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Soluble HSPB1 regulates VEGF-mediated angiogenesis through their direct interaction

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Abstract

Endothelial cell function is critical for angiogenic balance in both physiological and pathological conditions, such as wound healing and cancer, respectively. We report here that soluble heat shock protein beta-1 (HSPB1) is released primarily from endothelial cells (ECs), and plays a key role in regulating angiogenic balance via direct interaction with vascular endothelial growth factor (VEGF). VEGF-mediated phosphorylation of intracellular HSPB1 inhibited the secretion of HSPB1 and their binding activity in ECs. Interestingly, co-culture of tumor ECs with tumor cells decreased HSPB1 secretion from tumor ECs, suggesting that inhibition of HSPB1 secretion allows VEGF to promote angiogenesis. Additionally, neutralization of HSPB1 in a primary mouse sarcoma model promoted tumor growth, indicating the anti-angiogenic role of soluble HSPB1. Overexpression of HSPB1 by HSPB1 adenovirus was sufficient to suppress lung metastases of CT26 colon carcinoma in vivo, while neutralization of HSPB1 promoted in vivo wound healing. While VEGF-induced regulation of angiogenesis has been studied extensively, these findings illustrate the key contribution of HSPB1-VEGF interactions in the balance between physiological and pathological angiogenesis.

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References

  1. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676. doi:10.1038/nm0603-669

    Article  PubMed  CAS  Google Scholar 

  2. Chung AS, Ferrara N (2010) Targeting the tumor microenvironment with SRC kinase inhibition. Clin Cancer Res 16(3):775–777. doi:10.1158/1078-0432.CCR-09-3081

    Article  PubMed  CAS  Google Scholar 

  3. Ferrara N, Gerber HP (2001) The role of vascular endothelial growth factor in angiogenesis. Acta Haematol 106(4):148–156

    Article  PubMed  CAS  Google Scholar 

  4. Folkman J (2003) Angiogenesis inhibitors: a new class of drugs. Cancer Biol Ther 2(4 Suppl 1):S127–133

    PubMed  CAS  Google Scholar 

  5. Folkman J, Ryeom S (2005) Is oncogene addiction angiogenesis-dependent? Cold Spring Harb Symp Quant Biol 70:389–397. doi:10.1101/sqb.2005.70.042

    Article  PubMed  CAS  Google Scholar 

  6. Evans IM, Britton G, Zachary IC (2008) Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase. Cell Signal 20(7):1375–1384. doi:10.1016/j.cellsig.2008.03.002

    Article  PubMed  CAS  Google Scholar 

  7. Yancopoulos GD (2010) Clinical application of therapies targeting VEGF. Cell 143(1):13–16. doi:10.1016/j.cell.2010.09.028

    Article  PubMed  CAS  Google Scholar 

  8. Fernando NT, Koch M, Rothrock C, Gollogly LK, D’Amore PA, Ryeom S, Yoon SS (2008) Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 14(5):1529–1539. doi:10.1158/1078-0432.CCR-07-4126

    Article  PubMed  CAS  Google Scholar 

  9. Richter K, Haslbeck M, Buchner J (2010) The heat shock response: life on the verge of death. Mol Cell 40(2):253–266. doi:10.1016/j.molcel.2010.10.006

    Article  PubMed  CAS  Google Scholar 

  10. Ousman SS, Tomooka BH, van Noort JM, Wawrousek EF, O’Connor KC, Hafler DA, Sobel RA, Robinson WH, Steinman L (2007) Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature 448(7152):474–479. doi:10.1038/nature05935

    Article  PubMed  CAS  Google Scholar 

  11. Didelot C, Schmitt E, Brunet M, Maingret L, Parcellier A, Garrido C (2006) Heat shock proteins: endogenous modulators of apoptotic cell death. Mol Chaperones Health Dis 171–198

  12. Kase S, He S, Sonoda S, Kitamura M, Spee C, Wawrousek E, Ryan SJ, Kannan R, Hinton DR (2010) AlphaB-crystallin regulation of angiogenesis by modulation of VEGF. Blood 115(16):3398–3406. doi:10.1182/blood-2009-01-197095

    Article  PubMed  CAS  Google Scholar 

  13. Dimberg A, Rylova S, Dieterich LC, Olsson AK, Schiller P, Wikner C, Bohman S, Botling J, Lukinius A, Wawrousek EF, Claesson-Welsh L (2008) AlphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis. Blood 111(4):2015–2023. doi:10.1182/blood-2007-04-087841

    Article  PubMed  CAS  Google Scholar 

  14. Liao WC, Wu MS, Wang HP, Tien YW, Lin JT (2009) Serum heat shock protein 27 is increased in chronic pancreatitis and pancreatic carcinoma. Pancreas 38(4):422–426. doi:10.1097/MPA.0b013e318198281d

    Article  PubMed  CAS  Google Scholar 

  15. Huang Q, Ye J, Chen W, Wang L, Lin W, Lin J, Lin X (2010) Heat shock protein 27 is over-expressed in tumor tissues and increased in sera of patients with gastric adenocarcinoma. Clin Chem Lab Med 48(2):263–269. doi:10.1515/CCLM.2010.043

    Article  PubMed  CAS  Google Scholar 

  16. Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C (2007) Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol 81(1):15–27. doi:10.1189/jlb.0306167

    Article  PubMed  CAS  Google Scholar 

  17. Lee Y, Lee D, Cho C, Chung H, Bae S, Jhon G, Soh J, Jeoung D, Lee S, Lee Y (2005) HSP25 inhibits radiation-induced apoptosis through reduction of PKC¥ä-mediated ROS production. Oncogene 24(23):3715–3725

    Article  PubMed  CAS  Google Scholar 

  18. Lee YJ, Lee DH, Cho CK, Bae S, Jhon GJ, Lee SJ, Soh JW, Lee YS (2005) HSP25 inhibits protein kinase C delta-mediated cell death through direct interaction. J Biol Chem 280(18):18108–18119. doi:10.1074/jbc.M501131200

    Article  PubMed  CAS  Google Scholar 

  19. Ciocca DR, Oesterreich S, Chamness GC, McGuire WL, Fuqua SA (1993) Biological and clinical implications of heat shock protein 27,000 (Hsp27): a review. J Natl Cancer Inst 85(19):1558–1570

    Article  PubMed  CAS  Google Scholar 

  20. Geum D, Son GH, Kim K (2002) Phosphorylation-dependent cellular localization and thermoprotective role of heat shock protein 25 in hippocampal progenitor cells. J Biol Chem 277(22):19913–19921. doi:10.1074/jbc.M104396200

    Article  PubMed  CAS  Google Scholar 

  21. Lee YJ, Koch M, Karl D, Torres-Collado AX, Fernando NT, Rothrock C, Kuruppu D, Ryeom S, Iruela-Arispe ML, Yoon SS (2010) Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1. Cancer Res 70(3):948–956. doi:10.1158/0008-5472.CAN-09-3094

    Article  PubMed  CAS  Google Scholar 

  22. DuPage M, Dooley AL, Jacks T (2009) Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat Protoc 4(7):1064–1072. doi:10.1038/nprot.2009.95

    Article  PubMed  CAS  Google Scholar 

  23. Kirsch DG, Dinulescu DM, Miller JB, Grimm J, Santiago PM, Young NP, Nielsen GP, Quade BJ, Chaber CJ, Schultz CP, Takeuchi O, Bronson RT, Crowley D, Korsmeyer SJ, Yoon SS, Hornicek FJ, Weissleder R, Jacks T (2007) A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat Med 13(8):992–997. doi:10.1038/nm1602

    Article  PubMed  CAS  Google Scholar 

  24. Ryeom S, Baek KH, Rioth MJ, Lynch RC, Zaslavsky A, Birsner A, Yoon SS, McKeon F (2008) Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer Cell 13(5):420–431. doi:10.1016/j.ccr.2008.02.018

    Article  PubMed  CAS  Google Scholar 

  25. Montrucchio G, Lupia E, Battaglia E, Del Sorbo L, Boccellino M, Biancone L, Emanuelli G, Camussi G (2000) Platelet-activating factor enhances vascular endothelial growth factor-induced endothelial cell motility and neoangiogenesis in a murine matrigel model. Arterioscler Thromb Vasc Biol 20(1):80–88

    Article  PubMed  CAS  Google Scholar 

  26. Detwiller KY, Fernando NT, Segal NH, Ryeom SW, D’Amore PA, Yoon SS (2005) Analysis of hypoxia-related gene expression in sarcomas and effect of hypoxia on RNA interference of vascular endothelial cell growth factor A. Cancer Res 65(13):5881–5889. doi:10.1158/0008-5472.CAN-04-4078

    Article  PubMed  CAS  Google Scholar 

  27. Roeckl W, Hecht D, Sztajer H, Waltenberger J, Yayon A, Weich HA (1998) Differential binding characteristics and cellular inhibition by soluble VEGF receptors 1 and 2. Exp Cell Res 241(1):161–170. doi:10.1006/excr.1998.4039

    Article  PubMed  CAS  Google Scholar 

  28. Goldman CK, Kendall RL, Cabrera G, Soroceanu L, Heike Y, Gillespie GY, Siegal GP, Mao X, Bett AJ, Huckle WR, Thomas KA, Curiel DT (1998) Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate. Proc Natl Acad Sci USA 95(15):8795–8800

    Article  PubMed  CAS  Google Scholar 

  29. Krepuska M, Szeberin Z, Sotonyi P, Sarkadi H, Fehervari M, Apor A, Rimely E, Prohaszka Z, Acsady G (2010) Serum level of soluble Hsp70 is associated with vascular calcification. Cell Stress Chaperones. doi:10.1007/s12192-010-0237-3

    PubMed  Google Scholar 

  30. Rayner K, Chen YX, McNulty M, Simard T, Zhao X, Wells DJ, de Belleroche J, O’Brien ER (2008) Extracellular release of the atheroprotective heat shock protein 27 is mediated by estrogen and competitively inhibits acLDL binding to scavenger receptor-A. Circ Res 103(2):133–141. doi:10.1161/CIRCRESAHA.108.172155

    Article  PubMed  CAS  Google Scholar 

  31. Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10(2):86–103

    Article  PubMed  CAS  Google Scholar 

  32. Melle C, Ernst G, Escher N, Hartmann D, Schimmel B, Bleul A, Thieme H, Kaufmann R, Felix K, Friess HM, Settmacher U, Hommann M, Richter KK, Daffner W, Taubig H, Manger T, Claussen U, von Eggeling F (2007) Protein profiling of microdissected pancreas carcinoma and identification of HSP27 as a potential serum marker. Clin Chem 53(4):629–635. doi:10.1373/clinchem.2006.079194

    Article  PubMed  CAS  Google Scholar 

  33. Kim EH, Lee HJ, Lee DH, Bae S, Soh JW, Jeoung D, Kim J, Cho CK, Lee YJ, Lee YS (2007) Inhibition of heat shock protein 27-mediated resistance to DNA damaging agents by a novel PKC delta-V5 heptapeptide. Cancer Res 67(13):6333–6341. doi:10.1158/0008-5472.CAN-06-4344

    Article  PubMed  CAS  Google Scholar 

  34. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186

    Article  PubMed  CAS  Google Scholar 

  35. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989. doi:10.1038/nm0901-987

    Article  PubMed  CAS  Google Scholar 

  36. Wachsberger P, Burd R, Dicker AP (2003) Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction. Clin Cancer Res 9(6):1957–1971

    PubMed  CAS  Google Scholar 

  37. Dakappagari N, Neely L, Tangri S, Lundgren K, Hipolito L, Estrellado A, Burrows F, Zhang H (2010) An investigation into the potential use of serum Hsp70 as a novel tumour biomarker for Hsp90 inhibitors. Biomarkers 15(1):31–38. doi:10.3109/13547500903261347

    Article  PubMed  CAS  Google Scholar 

  38. Sreekumar PG, Kannan R, Kitamura M, Spee C, Barron E, Ryan SJ, Hinton DR (2010) AlphaB crystallin is apically secreted within exosomes by polarized human retinal pigment epithelium and provides neuroprotection to adjacent cells. PLoS One 5(10):e12578. doi:10.1371/journal.pone.0012578

    Article  PubMed  Google Scholar 

  39. Folkman J, Kalluri R (2004) Cancer without disease. Nature 427(6977):787. doi:10.1038/427787a

    Article  PubMed  CAS  Google Scholar 

  40. Feldman AL, Tamarkin L, Paciotti GF, Simpson BW, Linehan WM, Yang JC, Fogler WE, Turner EM, Alexander HR Jr, Libutti SK (2000) Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer. Clin Cancer Res 6(12):4628–4634

    PubMed  CAS  Google Scholar 

  41. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88(2):277–285

    Article  PubMed  Google Scholar 

  42. Zaslavsky A, Baek KH, Lynch RC, Short S, Grillo J, Folkman J, Italiano JE Jr, Ryeom S (2010) Platelet-derived thrombospondin-1 is a critical negative regulator and potential biomarker of angiogenesis. Blood 115(22):4605–4613. doi:10.1182/blood-2009-09-242065

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Sandra Ryeom (University of Pennsylvania Medical School) for helpful discussions and Dr. Christiana DelloRusso for assistance editing the manuscript. This work was supported by the Nuclear Research and Development Program (Grant No. M2AMA006), Basic Science Research Program (Grant No. R1A4A002), and Mid-career Researcher Program (Grat No. 2011-0013364) of the National Research Foundation of Korea (NRF) funded by the Korean Ministry of Education, Science, and Technology (MEST).

Conflicts of Interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Korea

    Yoon-Jin Lee, Hae-Jun Lee, Seo-hyun Choi & Yeung Bae Jin

  2. School of Life Sciences and Biotechnology, Korea University, Seoul, 136-701, Korea

    Seo-hyun Choi

  3. Division of Medical Oncology, Seoul St. Mary’s Hospital, The Catholic University, Seoul, 137-040, Korea

    Ho Jung An & Jin-Hyoung Kang

  4. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA

    Sam S. Yoon

  5. College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-750, Korea

    Yun-Sil Lee

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Lee, YJ., Lee, HJ., Choi, Sh. et al. Soluble HSPB1 regulates VEGF-mediated angiogenesis through their direct interaction. Angiogenesis 15, 229–242 (2012). https://doi.org/10.1007/s10456-012-9255-3

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