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Human proangiogenic circulating hematopoietic stem and progenitor cells promote tumor growth in an orthotopic melanoma xenograft model

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Abstract

We previously identified a distinct population of human circulating hematopoietic stem and progenitor cells (CHSPCs; CD14−glyA−CD34+AC133+/−CD45dimCD31+ cells) in the peripheral blood (PB) and bone marrow, and their frequency in the PB can correlate with disease state. The proangiogenic subset (pCHSPC) play a role in regulating tumor progression, for we previously demonstrated a statistically significant increase in C32 melanoma growth in NOD.Cg-Prkdcscid (NOD/SCID) injected with human pCHSPCs (p < 0.001). We now provide further evidence that pCHSPCs possess proangiogenic properties. In vitro bio-plex cytokine analyses and tube forming assays indicate that pCHSPCs secrete a proangiogenic profile and promote vessel formation respectively. We also developed a humanized bone marrow-melanoma orthotopic model to explore in vivo the biological significance of the pCHSPC population. Growth of melanoma xenografts increased more rapidly at 3–4 weeks post-tumor implantation in mice previously transplanted with human CD34+ cells compared to control mice. Increases in pCHSPCs in PB correlated with increases in tumor growth. Additionally, to determine if we could prevent the appearance of pCHSPCs in the PB, mice with humanized bone marrow-melanoma xenografts were administered Interferon α-2b, which is used clinically for treatment of melanoma. The mobilization of the pCHSPCs was decreased in the mice with the humanized bone marrow-melanoma xenografts. Taken together, these data indicate that pCHSPCs play a functional role in tumor growth. The novel in vivo model described here can be utilized to further validate pCHSPCs as a biomarker of tumor progression. The model can also be used to screen and optimize anticancer/anti-angiogenic therapies in a humanized system.

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References

  1. Cao Y, Arbiser J, D’Amato RJ, D’Amore PA, Ingber DE, Kerbel R, Klagsbrun M, Lim S, Moses MA, Zetter B, Dvorak H, Langer R (2011) Forty-year journey of angiogenesis translational research. Sci Transl Med 3 (114):114rv113. doi:10.1126/scitranslmed.3003149

  2. Asahara T, Kawamoto A (2004) Endothelial progenitor cells for postnatal vasculogenesis. Am J Physiol Cell Physiol 287(3):C572–C579. doi:10.1152/ajpcell.00330.2003

    Article  PubMed  CAS  Google Scholar 

  3. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85(3):221–228

    Article  PubMed  CAS  Google Scholar 

  4. Rafii S, Meeus S, Dias S, Hattori K, Heissig B, Shmelkov S, Rafii D, Lyden D (2002) Contribution of marrow-derived progenitors to vascular and cardiac regeneration. Semin Cell Dev Biol 13(1):61–67. doi:10.1006/scdb.2001.0285

    Article  PubMed  CAS  Google Scholar 

  5. Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K, Pollok K, Ferkowicz MJ, Gilley D, Yoder MC (2004) Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 104(9):2752–2760. doi:10.1182/blood-2004-04-1396

    Article  PubMed  CAS  Google Scholar 

  6. Critser PJ, Yoder MC (2010) Endothelial colony-forming cell role in neoangiogenesis and tissue repair. Curr Opin Organ Transplant 15(1):68–72. doi:10.1097/MOT.0b013e32833454b5

    Article  PubMed  Google Scholar 

  7. Estes ML, Mund JA, Mead LE, Prater DN, Cai S, Wang H, Pollok KE, Murphy MP, An CS, Srour EF, Ingram DA Jr, Case J (2010) Application of polychromatic flow cytometry to identify novel subsets of circulating cells with angiogenic potential. Cytometry Part A J Int Soc Anal Cytol 77(9):831–839. doi:10.1002/cyto.a.20921

    Article  Google Scholar 

  8. Mund JA, Estes ML, Yoder MC, Ingram DA Jr, Case J (2012) Flow cytometric identification and functional characterization of immature and mature circulating endothelial cells. Arterioscler Thromb Vasc Biol 32(4):1045–1053. doi:10.1161/ATVBAHA.111.244210

    Article  PubMed  CAS  Google Scholar 

  9. Pradhan KR, Mund JA, Johnson C, Vik TA, Ingram DA, Case J (2011) Polychromatic flow cytometry identifies novel subsets of circulating cells with angiogenic potential in pediatric solid tumors. Cytometry B Clin Cytom. doi:10.1002/cyto.b.20602

    PubMed  Google Scholar 

  10. Sarmiento R, Longo R, Gasparini G (2012) Antiangiogenic therapy of colorectal cancer: state of the art, challenges and new approaches. Int J Biol Mark 27(4):e286–e294. doi:10.5301/JBM.2012.10441

    Article  Google Scholar 

  11. Wilson PM, LaBonte MJ, Lenz HJ (2013) Assessing the in vivo efficacy of biologic antiangiogenic therapies. Cancer Chemother Pharmacol 71(1):1–12. doi:10.1007/s00280-012-1978-8

    Article  PubMed  CAS  Google Scholar 

  12. Zaki KA, Basu B, Corrie P (2012) The role of angiogenesis inhibitors in the management of melanoma. Curr Top Med Chem 12(1):32–49

    Article  PubMed  CAS  Google Scholar 

  13. Schneider BP, Shen F, Miller KD (2012) Pharmacogenetic biomarkers for the prediction of response to antiangiogenic treatment. Lancet Oncol 13(10):e427–e436. doi:10.1016/S1470-2045(12)70275-9

    Article  PubMed  CAS  Google Scholar 

  14. Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, Lahdenranta J, Chung DC, Fischman AJ, Lauwers GY, Shellito P, Czito BG, Wong TZ, Paulson E, Poleski M, Vujaskovic Z, Bentley R, Chen HX, Clark JW, Jain RK (2009) Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 27(18):3020–3026. doi:10.1200/JCO.2008.21.1771

    Article  PubMed  CAS  Google Scholar 

  15. DiMeglio LA, Tosh A, Saha C, Estes M, Mund J, Mead LE, Lien I, Ingram DA, Haneline LS (2010) Endothelial abnormalities in adolescents with type 1 diabetes: a biomarker for vascular sequelae? J Pediatr 157(4):540–546. doi:10.1016/j.jpeds.2010.04.050

    Article  PubMed  CAS  Google Scholar 

  16. Mahnke YD, Roederer M (2007) Optimizing a multicolor immunophenotyping assay. Clin Lab Med 27(3):469–485, v. doi:10.1016/j.cll.2007.05.002

    Google Scholar 

  17. Baumgarth N, Roederer M (2000) A practical approach to multicolor flow cytometry for immunophenotyping. J Immunol Methods 243(1–2):77–97

    Article  PubMed  CAS  Google Scholar 

  18. Tung JW, Heydari K, Tirouvanziam R, Sahaf B, Parks DR, Herzenberg LA, Herzenberg LA (2007) Modern flow cytometry: a practical approach. Clin Lab Med 27(3):453–468

    Article  PubMed  Google Scholar 

  19. Estes ML, Mund JA, Ingram DA, Case J (2010) Identification of endothelial cells and progenitor cell subsets in human peripheral blood. Current protocols in cytometry/editorial board, J Paul Robinson, managing editor [et al] Chapter 9:Unit 9 33:31–11. doi:10.1002/0471142956.cy0933s52

  20. Herzenberg LA, Tung J, Moore WA, Parks DR (2006) Interpreting flow cytometry data: a guide for the perplexed. Nat Immunol 7(7):681–685. doi:10.1038/ni0706-681

    Article  PubMed  CAS  Google Scholar 

  21. Ponce ML (2001) In vitro matrigel angiogenesis assays. Methods Mol Med 46:205–209. doi:10.1385/1-59259-143-4:205

    PubMed  CAS  Google Scholar 

  22. Kirkiles-Smith NC, Harding MJ, Shepherd BR, Fader SA, Yi T, Wang Y, McNiff JM, Snyder EL, Lorber MI, Tellides G, Pober JS (2009) Development of a humanized mouse model to study the role of macrophages in allograft injury. Transplantation 87(2):189–197. doi:10.1097/TP.0b013e318192e05d

    Article  PubMed  CAS  Google Scholar 

  23. Popa ER, Harmsen MC, Tio RA, van der Strate BW, Brouwer LA, Schipper M, Koerts J, De Jongste MJ, Hazenberg A, Hendriks M, van Luyn MJ (2006) Circulating CD34+ progenitor cells modulate host angiogenesis and inflammation in vivo. J Mol Cell Cardiol 41(1):86–96

    Article  PubMed  CAS  Google Scholar 

  24. Adini A, Adini I, Ghosh K, Benny O, Pravda E, Hu R, Luyindula D, D’Amato RJ (2013) The stem cell marker prominin-1/CD133 interacts with vascular endothelial growth factor and potentiates its action. Angiogenesis 16(2):405–416. doi:10.1007/s10456-012-9323-8

    Article  PubMed  CAS  Google Scholar 

  25. Bhatia S, Tykodi SS, Thompson JA (2009) Treatment of metastatic melanoma: an overview. Oncology (Williston Park) 23(6):488–496

    Google Scholar 

  26. Sarkaria JN, Carlson BL, Schroeder MA, Grogan P, Brown PD, Giannini C, Ballman KV, Kitange GJ, Guha A, Pandita A, James CD (2006) Use of an orthotopic xenograft model for assessing the effect of epidermal growth factor receptor amplification on glioblastoma radiation response. Clin Cancer Res 12(7 Pt 1):2264–2271. doi:10.1158/1078-0432.CCR-05-2510

    Article  PubMed  CAS  Google Scholar 

  27. Giannini C, Sarkaria JN, Saito A, Uhm JH, Galanis E, Carlson BL, Schroeder MA, James CD (2005) Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro-oncology 7(2):164–176. doi:10.1215/S1152851704000821

    Article  PubMed  CAS  Google Scholar 

  28. Chan DD, Van Dyke WS, Bahls M, Connell SD, Critser P, Kelleher JE, Kramer MA, Pearce SM, Sharma S, Neu CP (2011) Mechanostasis in apoptosis and medicine. Prog Biophys Mol Biol 106(3):517–524. doi:10.1016/j.pbiomolbio.2011.08.002

    Article  PubMed  CAS  Google Scholar 

  29. Critser PJ, Voytik-Harbin SL, Yoder MC (2011) Isolating and defining cells to engineer human blood vessels. Cell Prolif 44(Suppl 1):15–21. doi:10.1111/j.1365-2184.2010.00719.x

    Article  PubMed  Google Scholar 

  30. Shelley WC, Leapley AC, Huang L, Critser PJ, Zeng P, Prater D, Ingram DA, Tarantal AF, Yoder MC (2012) Changes in the frequency and in vivo vessel-forming ability of rhesus monkey circulating endothelial colony-forming cells across the lifespan (birth to aged). Pediatr Res 71(2):156–161. doi:10.1038/pr.2011.22

    Article  PubMed  Google Scholar 

  31. Sanz L, Cuesta AM, Salas C, Corbacho C, Bellas C, Alvarez-Vallina L (2009) Differential transplantability of human endothelial cells in colorectal cancer and renal cell carcinoma primary xenografts. Lab Inv 89(1):91–97. doi:10.1038/labinvest.2008.108

    Article  CAS  Google Scholar 

  32. De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E, Sitia G, Mazzoleni S, Moi D, Venneri MA, Indraccolo S, Falini A, Guidotti LG, Galli R, Naldini L (2008) Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14(4):299–311. doi:10.1016/j.ccr.2008.09.004

    Article  PubMed  Google Scholar 

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Acknowledgments

We acknowledge the assistance and state-of-the-art facilities of the Flow Cytometry Resource Facility at the Indiana University Simon Cancer Center. We also acknowledge Barbara Bailey of the In Vivo Therapeutics Core of the Indiana University Simon Cancer Center, as well as the nursing staff and Dr. Arthur Baluyut at the St. Vincent Hospital (Indianapolis, IN) for providing some of the UCB samples used for this study. We acknowledge Hui Lin Chau and Artur Plett of the Bio-Plex Core of the Indiana University Simon Cancer Center. Finally, we acknowledge the Angiogenesis, Endothelial and Pro-Angiogenic Cell Core of the Indiana University Simon Cancer Center for providing some of the CD34+ cells and ECFCs used for this study. We acknowledge the continuing support of the Riley Children’s Foundation and the Indiana University Simon Cancer Center. This work was supported by the American Cancer Society IRG-84-002-25 (J.C.), Showalter Trust Fund ERA 31948 (J.C.), NIH/NIDDK P30DK090948 CEMH (J.C., J.A.M and K.E.P.), RO1 CA138798 (H.W., S.C., and K.E.P.) and the Jeff Gordon Research Foundation (H.W. and K.E.P.).

Conflict of interest

All authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pediatrics, Indiana University School of Medicine, 1044 West Walnut St, R4-470, Indianapolis, IN, 46202, USA

    Julie A. Mund, Harlan Shannon, Kamnesh R. Pradhan, Karen E. Pollok & Jamie Case

  2. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    Julie A. Mund, Harlan Shannon, Shanbao Cai, Haiyan Wang, Karen E. Pollok & Jamie Case

  3. Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Julie A. Mund, Anthony L. Sinn, Shanbao Cai, Haiyan Wang, Kamnesh R. Pradhan, Karen E. Pollok & Jamie Case

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  1. Julie A. Mund
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Correspondence to Jamie Case.

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Mund, J.A., Shannon, H., Sinn, A.L. et al. Human proangiogenic circulating hematopoietic stem and progenitor cells promote tumor growth in an orthotopic melanoma xenograft model. Angiogenesis 16, 953–962 (2013). https://doi.org/10.1007/s10456-013-9368-3

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