Advertisement

Journal of Molecular Medicine

, Volume 86, Issue 7, pp 785–789 | Cite as

R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways

  • Yihai Cao
  • Renhai Cao
  • Eva-Maria Hedlund
Review

Abstract

In a fast-growing malignant tissue, tumor blood vessels are exposed to multiple growth factors and cytokines. Although the role of individual factors and their signaling pathways in regulation of tumor neovascularization is relatively well-studied, little is known about complex interactions between these factors and their cooperative effects in promoting tumor angiogenesis and metastasis. Our recent studies show that quiescent vascular endothelial cells usually remaining silence to platelet-derived growth factor (PDGF)-BB stimulation acquire their hyperresponsiveness after stimulation with fibroblast growth factor (FGF)-2, which transcriptionally switches on PDGF receptor expression in the activated endothelial cells. Interestingly, PDGF-BB also transduces positive feedback signals to the FGF-2 signaling system by amplifying its receptor expression in vascular mural cells. These uncoordinated reciprocal interactions in the tumor environment lead to the formation of disorganized and primitive vasculatures that facilitate tumor growth and metastasis in mice. These findings provide an example of complex interaction between tumor angiogenic factors. Thus, therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops.

Keywords

Angiogenesis Cancer Metastasis Growth factor Inhibitor 

References

  1. 1.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedGoogle Scholar
  2. 2.
    Cao Y (2005) Opinion: emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis. Nat Rev Cancer 5:735–743PubMedCrossRefGoogle Scholar
  3. 3.
    Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257PubMedCrossRefGoogle Scholar
  4. 4.
    Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974PubMedCrossRefGoogle Scholar
  5. 5.
    Balkwill F, Coussens LM (2004) Cancer: an inflammatory link. Nature 431:405–406PubMedCrossRefGoogle Scholar
  6. 6.
    Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103:481–490PubMedCrossRefGoogle Scholar
  7. 7.
    Zhou Z, Apte SS, Soininen R, Cao R, Baaklini GY, Rauser RW, Wang J, Cao Y, Tryggvason K (2000) Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc Natl Acad Sci U S A 97:4052–4057PubMedCrossRefGoogle Scholar
  8. 8.
    Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744PubMedCrossRefGoogle Scholar
  9. 9.
    Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1:46–54PubMedCrossRefGoogle Scholar
  10. 10.
    Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849PubMedCrossRefGoogle Scholar
  11. 11.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62PubMedCrossRefGoogle Scholar
  12. 12.
    Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H, Pietras A, Vallon-Christersson J, Borg A, Gradin K et al (2006) Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell 10:413–423PubMedCrossRefGoogle Scholar
  13. 13.
    Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414:550–554PubMedCrossRefGoogle Scholar
  14. 14.
    Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, Ferrara N, Johnson RS (2004) Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6:485–495PubMedCrossRefGoogle Scholar
  15. 15.
    Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, Leboulch P, Cao Y (2003) Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med 9:604–613PubMedCrossRefGoogle Scholar
  16. 16.
    Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J (2004) Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res 94:664–670PubMedCrossRefGoogle Scholar
  17. 17.
    Lu H, Xu X, Zhang M, Cao R, Brakenhielm E, Li C, Lin H, Yao G, Sun H, Qi L et al (2007) Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs. Proc Natl Acad Sci U S A 104:12140–12145PubMedCrossRefGoogle Scholar
  18. 18.
    Nissen LJ, Cao R, Hedlund EM, Wang Z, Zhao X, Wetterskog D, Funa K, Brakenhielm E, Cao Y (2007) Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. J Clin Invest 117:2766–2777PubMedCrossRefGoogle Scholar
  19. 19.
    Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245PubMedCrossRefGoogle Scholar
  20. 20.
    Soriano P (1997) The PDGF alpha receptor is required for neural crest cell development and for normal patterning of the somites. Development 124:2691–2700PubMedGoogle Scholar
  21. 21.
    McCarty MF, Somcio RJ, Stoeltzing O, Wey J, Fan F, Liu W, Bucana C, Ellis LM (2007) Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content. J Clin Invest 117:2114–2122PubMedCrossRefGoogle Scholar
  22. 22.
    Sennino B, Falcon BL, McCauley D, Le T, McCauley T, Kurz JC, Haskell A, Epstein DM, McDonald DM (2007) Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of platelet-derived growth factor B by selective aptamer AX102. Cancer Res 67:7358–7367PubMedCrossRefGoogle Scholar
  23. 23.
    Funa K, Papanicolaou V, Juhlin C, Rastad J, Akerstrom G, Heldin CH, Oberg K (1990) Expression of platelet-derived growth factor beta-receptors on stromal tissue cells in human carcinoid tumors. Cancer Res 50:748–753PubMedGoogle Scholar
  24. 24.
    Nister M, Enblad P, Backstrom G, Soderman T, Persson L, Heldin CH, Westermark B (1994) Platelet-derived growth factor (PDGF) in neoplastic and non-neoplastic cystic lesions of the central nervous system and in the cerebrospinal fluid. Br J Cancer 69:952–956PubMedGoogle Scholar
  25. 25.
    Ostman A, Heldin CH (2001) Involvement of platelet-derived growth factor in disease: development of specific antagonists. Adv Cancer Res 80:1–38PubMedCrossRefGoogle Scholar
  26. 26.
    Westermark B, Heldin CH, Nister M (1995) Platelet-derived growth factor in human glioma. Glia 15:257–263PubMedCrossRefGoogle Scholar
  27. 27.
    Cao Y (2001) Endogenous angiogenesis inhibitors and their therapeutic implications. Int J Biochem Cell Biol 33:357–369PubMedCrossRefGoogle Scholar
  28. 28.
    Folkman J (2004) Endogenous angiogenesis inhibitors. APMIS 112:496–507PubMedCrossRefGoogle Scholar
  29. 29.
    Nyberg P, Xie L, Kalluri R (2005) Endogenous inhibitors of angiogenesis. Cancer Res 65:3967–3979PubMedCrossRefGoogle Scholar
  30. 30.
    Heldin CH (2004) Development and possible clinical use of antagonists for PDGF and TGF-beta. Ups J Med Sci 109:165–178PubMedCrossRefGoogle Scholar
  31. 31.
    Auguste P, Javerzat S, Bikfalvi A (2003) Regulation of vascular development by fibroblast growth factors. Cell Tissue Res 314:157–166PubMedCrossRefGoogle Scholar
  32. 32.
    Cao Y, Pettersson RF (1990) Human acidic fibroblast growth factor overexpressed in insect cells is not secreted into the medium. Growth Factors 3:1–13PubMedCrossRefGoogle Scholar
  33. 33.
    Ostman A, Heldin CH (2007) PDGF receptors as targets in tumor treatment. Adv Cancer Res 97:247–274PubMedCrossRefGoogle Scholar
  34. 34.
    Soutter AD, Nguyen M, Watanabe H, Folkman J (1993) Basic fibroblast growth factor secreted by an animal tumor is detectable in urine. Cancer Res 53:5297–5299PubMedGoogle Scholar
  35. 35.
    Malek AM, Connors S, Robertson RL, Folkman J, Scott RM (1997) Elevation of cerebrospinal fluid levels of basic fibroblast growth factor in moyamoya and central nervous system disorders. Pediatr Neurosurg 27:182–189PubMedCrossRefGoogle Scholar
  36. 36.
    Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J (1994) Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 86:356–361PubMedCrossRefGoogle Scholar
  37. 37.
    Abramsson A, Lindblom P, Betsholtz C (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Invest 112:1142–1151PubMedGoogle Scholar
  38. 38.
    Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, Hanahan D (1991) Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell 66:1095–1104PubMedCrossRefGoogle Scholar
  39. 39.
    Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–286PubMedCrossRefGoogle Scholar
  40. 40.
    Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Laboratory of Angiogenesis Research, Department of Microbiology, Tumor and Cell BiologyKarolinska InstituteStockholmSweden

Personalised recommendations