Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998 Mar;77(6):956–964. doi: 10.1038/bjc.1998.158

Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology.

R E Banks 1, M A Forbes 1, S E Kinsey 1, A Stanley 1, E Ingham 1, C Walters 1, P J Selby 1
PMCID: PMC2150108  PMID: 9528841

Abstract

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor with a key role in several pathological processes, including tumour vascularization. Our preliminary observations indicated higher VEGF concentrations in serum samples than in matched plasma samples. We have now demonstrated that this difference is due to the presence of VEGF within platelets and its release upon their activation during coagulation. In eight healthy volunteers, serum VEGF concentrations ranged from 76 to 854 pg ml(-1) and were significantly higher (P < 0.01) than the matched citrated plasma VEGF concentrations, which ranged from < 9 to 42 pg ml(-1). Using platelet-rich plasma, mean (s.d.) platelet VEGF contents of 0.56 (0.36) pg of VEGF 10(-6) platelets were found. Immunocytochemistry demonstrated the cytoplasmic presence of VEGF within megakaryocytes and other cell types within the bone marrow. From examination of the effects of blood sample processing on circulating VEGF concentrations, it is apparent that for accurate measurements, citrated plasma processed within 1 h of venepuncture should be used. Serum is completely unsuitable. The presence of VEGF within platelets has implications for processes involving platelet and endothelial cell interactions. e.g. wound healing, and in tumour metastasis, when platelets adhering to circulating tumour cells may release VEGF at points of adhesion to endothelium, leading to hyperpermeability and extravasation of cells.

Full text

PDF
956

Images in this article

959Figure 4
on p.959
959Figure 3
on p.959

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abu-Jawdeh G. M., Faix J. D., Niloff J., Tognazzi K., Manseau E., Dvorak H. F., Brown L. F. Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. Lab Invest. 1996 Jun;74(6):1105–1115. [PubMed] [Google Scholar]
  2. Anan K., Morisaki T., Katano M., Ikubo A., Kitsuki H., Uchiyama A., Kuroki S., Tanaka M., Torisu M. Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer. Surgery. 1996 Mar;119(3):333–339. doi: 10.1016/s0039-6060(96)80120-6. [DOI] [PubMed] [Google Scholar]
  3. Asano M., Yukita A., Matsumoto T., Kondo S., Suzuki H. Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor121. Cancer Res. 1995 Nov 15;55(22):5296–5301. [PubMed] [Google Scholar]
  4. Aye M. T., Palmer D. S., Giulivi A., Hashemi S. Effect of filtration of platelet concentrates on the accumulation of cytokines and platelet release factors during storage. Transfusion. 1995 Feb;35(2):117–124. doi: 10.1046/j.1537-2995.1995.35295125733.x. [DOI] [PubMed] [Google Scholar]
  5. Baker P. N., Krasnow J., Roberts J. M., Yeo K. T. Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol. 1995 Nov;86(5):815–821. doi: 10.1016/0029-7844(95)00259-T. [DOI] [PubMed] [Google Scholar]
  6. Barleon B., Sozzani S., Zhou D., Weich H. A., Mantovani A., Marmé D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood. 1996 Apr 15;87(8):3336–3343. [PubMed] [Google Scholar]
  7. Blood C. H., Zetter B. R. Tumor interactions with the vasculature: angiogenesis and tumor metastasis. Biochim Biophys Acta. 1990 Jun 1;1032(1):89–118. doi: 10.1016/0304-419x(90)90014-r. [DOI] [PubMed] [Google Scholar]
  8. Boocock C. A., Charnock-Jones D. S., Sharkey A. M., McLaren J., Barker P. J., Wright K. A., Twentyman P. R., Smith S. K. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst. 1995 Apr 5;87(7):506–516. doi: 10.1093/jnci/87.7.506. [DOI] [PubMed] [Google Scholar]
  9. Brown L. F., Berse B., Jackman R. W., Tognazzi K., Guidi A. J., Dvorak H. F., Senger D. R., Connolly J. L., Schnitt S. J. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol. 1995 Jan;26(1):86–91. doi: 10.1016/0046-8177(95)90119-1. [DOI] [PubMed] [Google Scholar]
  10. Brown L. F., Berse B., Jackman R. W., Tognazzi K., Manseau E. J., Dvorak H. F., Senger D. R. Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol. 1993 Nov;143(5):1255–1262. [PMC free article] [PubMed] [Google Scholar]
  11. Broxmeyer H. E., Cooper S., Li Z. H., Lu L., Song H. Y., Kwon B. S., Warren R. E., Donner D. B. Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor. Int J Hematol. 1995 Dec;62(4):203–215. doi: 10.1016/0925-5710(95)00412-2. [DOI] [PubMed] [Google Scholar]
  12. Carmeliet P., Ferreira V., Breier G., Pollefeyt S., Kieckens L., Gertsenstein M., Fahrig M., Vandenhoeck A., Harpal K., Eberhardt C. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996 Apr 4;380(6573):435–439. doi: 10.1038/380435a0. [DOI] [PubMed] [Google Scholar]
  13. Claffey K. P., Brown L. F., del Aguila L. F., Tognazzi K., Yeo K. T., Manseau E. J., Dvorak H. F. Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res. 1996 Jan 1;56(1):172–181. [PubMed] [Google Scholar]
  14. Dirix L. Y., Vermeulen P. B., Pawinski A., Prové A., Benoy I., De Pooter C., Martin M., Van Oosterom A. T. Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. Br J Cancer. 1997;76(2):238–243. doi: 10.1038/bjc.1997.368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dvorak H. F., Brown L. F., Detmar M., Dvorak A. M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995 May;146(5):1029–1039. [PMC free article] [PubMed] [Google Scholar]
  16. Díaz-Flores L., Gutiérrez R., Varela H. Angiogenesis: an update. Histol Histopathol. 1994 Oct;9(4):807–843. [PubMed] [Google Scholar]
  17. Ferrara N., Carver-Moore K., Chen H., Dowd M., Lu L., O'Shea K. S., Powell-Braxton L., Hillan K. J., Moore M. W. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996 Apr 4;380(6573):439–442. doi: 10.1038/380439a0. [DOI] [PubMed] [Google Scholar]
  18. Ferrara N., Heinsohn H., Walder C. E., Bunting S., Thomas G. R. The regulation of blood vessel growth by vascular endothelial growth factor. Ann N Y Acad Sci. 1995 Mar 27;752:246–256. doi: 10.1111/j.1749-6632.1995.tb17435.x. [DOI] [PubMed] [Google Scholar]
  19. Ferrari G., Scagliotti G. V. Serum and urinary vascular endothelial growth factor levels in non-small cell lung cancer patients. Eur J Cancer. 1996 Dec;32A(13):2368–2369. doi: 10.1016/s0959-8049(96)00272-9. [DOI] [PubMed] [Google Scholar]
  20. Flegel W. A., Wiesneth M., Stampe D., Koerner K. Low cytokine contamination in buffy coat-derived platelet concentrates without filtration. Transfusion. 1995 Nov-Dec;35(11):917–920. doi: 10.1046/j.1537-2995.1995.351196110895.x. [DOI] [PubMed] [Google Scholar]
  21. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med. 1995 Dec 28;333(26):1757–1763. doi: 10.1056/NEJM199512283332608. [DOI] [PubMed] [Google Scholar]
  22. Folkman J., Shing Y. Angiogenesis. J Biol Chem. 1992 Jun 5;267(16):10931–10934. [PubMed] [Google Scholar]
  23. Freeman M. R., Schneck F. X., Gagnon M. L., Corless C., Soker S., Niknejad K., Peoples G. E., Klagsbrun M. Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. Cancer Res. 1995 Sep 15;55(18):4140–4145. [PubMed] [Google Scholar]
  24. Grimmond S., Lagercrantz J., Drinkwater C., Silins G., Townson S., Pollock P., Gotley D., Carson E., Rakar S., Nordenskjöld M. Cloning and characterization of a novel human gene related to vascular endothelial growth factor. Genome Res. 1996 Feb;6(2):124–131. doi: 10.1101/gr.6.2.124. [DOI] [PubMed] [Google Scholar]
  25. Guidi A. J., Fischer L., Harris J. R., Schnitt S. J. Microvessel density and distribution in ductal carcinoma in situ of the breast. J Natl Cancer Inst. 1994 Apr 20;86(8):614–619. doi: 10.1093/jnci/86.8.614. [DOI] [PubMed] [Google Scholar]
  26. Hanatani M., Tanaka Y., Kondo S., Ohmori I., Suzuki H. Sensitive chemiluminescence enzyme immunoassay for vascular endothelial growth factor/vascular permeability factor in human serum. Biosci Biotechnol Biochem. 1995 Oct;59(10):1958–1959. doi: 10.1271/bbb.59.1958. [DOI] [PubMed] [Google Scholar]
  27. Harrison P., Cramer E. M. Platelet alpha-granules. Blood Rev. 1993 Mar;7(1):52–62. doi: 10.1016/0268-960x(93)90024-x. [DOI] [PubMed] [Google Scholar]
  28. Hauser S., Weich H. A. A heparin-binding form of placenta growth factor (PlGF-2) is expressed in human umbilical vein endothelial cells and in placenta. Growth Factors. 1993;9(4):259–268. doi: 10.3109/08977199308991586. [DOI] [PubMed] [Google Scholar]
  29. Hawrylowicz C. M., Santoro S. A., Platt F. M., Unanue E. R. Activated platelets express IL-1 activity. J Immunol. 1989 Dec 15;143(12):4015–4018. [PubMed] [Google Scholar]
  30. Houck K. A., Ferrara N., Winer J., Cachianes G., Li B., Leung D. W. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991 Dec;5(12):1806–1814. doi: 10.1210/mend-5-12-1806. [DOI] [PubMed] [Google Scholar]
  31. Houck K. A., Leung D. W., Rowland A. M., Winer J., Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem. 1992 Dec 25;267(36):26031–26037. [PubMed] [Google Scholar]
  32. Jiang X., Kanai H., Hiromura K., Sawamura M., Yano S. Increased intraplatelet and urinary transforming growth factor-beta in patients with multiple myeloma. Acta Haematol. 1995;94(1):1–6. doi: 10.1159/000203962. [DOI] [PubMed] [Google Scholar]
  33. Joukov V., Pajusola K., Kaipainen A., Chilov D., Lahtinen I., Kukk E., Saksela O., Kalkkinen N., Alitalo K. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 1996 Jan 15;15(2):290–298. [PMC free article] [PubMed] [Google Scholar]
  34. Katoh O., Tauchi H., Kawaishi K., Kimura A., Satow Y. Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res. 1995 Dec 1;55(23):5687–5692. [PubMed] [Google Scholar]
  35. Kendall R. L., Thomas K. A. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10705–10709. doi: 10.1073/pnas.90.22.10705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Klüter H., Müller-Steinhardt M., Danzer S., Wilhelm D., Kirchner H. Cytokines in platelet concentrates prepared from pooled buffy coats. Vox Sang. 1995;69(1):38–43. doi: 10.1111/j.1423-0410.1995.tb00345.x. [DOI] [PubMed] [Google Scholar]
  37. Kondo S., Asano M., Matsuo K., Ohmori I., Suzuki H. Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochim Biophys Acta. 1994 Mar 31;1221(2):211–214. doi: 10.1016/0167-4889(94)90016-7. [DOI] [PubMed] [Google Scholar]
  38. Lyall F., Greer I. A., Boswell F., Fleming R. Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia. Br J Obstet Gynaecol. 1997 Feb;104(2):223–228. doi: 10.1111/j.1471-0528.1997.tb11050.x. [DOI] [PubMed] [Google Scholar]
  39. Maeda K., Chung Y. S., Ogawa Y., Takatsuka S., Kang S. M., Ogawa M., Sawada T., Sowa M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 1996 Mar 1;77(5):858–863. doi: 10.1002/(sici)1097-0142(19960301)77:5<858::aid-cncr8>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  40. Maglione D., Guerriero V., Viglietto G., Delli-Bovi P., Persico M. G. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9267–9271. doi: 10.1073/pnas.88.20.9267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Maglione D., Guerriero V., Viglietto G., Ferraro M. G., Aprelikova O., Alitalo K., Del Vecchio S., Lei K. J., Chou J. Y., Persico M. G. Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene. 1993 Apr;8(4):925–931. [PubMed] [Google Scholar]
  42. Mattern J., Koomägi R., Volm M. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumour cell proliferation in human epidermoid lung carcinoma. Br J Cancer. 1996 Apr;73(7):931–934. doi: 10.1038/bjc.1996.166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Matthews W., Jordan C. T., Gavin M., Jenkins N. A., Copeland N. G., Lemischka I. R. A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9026–9030. doi: 10.1073/pnas.88.20.9026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Millauer B., Wizigmann-Voos S., Schnürch H., Martinez R., Møller N. P., Risau W., Ullrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993 Mar 26;72(6):835–846. doi: 10.1016/0092-8674(93)90573-9. [DOI] [PubMed] [Google Scholar]
  45. Muylle L., Joos M., Wouters E., De Bock R., Peetermans M. E. Increased tumor necrosis factor alpha (TNF alpha), interleukin 1, and interleukin 6 (IL-6) levels in the plasma of stored platelet concentrates: relationship between TNF alpha and IL-6 levels and febrile transfusion reactions. Transfusion. 1993 Mar;33(3):195–199. doi: 10.1046/j.1537-2995.1993.33393174443.x. [DOI] [PubMed] [Google Scholar]
  46. Muylle L., Peetermans M. E. Effect of prestorage leukocyte removal on the cytokine levels in stored platelet concentrates. Vox Sang. 1994;66(1):14–17. doi: 10.1111/j.1423-0410.1994.tb00270.x. [DOI] [PubMed] [Google Scholar]
  47. O'Brien T., Cranston D., Fuggle S., Bicknell R., Harris A. L. Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res. 1995 Feb 1;55(3):510–513. [PubMed] [Google Scholar]
  48. Oksanen K., Ebeling F., Kekomäki R., Elonen E., Sahlstedt L., Volin L., Myllylä G. Adverse reactions to platelet transfusions are reduced by use of platelet concentrates derived from buffy coat. Vox Sang. 1994;67(4):356–361. doi: 10.1111/j.1423-0410.1994.tb01273.x. [DOI] [PubMed] [Google Scholar]
  49. Olofsson B., Pajusola K., Kaipainen A., von Euler G., Joukov V., Saksela O., Orpana A., Pettersson R. F., Alitalo K., Eriksson U. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2576–2581. doi: 10.1073/pnas.93.6.2576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Paavonen K., Horelli-Kuitunen N., Chilov D., Kukk E., Pennanen S., Kallioniemi O. P., Pajusola K., Olofsson B., Eriksson U., Joukov V. Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively. Circulation. 1996 Mar 15;93(6):1079–1082. doi: 10.1161/01.cir.93.6.1079. [DOI] [PubMed] [Google Scholar]
  51. Saleh M., Stacker S. A., Wilks A. F. Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res. 1996 Jan 15;56(2):393–401. [PubMed] [Google Scholar]
  52. Sato K., Terada K., Sugiyama T., Takahashi S., Saito M., Moriyama M., Kakinuma H., Suzuki Y., Kato M., Kato T. Frequent overexpression of vascular endothelial growth factor gene in human renal cell carcinoma. Tohoku J Exp Med. 1994 Jul;173(3):355–360. doi: 10.1620/tjem.173.355. [DOI] [PubMed] [Google Scholar]
  53. Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
  54. Senger D. R., Perruzzi C. A., Feder J., Dvorak H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986 Nov;46(11):5629–5632. [PubMed] [Google Scholar]
  55. Shibuya M., Yamaguchi S., Yamane A., Ikeda T., Tojo A., Matsushime H., Sato M. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene. 1990 Apr;5(4):519–524. [PubMed] [Google Scholar]
  56. Soker S., Svahn C. M., Neufeld G. Vascular endothelial growth factor is inactivated by binding to alpha 2-macroglobulin and the binding is inhibited by heparin. J Biol Chem. 1993 Apr 15;268(11):7685–7691. [PubMed] [Google Scholar]
  57. Stack G., Snyder E. L. Cytokine generation in stored platelet concentrates. Transfusion. 1994 Jan;34(1):20–25. doi: 10.1046/j.1537-2995.1994.34194098597.x. [DOI] [PubMed] [Google Scholar]
  58. Takahashi A., Sasaki H., Kim S. J., Tobisu K., Kakizoe T., Tsukamoto T., Kumamoto Y., Sugimura T., Terada M. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994 Aug 1;54(15):4233–4237. [PubMed] [Google Scholar]
  59. Takahashi Y., Kitadai Y., Bucana C. D., Cleary K. R., Ellis L. M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995 Sep 15;55(18):3964–3968. [PubMed] [Google Scholar]
  60. Takano S., Yoshii Y., Kondo S., Suzuki H., Maruno T., Shirai S., Nose T. Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res. 1996 May 1;56(9):2185–2190. [PubMed] [Google Scholar]
  61. Terman B. I., Carrion M. E., Kovacs E., Rasmussen B. A., Eddy R. L., Shows T. B. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene. 1991 Sep;6(9):1677–1683. [PubMed] [Google Scholar]
  62. Thomas K. A. Vascular endothelial growth factor, a potent and selective angiogenic agent. J Biol Chem. 1996 Jan 12;271(2):603–606. doi: 10.1074/jbc.271.2.603. [DOI] [PubMed] [Google Scholar]
  63. Tischer E., Mitchell R., Hartman T., Silva M., Gospodarowicz D., Fiddes J. C., Abraham J. A. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947–11954. [PubMed] [Google Scholar]
  64. Toi M., Hoshina S., Takayanagi T., Tominaga T. Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer. Jpn J Cancer Res. 1994 Oct;85(10):1045–1049. doi: 10.1111/j.1349-7006.1994.tb02904.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Toi M., Kashitani J., Tominaga T. Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int J Cancer. 1993 Sep 30;55(3):371–374. doi: 10.1002/ijc.2910550305. [DOI] [PubMed] [Google Scholar]
  66. Warren R. S., Yuan H., Matli M. R., Gillett N. A., Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest. 1995 Apr;95(4):1789–1797. doi: 10.1172/JCI117857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Watanabe O., Arimura K., Kitajima I., Osame M., Maruyama I. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome. Lancet. 1996 Mar 9;347(9002):702–702. doi: 10.1016/s0140-6736(96)91261-1. [DOI] [PubMed] [Google Scholar]
  68. de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES