Skip to main content
Top
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Platelet factor-4 and its p17-70 peptide inhibit myeloma proliferation and angiogenesis in vivo

Authors: Longjiang Yang, Juan Du, Jian Hou, Hua Jiang, Jianfeng Zou

Published in: BMC Cancer | Issue 1/2011

Login to get access

Abstract

Background

Angiogenesis plays an important role in the development of multiple myeloma (MM). The interaction between MM cells and the bone marrow microenvironment stimulates the proliferation and migration of endothelial progenitor cells (EPCs). Vascular endothelial growth factor (VEGF) contributes to the formation of new blood vessels by actively recruiting circulating EPCs. The production of proangiogenic and antiangiogenic factors is also dysregulated in MM. Platelet factor 4 (PF4) is a potent angiostatic cytokine that inhibits angiogenesis and tumor growth in several animal models.

Methods

In this study, we stably transfected human myeloma cell lines with the PF4 gene or the sequence encoding its more potent p17-70 peptide and investigated the effects of PF4 and p17-70 on angiogenesis and tumor growth in vitro and in a SCID-rab myeloma model.

Results

PF4 and p17-70 significantly attenuated VEGF production, both in vitro and in vivo. In a migration study using a Transwell system, PF4 or p17-70 markedly suppressed the migration of co-cultured human endothelial progenitor cells. PF4 or p17-70 also caused a significant reduction in microvessel densities in myeloma xenografts and markedly reduced the tumor volume in the SCID mice. Kaplan-Meier analysis demonstrated that PF4 and p17-70 significantly extended the overall survival of SCID mice bearing human myeloma xenografts.

Conclusions

Our findings indicate that PF4 or p17-70 could be valuable in combating multiple myeloma by disrupting tumor angiogenesis.
Appendix
Available only for authorised users
Literature
2.
go back to reference Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 2009, 59: 225-249. 10.3322/caac.20006.CrossRefPubMed Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 2009, 59: 225-249. 10.3322/caac.20006.CrossRefPubMed
3.
go back to reference Ludwig H, Beksac M, Blade J, Boccadoro M, Cavenagh J, Cavo M, Dimopoulos M, Drach J, Einsele H, Facon T, Goldschmidt H, Harousseau JL, Hess U, Ketterer N, Kropff M, Mendeleeva L, Morgan G, Palumbo A, Plesner T, San MJ, Shpilberg O, Sondergeld P, Sonneveld P, Zweegman S: Current multiple myeloma treatment strategies with novel agents: a European perspective. Oncologist. 2010, 15: 6-25. 10.1634/theoncologist.2009-0203.CrossRefPubMedPubMedCentral Ludwig H, Beksac M, Blade J, Boccadoro M, Cavenagh J, Cavo M, Dimopoulos M, Drach J, Einsele H, Facon T, Goldschmidt H, Harousseau JL, Hess U, Ketterer N, Kropff M, Mendeleeva L, Morgan G, Palumbo A, Plesner T, San MJ, Shpilberg O, Sondergeld P, Sonneveld P, Zweegman S: Current multiple myeloma treatment strategies with novel agents: a European perspective. Oncologist. 2010, 15: 6-25. 10.1634/theoncologist.2009-0203.CrossRefPubMedPubMedCentral
4.
go back to reference Kumar S, Rajkumar SV: Thalidomide and dexamethasone: therapy for multiple myeloma. Expert Rev Anticancer Ther. 2005, 5: 759-766. 10.1586/14737140.5.5.759.CrossRefPubMed Kumar S, Rajkumar SV: Thalidomide and dexamethasone: therapy for multiple myeloma. Expert Rev Anticancer Ther. 2005, 5: 759-766. 10.1586/14737140.5.5.759.CrossRefPubMed
5.
go back to reference Hose D, Moreaux J, Meissner T, Seckinger A, Goldschmidt H, Benner A, Mahtouk K, Hillengass J, Reme T, De Vos J, Hundemer M, Condomines M, Bertsch U, Rossi JF, Jauch A, Klein B, Mohler T: Induction of angiogenesis by normal and malignant plasma cells. Blood. 2009, 114: 128-143. 10.1182/blood-2008-10-184226.CrossRefPubMed Hose D, Moreaux J, Meissner T, Seckinger A, Goldschmidt H, Benner A, Mahtouk K, Hillengass J, Reme T, De Vos J, Hundemer M, Condomines M, Bertsch U, Rossi JF, Jauch A, Klein B, Mohler T: Induction of angiogenesis by normal and malignant plasma cells. Blood. 2009, 114: 128-143. 10.1182/blood-2008-10-184226.CrossRefPubMed
6.
go back to reference Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S: Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001, 7: 1194-1201. 10.1038/nm1101-1194.CrossRefPubMed Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S: Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001, 7: 1194-1201. 10.1038/nm1101-1194.CrossRefPubMed
7.
go back to reference Li X, Liu X, Wang J, Wang Z, Jiang W, Reed E, Zhang Y, Liu Y, Li QQ: Thalidomide down-regulates the expression of VEGF and bFGF in cisplatin-resistant human lung carcinoma cells. Anticancer Res. 2003, 23: 2481-2487.PubMed Li X, Liu X, Wang J, Wang Z, Jiang W, Reed E, Zhang Y, Liu Y, Li QQ: Thalidomide down-regulates the expression of VEGF and bFGF in cisplatin-resistant human lung carcinoma cells. Anticancer Res. 2003, 23: 2481-2487.PubMed
8.
go back to reference Yabu T, Tomimoto H, Taguchi Y, Yamaoka S, Igarashi Y, Okazaki T: Thalidomide-induced antiangiogenic action is mediated by ceramide through depletion of VEGF receptors, and is antagonized by sphingosine-1-phosphate. Blood. 2005, 106: 125-134. 10.1182/blood-2004-09-3679.CrossRefPubMed Yabu T, Tomimoto H, Taguchi Y, Yamaoka S, Igarashi Y, Okazaki T: Thalidomide-induced antiangiogenic action is mediated by ceramide through depletion of VEGF receptors, and is antagonized by sphingosine-1-phosphate. Blood. 2005, 106: 125-134. 10.1182/blood-2004-09-3679.CrossRefPubMed
9.
go back to reference Deuel TF, Keim PS, Farmer M, Heinrikson RL: Amino acid sequence of human platelet factor 4. Proc Natl Acad Sci USA. 1977, 74: 2256-2258. 10.1073/pnas.74.6.2256.CrossRefPubMedPubMedCentral Deuel TF, Keim PS, Farmer M, Heinrikson RL: Amino acid sequence of human platelet factor 4. Proc Natl Acad Sci USA. 1977, 74: 2256-2258. 10.1073/pnas.74.6.2256.CrossRefPubMedPubMedCentral
10.
go back to reference Hermodson M, Schmer G, Kurachi K: Isolation, crystallization, and primary amino acid sequence of human platelet factor 4. J Biol Chem. 1977, 252: 6276-6279.PubMed Hermodson M, Schmer G, Kurachi K: Isolation, crystallization, and primary amino acid sequence of human platelet factor 4. J Biol Chem. 1977, 252: 6276-6279.PubMed
11.
go back to reference Lasagni L, Grepin R, Mazzinghi B, Lazzeri E, Meini C, Sagrinati C, Liotta F, Frosali F, Ronconi E, Alain-Courtois N, Ballerini L, Netti GS, Maggi E, Annunziato F, Serio M, Romagnani S, Bikfalvi A, Romagnani P: PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion. Blood. 2007, 109: 4127-4134. 10.1182/blood-2006-10-052035.CrossRefPubMed Lasagni L, Grepin R, Mazzinghi B, Lazzeri E, Meini C, Sagrinati C, Liotta F, Frosali F, Ronconi E, Alain-Courtois N, Ballerini L, Netti GS, Maggi E, Annunziato F, Serio M, Romagnani S, Bikfalvi A, Romagnani P: PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion. Blood. 2007, 109: 4127-4134. 10.1182/blood-2006-10-052035.CrossRefPubMed
12.
go back to reference Maione TE, Gray GS, Petro J, Hunt AJ, Donner AL, Bauer SI, Carson HF, Sharpe RJ: Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science. 1990, 247: 77-79. 10.1126/science.1688470.CrossRefPubMed Maione TE, Gray GS, Petro J, Hunt AJ, Donner AL, Bauer SI, Carson HF, Sharpe RJ: Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science. 1990, 247: 77-79. 10.1126/science.1688470.CrossRefPubMed
13.
go back to reference Vandercappellen J, Liekens S, Bronckaers A, Noppen S, Ronsse I, Dillen C, Belleri M, Mitola S, Proost P, Presta M, Struyf S, Van Damme J: The COOH-terminal peptide of platelet factor-4 variant (CXCL4L1/PF-4var47-70) strongly inhibits angiogenesis and suppresses B16 melanoma growth in vivo. Mol Cancer Res. 2010, 8: 322-334. 10.1158/1541-7786.MCR-09-0176.CrossRefPubMed Vandercappellen J, Liekens S, Bronckaers A, Noppen S, Ronsse I, Dillen C, Belleri M, Mitola S, Proost P, Presta M, Struyf S, Van Damme J: The COOH-terminal peptide of platelet factor-4 variant (CXCL4L1/PF-4var47-70) strongly inhibits angiogenesis and suppresses B16 melanoma growth in vivo. Mol Cancer Res. 2010, 8: 322-334. 10.1158/1541-7786.MCR-09-0176.CrossRefPubMed
14.
go back to reference Hagedorn M, Zilberberg L, Wilting J, Canron X, Carrabba G, Giussani C, Pluderi M, Bello L, Bikfalvi A: Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors. Cancer Res. 2002, 62: 6884-6890.PubMed Hagedorn M, Zilberberg L, Wilting J, Canron X, Carrabba G, Giussani C, Pluderi M, Bello L, Bikfalvi A: Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors. Cancer Res. 2002, 62: 6884-6890.PubMed
15.
go back to reference Perollet C, Han ZC, Savona C, Caen JP, Bikfalvi A: Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization. Blood. 1998, 91: 3289-3299.PubMed Perollet C, Han ZC, Savona C, Caen JP, Bikfalvi A: Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization. Blood. 1998, 91: 3289-3299.PubMed
16.
go back to reference Sato Y, Abe M, Takaki R: Platelet factor 4 blocks the binding of basic fibroblast growth factor to the receptor and inhibits the spontaneous migration of vascular endothelial cells. Biochem Biophys Res Commun. 1990, 172: 595-600. 10.1016/0006-291X(90)90715-Y.CrossRefPubMed Sato Y, Abe M, Takaki R: Platelet factor 4 blocks the binding of basic fibroblast growth factor to the receptor and inhibits the spontaneous migration of vascular endothelial cells. Biochem Biophys Res Commun. 1990, 172: 595-600. 10.1016/0006-291X(90)90715-Y.CrossRefPubMed
17.
go back to reference Sulpice E, Bryckaert M, Lacour J, Contreres JO, Tobelem G: Platelet factor 4 inhibits FGF2-induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phosphatidylinositol 3-kinase pathway. Blood. 2002, 100: 3087-3094. 10.1182/blood.V100.9.3087.CrossRefPubMed Sulpice E, Bryckaert M, Lacour J, Contreres JO, Tobelem G: Platelet factor 4 inhibits FGF2-induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phosphatidylinositol 3-kinase pathway. Blood. 2002, 100: 3087-3094. 10.1182/blood.V100.9.3087.CrossRefPubMed
18.
go back to reference Jouan V, Canron X, Alemany M, Caen JP, Quentin G, Plouet J, Bikfalvi A: Inhibition of in vitro angiogenesis by platelet factor-4-derived peptides and mechanism of action. Blood. 1999, 94: 984-993.PubMed Jouan V, Canron X, Alemany M, Caen JP, Quentin G, Plouet J, Bikfalvi A: Inhibition of in vitro angiogenesis by platelet factor-4-derived peptides and mechanism of action. Blood. 1999, 94: 984-993.PubMed
19.
go back to reference Sulpice E, Contreres JO, Lacour J, Bryckaert M, Tobelem G: Platelet factor 4 disrupts the intracellular signalling cascade induced by vascular endothelial growth factor by both KDR dependent and independent mechanisms. Eur J Biochem. 2004, 271: 3310-3318. 10.1111/j.1432-1033.2004.04263.x.CrossRefPubMed Sulpice E, Contreres JO, Lacour J, Bryckaert M, Tobelem G: Platelet factor 4 disrupts the intracellular signalling cascade induced by vascular endothelial growth factor by both KDR dependent and independent mechanisms. Eur J Biochem. 2004, 271: 3310-3318. 10.1111/j.1432-1033.2004.04263.x.CrossRefPubMed
20.
go back to reference Cheng SH, Ng MH, Lau KM, Liu HS, Chan JC, Hui AB, Lo KW, Jiang H, Hou J, Chu RW, Wong WS, Chan NP, Ng HK: 4q loss is potentially an important genetic event in MM tumorigenesis: identification of a tumor suppressor gene regulated by promoter methylation at 4q13.3, platelet factor 4. Blood. 2007, 109: 2089-2099. 10.1182/blood-2006-04-018770.CrossRefPubMed Cheng SH, Ng MH, Lau KM, Liu HS, Chan JC, Hui AB, Lo KW, Jiang H, Hou J, Chu RW, Wong WS, Chan NP, Ng HK: 4q loss is potentially an important genetic event in MM tumorigenesis: identification of a tumor suppressor gene regulated by promoter methylation at 4q13.3, platelet factor 4. Blood. 2007, 109: 2089-2099. 10.1182/blood-2006-04-018770.CrossRefPubMed
21.
go back to reference Sun C, Liang C, Ren Y, Zhen Y, He Z, Wang H, Tan H, Pan X, Wu Z: Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic Res Cardiol. 2009, 104: 42-49. 10.1007/s00395-008-0738-8.CrossRefPubMed Sun C, Liang C, Ren Y, Zhen Y, He Z, Wang H, Tan H, Pan X, Wu Z: Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic Res Cardiol. 2009, 104: 42-49. 10.1007/s00395-008-0738-8.CrossRefPubMed
22.
go back to reference Condon RG, Schaefer EJ, Santoro M, Longley R, Tsao YS, Zurawski SM, Liu Z: Development of a Chinese hamster ovary cell line for recombinant adenovirus-mediated gene expression. Biotechnol Prog. 2003, 19: 137-143. 10.1021/bp0200696.CrossRefPubMed Condon RG, Schaefer EJ, Santoro M, Longley R, Tsao YS, Zurawski SM, Liu Z: Development of a Chinese hamster ovary cell line for recombinant adenovirus-mediated gene expression. Biotechnol Prog. 2003, 19: 137-143. 10.1021/bp0200696.CrossRefPubMed
23.
go back to reference Stommel JM, Wahl GM: Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J. 2004, 23: 1547-1556. 10.1038/sj.emboj.7600145.CrossRefPubMedPubMedCentral Stommel JM, Wahl GM: Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J. 2004, 23: 1547-1556. 10.1038/sj.emboj.7600145.CrossRefPubMedPubMedCentral
24.
go back to reference Cui B, Johnson SP, Bullock N, Ali-Osman F, Bigner DD, Friedman HS: Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway. Mol Pharmacol. 2009, 75: 1356-1363. 10.1124/mol.108.053124.CrossRefPubMedPubMedCentral Cui B, Johnson SP, Bullock N, Ali-Osman F, Bigner DD, Friedman HS: Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway. Mol Pharmacol. 2009, 75: 1356-1363. 10.1124/mol.108.053124.CrossRefPubMedPubMedCentral
25.
go back to reference Zhang H, Vakil V, Braunstein M, Smith EL, Maroney J, Chen L, Dai K, Berenson JR, Hussain MM, Klueppelberg U, Norin AJ, Akman HO, Ozcelik T, Batuman OA: Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood. 2005, 105: 3286-3294. 10.1182/blood-2004-06-2101.CrossRefPubMed Zhang H, Vakil V, Braunstein M, Smith EL, Maroney J, Chen L, Dai K, Berenson JR, Hussain MM, Klueppelberg U, Norin AJ, Akman HO, Ozcelik T, Batuman OA: Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood. 2005, 105: 3286-3294. 10.1182/blood-2004-06-2101.CrossRefPubMed
26.
go back to reference Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E, Sanderson R, Yang Y, Wilson C, Zangari M, Anaissie E, Morris C, Muwalla F, van RF, Fassas A, Crowley J, Tricot G, Barlogie B, Shaughnessy J: Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood. 2002, 99: 1745-1757. 10.1182/blood.V99.5.1745.CrossRefPubMed Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E, Sanderson R, Yang Y, Wilson C, Zangari M, Anaissie E, Morris C, Muwalla F, van RF, Fassas A, Crowley J, Tricot G, Barlogie B, Shaughnessy J: Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood. 2002, 99: 1745-1757. 10.1182/blood.V99.5.1745.CrossRefPubMed
27.
go back to reference Yata K, Yaccoby S: The SCID-rab model: a novel in vivo system for primary human myeloma demonstrating growth of CD138-expressing malignant cells. Leukemia. 2004, 18: 1891-1897. 10.1038/sj.leu.2403513.CrossRefPubMed Yata K, Yaccoby S: The SCID-rab model: a novel in vivo system for primary human myeloma demonstrating growth of CD138-expressing malignant cells. Leukemia. 2004, 18: 1891-1897. 10.1038/sj.leu.2403513.CrossRefPubMed
28.
go back to reference Vacca A, Ribatti D: Bone marrow angiogenesis in multiple myeloma. Leukemia. 2006, 20: 193-199. 10.1038/sj.leu.2404067.CrossRefPubMed Vacca A, Ribatti D: Bone marrow angiogenesis in multiple myeloma. Leukemia. 2006, 20: 193-199. 10.1038/sj.leu.2404067.CrossRefPubMed
29.
go back to reference Tanaka T, Manome Y, Wen P, Kufe DW, Fine HA: Viral vector-mediated transduction of a modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth. Nat Med. 1997, 3: 437-442. 10.1038/nm0497-437.CrossRefPubMed Tanaka T, Manome Y, Wen P, Kufe DW, Fine HA: Viral vector-mediated transduction of a modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth. Nat Med. 1997, 3: 437-442. 10.1038/nm0497-437.CrossRefPubMed
30.
go back to reference Yamaguchi K, Ogawa K, Katsube T, Shimao K, Konno S, Shimakawa T, Yoshimatsu K, Naritaka Y, Yagawa H, Hirose K: Platelet factor 4 gene transfection into tumor cells inhibits angiogenesis, tumor growth and metastasis. Anticancer Res. 2005, 25: 847-851.PubMed Yamaguchi K, Ogawa K, Katsube T, Shimao K, Konno S, Shimakawa T, Yoshimatsu K, Naritaka Y, Yagawa H, Hirose K: Platelet factor 4 gene transfection into tumor cells inhibits angiogenesis, tumor growth and metastasis. Anticancer Res. 2005, 25: 847-851.PubMed
31.
go back to reference Benny O, Kim SK, Gvili K, Radzishevsky IS, Mor A, Verduzco L, Menon LG, Black PM, Machluf M, Carroll RS: In vivo fate and therapeutic efficacy of PF-4/CTF microspheres in an orthotopic human glioblastoma model. FASEB J. 2008, 22: 488-499.CrossRefPubMed Benny O, Kim SK, Gvili K, Radzishevsky IS, Mor A, Verduzco L, Menon LG, Black PM, Machluf M, Carroll RS: In vivo fate and therapeutic efficacy of PF-4/CTF microspheres in an orthotopic human glioblastoma model. FASEB J. 2008, 22: 488-499.CrossRefPubMed
Metadata
Title
Platelet factor-4 and its p17-70 peptide inhibit myeloma proliferation and angiogenesis in vivo
Authors
Longjiang Yang
Juan Du
Jian Hou
Hua Jiang
Jianfeng Zou
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-261

Other articles of this Issue 1/2011

BMC Cancer 1/2011 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine