Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998;77(1):51–56. doi: 10.1038/bjc.1998.8

Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis.

K G Peters 1, A Coogan 1, D Berry 1, J Marks 1, J D Iglehart 1, C D Kontos 1, P Rao 1, S Sankar 1, E Trogan 1
PMCID: PMC2151265  PMID: 9459145

Abstract

Endothelial receptor tyrosine kinases may play important roles in pathological vascular growth, particularly in tumours. In this study, immunohistochemistry was used to evaluate the expression of a novel endothelial receptor tyrosine kinase, Tie2/Tek, in the endothelium of vascular 'hotspots' in normal breast tissue (n = 10), benign breast lesions (n = 10) and in breast tumours (n = 123). Tie2 expression was detected in the endothelium of all breast tissues examined. However, the strongest expression of Tie-2 was seen in vascular 'hot spots' within the inflammatory infiltrate at the periphery of invasive tumours. Moreover, the proportion of Tie2-positive vessels (Tie2 counts/CD31 counts) was significantly higher in breast tumours than the proportion of Tie2-positive vessels in either normal breast tissue or benign breast lesions (P = 0.004 and 0.0001 respectively). These data are consistent with a role for Tie2 in tumour angiogenesis and demonstrate the potential use of Tie2 expression as a novel marker of the tumour vasculature.

Full text

PDF
56

Images in this article

52Figure 1
on p.52
52Figure 2
on p.52

Selected References

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

  1. Axelsson K., Ljung B. M., Moore D. H., 2nd, Thor A. D., Chew K. L., Edgerton S. M., Smith H. S., Mayall B. H. Tumor angiogenesis as a prognostic assay for invasive ductal breast carcinoma. J Natl Cancer Inst. 1995 Jul 5;87(13):997–1008. doi: 10.1093/jnci/87.13.997. [DOI] [PubMed] [Google Scholar]
  2. Borgström P., Hillan K. J., Sriramarao P., Ferrara N. Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res. 1996 Sep 1;56(17):4032–4039. [PubMed] [Google Scholar]
  3. Bosari S., Lee A. K., DeLellis R. A., Wiley B. D., Heatley G. J., Silverman M. L. Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Pathol. 1992 Jul;23(7):755–761. doi: 10.1016/0046-8177(92)90344-3. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Craft P. S., Harris A. L. Clinical prognostic significance of tumour angiogenesis. Ann Oncol. 1994 Apr;5(4):305–311. doi: 10.1093/oxfordjournals.annonc.a058829. [DOI] [PubMed] [Google Scholar]
  6. Dumont D. J., Gradwohl G. J., Fong G. H., Auerbach R., Breitman M. L. The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors. Oncogene. 1993 May;8(5):1293–1301. [PubMed] [Google Scholar]
  7. Dumont D. J., Gradwohl G., Fong G. H., Puri M. C., Gertsenstein M., Auerbach A., Breitman M. L. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 1994 Aug 15;8(16):1897–1909. doi: 10.1101/gad.8.16.1897. [DOI] [PubMed] [Google Scholar]
  8. Dvorak H. F., Sioussat T. M., Brown L. F., Berse B., Nagy J. A., Sotrel A., Manseau E. J., Van de Water L., Senger D. R. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med. 1991 Nov 1;174(5):1275–1278. doi: 10.1084/jem.174.5.1275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Easty D. J., Herlyn M., Bennett D. C. Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. Int J Cancer. 1995 Jan 3;60(1):129–136. doi: 10.1002/ijc.2910600119. [DOI] [PubMed] [Google Scholar]
  10. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995 Jan;1(1):27–31. doi: 10.1038/nm0195-27. [DOI] [PubMed] [Google Scholar]
  11. Folkman J., D'Amore P. A. Blood vessel formation: what is its molecular basis? Cell. 1996 Dec 27;87(7):1153–1155. doi: 10.1016/s0092-8674(00)81810-3. [DOI] [PubMed] [Google Scholar]
  12. Fox S. B., Gatter K. C., Bicknell R., Going J. J., Stanton P., Cooke T. G., Harris A. L. Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res. 1993 Sep 15;53(18):4161–4163. [PubMed] [Google Scholar]
  13. Fox S. B., Leek R. D., Smith K., Hollyer J., Greenall M., Harris A. L. Tumor angiogenesis in node-negative breast carcinomas--relationship with epidermal growth factor receptor, estrogen receptor, and survival. Breast Cancer Res Treat. 1994 Jan;29(1):109–116. doi: 10.1007/BF00666186. [DOI] [PubMed] [Google Scholar]
  14. Gasparini G., Weidner N., Bevilacqua P., Maluta S., Dalla Palma P., Caffo O., Barbareschi M., Boracchi P., Marubini E., Pozza F. Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol. 1994 Mar;12(3):454–466. doi: 10.1200/JCO.1994.12.3.454. [DOI] [PubMed] [Google Scholar]
  15. Goulding H., Abdul Rashid N. F., Robertson J. F., Bell J. A., Elston C. W., Blamey R. W., Ellis I. O. Assessment of angiogenesis in breast carcinoma: an important factor in prognosis? Hum Pathol. 1995 Nov;26(11):1196–1200. doi: 10.1016/0046-8177(95)90193-0. [DOI] [PubMed] [Google Scholar]
  16. Hatva E., Kaipainen A., Mentula P., Jäskeläinen J., Paetau A., Haltia M., Alitalo K. Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am J Pathol. 1995 Feb;146(2):368–378. [PMC free article] [PubMed] [Google Scholar]
  17. Hayes D. F. Angiogenesis and breast cancer. Hematol Oncol Clin North Am. 1994 Feb;8(1):51–71. [PubMed] [Google Scholar]
  18. Heimann R., Ferguson D., Powers C., Recant W. M., Weichselbaum R. R., Hellman S. Angiogenesis as a predictor of long-term survival for patients with node-negative breast cancer. J Natl Cancer Inst. 1996 Dec 4;88(23):1764–1769. doi: 10.1093/jnci/88.23.1764. [DOI] [PubMed] [Google Scholar]
  19. Horak E. R., Leek R., Klenk N., LeJeune S., Smith K., Stuart N., Greenall M., Stepniewska K., Harris A. L. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet. 1992 Nov 7;340(8828):1120–1124. doi: 10.1016/0140-6736(92)93150-l. [DOI] [PubMed] [Google Scholar]
  20. Kaipainen A., Vlaykova T., Hatva E., Böhling T., Jekunen A., Pyrhönen S., Alitalo K. Enhanced expression of the tie receptor tyrosine kinase mesenger RNA in the vascular endothelium of metastatic melanomas. Cancer Res. 1994 Dec 15;54(24):6571–6577. [PubMed] [Google Scholar]
  21. Kim K. J., Li B., Winer J., Armanini M., Gillett N., Phillips H. S., Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841–844. doi: 10.1038/362841a0. [DOI] [PubMed] [Google Scholar]
  22. Korhonen J., Partanen J., Armstrong E., Vaahtokari A., Elenius K., Jalkanen M., Alitalo K. Enhanced expression of the tie receptor tyrosine kinase in endothelial cells during neovascularization. Blood. 1992 Nov 15;80(10):2548–2555. [PubMed] [Google Scholar]
  23. Maisonpierre P. C., Goldfarb M., Yancopoulos G. D., Gao G. Distinct rat genes with related profiles of expression define a TIE receptor tyrosine kinase family. Oncogene. 1993 Jun;8(6):1631–1637. [PubMed] [Google Scholar]
  24. Millauer B., Longhi M. P., Plate K. H., Shawver L. K., Risau W., Ullrich A., Strawn L. M. Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res. 1996 Apr 1;56(7):1615–1620. [PubMed] [Google Scholar]
  25. Millauer B., Shawver L. K., Plate K. H., Risau W., Ullrich A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature. 1994 Feb 10;367(6463):576–579. doi: 10.1038/367576a0. [DOI] [PubMed] [Google Scholar]
  26. Mustonen T., Alitalo K. Endothelial receptor tyrosine kinases involved in angiogenesis. J Cell Biol. 1995 May;129(4):895–898. doi: 10.1083/jcb.129.4.895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Partanen J., Armstrong E., Mäkelä T. P., Korhonen J., Sandberg M., Renkonen R., Knuutila S., Huebner K., Alitalo K. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol. 1992 Apr;12(4):1698–1707. doi: 10.1128/mcb.12.4.1698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Plate K. H., Breier G., Weich H. A., Mennel H. D., Risau W. Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer. 1994 Nov 15;59(4):520–529. doi: 10.1002/ijc.2910590415. [DOI] [PubMed] [Google Scholar]
  29. Puri M. C., Rossant J., Alitalo K., Bernstein A., Partanen J. The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J. 1995 Dec 1;14(23):5884–5891. doi: 10.1002/j.1460-2075.1995.tb00276.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rak J. W., St Croix B. D., Kerbel R. S. Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. Anticancer Drugs. 1995 Feb;6(1):3–18. doi: 10.1097/00001813-199502000-00001. [DOI] [PubMed] [Google Scholar]
  31. Salvén P., Joensuu H., Heikkilä P., Matikainen M. T., Wasenius V. M., Alanko A., Alitalo K. Endothelial Tie growth factor receptor provides antigenic marker for assessment of breast cancer angiogenesis. Br J Cancer. 1996 Jul;74(1):69–72. doi: 10.1038/bjc.1996.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sato T. N., Qin Y., Kozak C. A., Audus K. L. Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9355–9358. doi: 10.1073/pnas.90.20.9355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sato T. N., Tozawa Y., Deutsch U., Wolburg-Buchholz K., Fujiwara Y., Gendron-Maguire M., Gridley T., Wolburg H., Risau W., Qin Y. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. 1995 Jul 6;376(6535):70–74. doi: 10.1038/376070a0. [DOI] [PubMed] [Google Scholar]
  34. Senger D. R., Brown L. F., Claffey K. P., Dvorak H. F. Vascular permeability factor, tumor angiogenesis and stroma generation. Invasion Metastasis. 1994;14(1-6):385–394. [PubMed] [Google Scholar]
  35. Siitonen S. M., Haapasalo H. K., Rantala I. S., Helin H. J., Isola J. J. Comparison of different immunohistochemical methods in the assessment of angiogenesis: lack of prognostic value in a group of 77 selected node-negative breast carcinomas. Mod Pathol. 1995 Sep;8(7):745–752. [PubMed] [Google Scholar]
  36. Suri C., Jones P. F., Patan S., Bartunkova S., Maisonpierre P. C., Davis S., Sato T. N., Yancopoulos G. D. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996 Dec 27;87(7):1171–1180. doi: 10.1016/s0092-8674(00)81813-9. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. 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]
  39. Van Hoef M. E., Knox W. F., Dhesi S. S., Howell A., Schor A. M. Assessment of tumour vascularity as a prognostic factor in lymph node negative invasive breast cancer. Eur J Cancer. 1993;29A(8):1141–1145. doi: 10.1016/s0959-8049(05)80304-1. [DOI] [PubMed] [Google Scholar]
  40. Vikkula M., Boon L. M., Carraway K. L., 3rd, Calvert J. T., Diamonti A. J., Goumnerov B., Pasyk K. A., Marchuk D. A., Warman M. L., Cantley L. C. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996 Dec 27;87(7):1181–1190. doi: 10.1016/s0092-8674(00)81814-0. [DOI] [PubMed] [Google Scholar]
  41. Weidner N., Folkman J., Pozza F., Bevilacqua P., Allred E. N., Moore D. H., Meli S., Gasparini G. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst. 1992 Dec 16;84(24):1875–1887. doi: 10.1093/jnci/84.24.1875. [DOI] [PubMed] [Google Scholar]
  42. Ziegler S. F., Bird T. A., Schneringer J. A., Schooley K. A., Baum P. R. Molecular cloning and characterization of a novel receptor protein tyrosine kinase from human placenta. Oncogene. 1993 Mar;8(3):663–670. [PubMed] [Google Scholar]

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

RESOURCES