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. 1999 Mar;79(9-10):1392–1398. doi: 10.1038/sj.bjc.6690223

Stimulation of tumour growth by wound-derived growth factors

R Abramovitch 1, M Marikovsky 1,1,#, G Meir 1, M Neeman 1
PMCID: PMC2362730  PMID: 10188881

Abstract

The goal of this work was to determine the molecular basis for the induction of tumour vascularization and progression by injury. Magnetic resonance imaging (MRI) studies demonstrated that administration of wound fluid derived from cutaneous injuries in pigs reduced the lag for vascularization and initiation of growth of C6 glioma spheroids, implanted in nude mice, and accelerated tumour doubling time. The former effect can be attributed to the angiogenic capacity of wound fluid as detected in vivo by MRI, and in vitro in promoting endothelial cell proliferation. The latter effect, namely the induced rate of tumour growth, is consistent with the angiogenic activity of wound fluid as well as with the finding that wound fluid was directly mitogenic to the tumour cells, and accelerated growth of C6 glioma in spheroid culture. Of the multiple growth factors present in wound fluid, two key factors, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and platelet-derived growth factor (PDGF), were identified as the dominant mitogens for C6 glioma, and inhibition of their activity using specific neutralizing antibodies suppressed the mitogenic effect of wound fluid on DNA synthesis in C6 glioma. This study suggests that the stimulatory effect of injury on tumour progression can possibly be attenuated by therapeutic targeting directed against a limited number of specific growth factors. © 1999 Cancer Research Campaign

Keywords: heparin-binding epidermal growth factor, magnetic resonance imaging, C6 glioma spheroid, tumour growth, angiogenesis

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Selected References

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  1. Abramovitch R., Frenkiel D., Neeman M. Analysis of subcutaneous angiogenesis by gradient echo magnetic resonance imaging. Magn Reson Med. 1998 May;39(5):813–824. doi: 10.1002/mrm.1910390519. [DOI] [PubMed] [Google Scholar]
  2. Abramovitch R., Marikovsky M., Meir G., Neeman M. Stimulation of tumour angiogenesis by proximal wounds: spatial and temporal analysis by MRI. Br J Cancer. 1998;77(3):440–447. doi: 10.1038/bjc.1998.70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Abramovitch R., Meir G., Neeman M. Neovascularization induced growth of implanted C6 glioma multicellular spheroids: magnetic resonance microimaging. Cancer Res. 1995 May 1;55(9):1956–1962. [PubMed] [Google Scholar]
  4. Abramovitch R., Neeman M., Reich R., Stein I., Keshet E., Abraham J., Solomon A., Marikovsky M. Intercellular communication between vascular smooth muscle and endothelial cells mediated by heparin-binding epidermal growth factor-like growth factor and vascular endothelial growth factor. FEBS Lett. 1998 Apr 3;425(3):441–447. doi: 10.1016/s0014-5793(98)00283-x. [DOI] [PubMed] [Google Scholar]
  5. Bogden A. E., Moreau J. P., Eden P. A. Proliferative response of human and animal tumours to surgical wounding of normal tissues: onset, duration and inhibition. Br J Cancer. 1997;75(7):1021–1027. doi: 10.1038/bjc.1997.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Deelman H. T. THE PART PLAYED BY INJURY AND REPAIR IN THE DEVELOPMENT OF CANCER. Br Med J. 1927 May 14;1(3462):872–872. doi: 10.1136/bmj.1.3462.872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Frank S., Hübner G., Breier G., Longaker M. T., Greenhalgh D. G., Werner S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem. 1995 May 26;270(21):12607–12613. doi: 10.1074/jbc.270.21.12607. [DOI] [PubMed] [Google Scholar]
  9. Higashiyama S., Abraham J. A., Miller J., Fiddes J. C., Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991 Feb 22;251(4996):936–939. doi: 10.1126/science.1840698. [DOI] [PubMed] [Google Scholar]
  10. Libermann T. A., Nusbaum H. R., Razon N., Kris R., Lax I., Soreq H., Whittle N., Waterfield M. D., Ullrich A., Schlessinger J. Amplification and overexpression of the EGF receptor gene in primary human glioblastomas. J Cell Sci Suppl. 1985;3:161–172. doi: 10.1242/jcs.1985.supplement_3.16. [DOI] [PubMed] [Google Scholar]
  11. Lynch S. E. Interactions of growth factors in tissue repair. Prog Clin Biol Res. 1991;365:341–357. [PubMed] [Google Scholar]
  12. Marikovsky M., Breuing K., Liu P. Y., Eriksson E., Higashiyama S., Farber P., Abraham J., Klagsbrun M. Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3889–3893. doi: 10.1073/pnas.90.9.3889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Marikovsky M., Vogt P., Eriksson E., Rubin J. S., Taylor W. G., Joachim S., Klagsbrun M. Wound fluid-derived heparin-binding EGF-like growth factor (HB-EGF) is synergistic with insulin-like growth factor-I for Balb/MK keratinocyte proliferation. J Invest Dermatol. 1996 Apr;106(4):616–621. doi: 10.1111/1523-1747.ep12345413. [DOI] [PubMed] [Google Scholar]
  14. Moulin V. Growth factors in skin wound healing. Eur J Cell Biol. 1995 Sep;68(1):1–7. [PubMed] [Google Scholar]
  15. Murthy M. S., Summaria L. J., Miller R. J., Wyse T. B., Goldschmidt R. A., Scanlon E. F. Inhibition of tumor implantation at sites of trauma by plasminogen activators. Cancer. 1991 Oct 15;68(8):1724–1730. doi: 10.1002/1097-0142(19911015)68:8<1724::aid-cncr2820680813>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  16. Murthy S. M., Goldschmidt R. A., Rao L. N., Ammirati M., Buchmann T., Scanlon E. F. The influence of surgical trauma on experimental metastasis. Cancer. 1989 Nov 15;64(10):2035–2044. doi: 10.1002/1097-0142(19891115)64:10<2035::aid-cncr2820641012>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  17. O'Reilly M. S., Holmgren L., Chen C., Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med. 1996 Jun;2(6):689–692. doi: 10.1038/nm0696-689. [DOI] [PubMed] [Google Scholar]
  18. O'Reilly M. S., Holmgren L., Shing Y., Chen C., Rosenthal R. A., Moses M., Lane W. S., Cao Y., Sage E. H., Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315–328. doi: 10.1016/0092-8674(94)90200-3. [DOI] [PubMed] [Google Scholar]
  19. Pedersen P. H., Ness G. O., Engebraaten O., Bjerkvig R., Lillehaug J. R., Laerum O. D. Heterogeneous response to the growth factors [EGF, PDGF (bb), TGF-alpha, bFGF, IL-2] on glioma spheroid growth, migration and invasion. Int J Cancer. 1994 Jan 15;56(2):255–261. doi: 10.1002/ijc.2910560219. [DOI] [PubMed] [Google Scholar]
  20. Peoples G. E., Blotnick S., Takahashi K., Freeman M. R., Klagsbrun M., Eberlein T. J. T lymphocytes that infiltrate tumors and atherosclerotic plaques produce heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor: a potential pathologic role. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6547–6551. doi: 10.1073/pnas.92.14.6547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pollack I. F., Randall M. S., Kristofik M. P., Kelly R. H., Selker R. G., Vertosick F. T., Jr Response of low-passage human malignant gliomas in vitro to stimulation and selective inhibition of growth factor-mediated pathways. J Neurosurg. 1991 Aug;75(2):284–293. doi: 10.3171/jns.1991.75.2.0284. [DOI] [PubMed] [Google Scholar]
  22. Schiffenbauer Y. S., Abramovitch R., Meir G., Nevo N., Holzinger M., Itin A., Keshet E., Neeman M. Loss of ovarian function promotes angiogenesis in human ovarian carcinoma. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13203–13208. doi: 10.1073/pnas.94.24.13203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Strawn L. M., Mann E., Elliger S. S., Chu L. M., Germain L. L., Niederfellner G., Ullrich A., Shawver L. K. Inhibition of glioma cell growth by a truncated platelet-derived growth factor-beta receptor. J Biol Chem. 1994 Aug 19;269(33):21215–21222. [PubMed] [Google Scholar]
  24. Tsai J. C., Goldman C. K., Gillespie G. Y. Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. J Neurosurg. 1995 May;82(5):864–873. doi: 10.3171/jns.1995.82.5.0864. [DOI] [PubMed] [Google Scholar]

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