zhang C, Silvany R, Iizuka S, Holzenberger M, Zhang W, Zhang CC: IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells. Blood. 2011, 118: 3236-3243. 10.1182/blood-2011-01-331876.PubMedCentralCrossRefPubMed

20.

Holmes KM, Annala M, Chua CY, Dunlap SM, Liu Y, Hugen N, Moore LM, Cogdell D, Hu L, Nykter M: Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-kappaB network. Proc Natl Acad Sci U S A. 2012, 109: 3475-3480. 10.1073/pnas.1120375109.PubMedCentralCrossRefPubMed

21.

Mehrian-Shai R, Chen CD, Shi T, Horvath S, Nelson SF, Reichardt JK, Sawyers CL: Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci U S A. 2007, 104: 5563-5568. 10.1073/pnas.0609139104.PubMedCentralCrossRefPubMed

22.

Perks CM, Vernon EG, Rosendahl AH, Tonge D, Holly JM: IGF-II and IGFBP-2 differentially regulate PTEN in human breast cancer cells. Oncogene. 2007, 26: 5966-5972. 10.1038/sj.onc.1210397.CrossRefPubMed

23.

Foulstone EJ, Zeng L, Perks CM, Holly JM: Insulin-like growth factor binding protein 2 (IGFBP-2) promotes growth and survival of breast epithelial cells: novel regulation of the estrogen receptor. Endocrinology. 2013, 154: 1780-1793. 10.1210/en.2012-1970.CrossRefPubMed

24.

Azar WJ, Azar SH, Higgins S, Hu JF, Hoffman AR, Newgreen DF, Werther GA, Russo VC: IGFBP-2 enhances VEGF gene promoter activity and consequent promotion of angiogenesis by neuroblastoma cells. Endocrinology. 2011, 152: 3332-3342. 10.1210/en.2011-1121.CrossRefPubMed

25.

Besnard V, Corroyer S, Trugnan G, Chadelat K, Nabeyrat E, Cazals V, Clement A: Distinct patterns of insulin-like growth factor binding protein (IGFBP)-2 and IGFBP-3 expression in oxidant exposed lung epithelial cells. Biochim Biophys Acta. 2001, 1538: 47-58. 10.1016/S0167-4889(00)00136-1.CrossRefPubMed

26.

Dawczynski K, Kauf E, Zintl F: Changes of serum growth factors (IGF-I,-II and IGFBP-2,-3) prior to and after stem cell transplantation in children with acute leukemia. Bone Marrow Transplant. 2003, 32: 411-415. 10.1038/sj.bmt.1704149.CrossRefPubMed

27.

Vorwerk P, Mohnike K, Wex H, Rohl FW, Zimmermann M, Blum WF, Mittler U: Insulin-like growth factor binding protein-2 at diagnosis of childhood acute lymphoblastic leukemia and the prediction of relapse risk. J Clin Endocrinol Metab. 2005, 90: 3022-3027. 10.1210/jc.2004-0461.CrossRefPubMed

28.

Hattori H, Matsuzaki A, Suminoe A, Koga Y, Tashiro K, Hara T: Identification of novel genes with prognostic value in childhood leukemia using cDNA microarray and quantitative RT-PCR. Pediatr Hematol Oncol. 2006, 23: 115-127. 10.1080/08880010500457780.CrossRefPubMed

29.

Dawczynski K, Kauf E, Schlenvoigt D, Gruhn B, Fuchs D, Zintl F: Elevated serum insulin-like growth factor binding protein-2 is associated with a high relapse risk after hematopoietic stem cell transplantation in childhood AML. Bone Marrow Transplant. 2006, 37: 589-594. 10.1038/sj.bmt.1705281.CrossRefPubMed

30.

Dawczynski K, Steinbach D, Wittig S, Pfaffendorf N, Kauf E, Zintl F: Expression of components of the IGF axis in childhood acute myelogenous leukemia. Pediatr Blood Cancer. 2008, 50: 24-28. 10.1002/pbc.21294.CrossRefPubMed

31.

Akmal SN, Yun K, MacLay J, Higami Y, Ikeda T: Insulin-like growth factor 2 and insulin-like growth factor binding protein 2 expression in hepatoblastoma. Hum Pathol. 1995, 26: 846-851. 10.1016/0046-8177(95)90005-5.CrossRefPubMed

32.

Zhang CC, Kaba M, Iizuka S, Huynh H, Lodish HF: Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood. 2008, 111: 3415-3423. 10.1182/blood-2007-11-122119.PubMedCentralCrossRefPubMed

33.

Huynh H, LIizuka S, Kaba M, Kirak O, Zheng J, Lodish HF, Zhang CC: GFBP2 secreted by a tumorigenic cell line supports ex vivo expansion of mouse hematopoietic stem cells. Stem Cells. 2008, 26: 1628-1635. 10.1634/stemcells.2008-0064.PubMedCentralCrossRefPubMed

34.

Ben-Shmuel A, Shvab A, Gavert N, Brabletz T, Ben-Ze’ev A: Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-kappaB signaling that promotes colon cancer progression. Oncogene. 2013, 32: 3220-3230. 10.1038/onc.2012.340.CrossRefPubMed

35.

Fukushima T, Tezuka T, Shimomura T, Nakano S, Kataoka H: Silencing of insulin-like growth factor-binding protein-2 in human glioblastoma cells reduces both invasiveness and expression of progression-associated gene CD24. J Biol Chem. 2007, 282: 18634-18644. 10.1074/jbc.M609567200.CrossRefPubMed

36.

Welch JS, Yuan W, Ley TJ: PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice. J Clin Invest. 2011, 121: 1636-1645. 10.1172/JCI42953.PubMedCentralCrossRefPubMed

37.

Mulloy JC, Jankovic V, Wunderlich M, Delwel R, Cammenga J, Krejci O, Zhao H, Valk PJ, Lowenberg B, Nimer SD: AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion. Proc Natl Acad Sci U S A. 2005, 102: 4016-4021. 10.1073/pnas.0404701102.PubMedCentralCrossRefPubMed

38.

Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y, Chen IM, Chen Z, Rowley JD, Willman CL, Zhang DE: A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med. 2006, 12: 945-949. 10.1038/nm1443.CrossRefPubMed

39.

Huynh H, Iizuka S, Kaba M, Kirak O, Zheng J, Lodish HF, Zhang CC: Insulin-like growth factor-binding protein 2 secreted by a tumorigenic cell line supports ex vivo expansion of mouse hematopoietic stem cells. Stem Cells. 2008, 26: 1628-1635. 10.1634/stemcells.2008-0064.PubMedCentralCrossRefPubMed

40.

Zheng J, Umikawa M, Cui C, Li J, Chen X, Zhang CC, Huynh H, Kang X, Silvany R, Wan X: Inhibitory receptors bind Angptls and support blood stem cells and leukemia development. Nature. 2012, 485: 656-660. 10.1038/nature11095.PubMedCentralCrossRefPubMed

41.

Zheng J, Umikawa M, Zhang S, Huynh H, Silvany R, Chen BP, Chen L, Zhang CC: Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. Cell Stem Cell. 2011, 9: 119-130. 10.1016/j.stem.2011.06.003.PubMedCentralCrossRefPubMed

Title: IGF binding protein 2 is a cell-autonomous factor supporting survival and migration of acute leukemia cells
Authors: Xiaoli Chen
Junke Zheng
Yizhou Zou
Chun Song
Xuemei Hu
Cheng Cheng Zhang
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2013
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/1756-8722-6-72

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