Skip to main content
Log in

Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Bevacizumab-resistant tumor vessels were characterized by an increased vessel diameter and normalization of vascular structures by the recruitment of mature pericytes and smooth muscle cells. Here, we analyzed human liver metastases which were taken at clinical relapse in patients with colorectal adenocarcinoma treated with anti-angiogenic therapy using the humanized monoclonal anti-VEGF bevacizumab. Tumor vessels which are resistant to anti-VEGF therapy are increased in size and characterized by a normalization of the vascular bed. These results were confirmed using NOD SCID mice as animal model and xenograft transplantation of human PC-3 prostate carcinoma cells in combination with bevacizumab treatment. Our results confirmed that anti-angiogenic therapy results in enhanced vascular remodeling by vascular stabilization. This process is apparently accompanied by enhanced necrosis of tumor tissue. These processes interfere with the efficacy of anti-angiogenic therapy because of reduced susceptibility of stabilized vessels by this therapy. These results demonstrate the importance for the development of second generation anti-angiogenic combination therapy concepts to rule out the balance between vascular stabilization followed by a possible de-stabilization making the remained vessels susceptible to a second wave of anti-angiogenic therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Benjamin LE, Hemo I, Keshet E (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125:1591–1598

    PubMed  CAS  Google Scholar 

  • Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E (1999) Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 103:159–165

    Article  PubMed  CAS  Google Scholar 

  • Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A, Vajkoczy P (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18:338–340

    PubMed  CAS  Google Scholar 

  • Ergün S, Kilic N, Wurmbach JH, Ebrahimnejad A, Fernando M, Sevinc S, Kilic E, Chalajour F, Fiedler W, Lauke H, Lamszus K, Hammerer P, Weil J, Herbst H, Folkman J (2001) Endostatin inhibits angiogenesis by stabilization of newly formed endothelial tubes. Angiogenesis 4:193–206

    Article  PubMed  Google Scholar 

  • Ergün S, Tilki D, Oliveira-Ferrer L, Schuch G, Kilic N (2006) Significance of vascular stabilization for tumor growth and metastasis. Cancer Lett 238:180–187

    Article  PubMed  Google Scholar 

  • Ergün S, Hohn HP, Kilic N, Singer BB, Tilki D (2008) Endothelial and hematopoietic progenitor cells (EPCs and HPCs): hand in hand fate determining partners for cancer cells. Stem Cell Rev 4:169–177

    Article  PubMed  Google Scholar 

  • Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333:328–335

    Article  PubMed  CAS  Google Scholar 

  • Gaengel K, Genové G, Armulik A, Betsholtz C (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29:630–638

    Article  PubMed  CAS  Google Scholar 

  • Gee MS, Procopio WN, Makonnen S, Feldman MD, Yeilding NM, Lee WM (2003) Tumor vessel development and maturation impose limits on the effectiveness of anti-vascular therapy. Am J Pathol 162:183–193

    Article  PubMed  Google Scholar 

  • Goede V, Coutelle O, Neuneier J, Reinacher-Schick A, Schnell R, Koslowsky TC, Weihrauch MR, Cremer B, Kashkar H, Odenthal M, Augustin HG, Schmiegel W, Hallek M, Hacker UT (2010) Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer 103:1407–1414

    Article  PubMed  CAS  Google Scholar 

  • Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh DA (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456:809–813

    Article  PubMed  CAS  Google Scholar 

  • Hasumi Y, Kłosowska-Wardega A, Furuhashi M, Ostman A, Heldin CH, Hellberg C (2007) Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling. Int J Cancer 121:2606–2614

    Article  PubMed  CAS  Google Scholar 

  • Heath VL, Bicknell R (2009) Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 6:395–404

    Article  PubMed  CAS  Google Scholar 

  • Helfrich I, Schadendorf D (2011) Blood vessel maturation, vascular phenotype and angiogenic potential in malignant melanoma: one step forward for overcoming anti-angiogenic drug resistance? Mol Oncol 5:137–149

    Article  PubMed  CAS  Google Scholar 

  • Helfrich I, Scheffrahn I, Bartling S, Weis J, von Felbert V, Middleton M, Kato M, Ergün S, Schadendorf D (2010) Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma. J Exp Med 207:491–503

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  PubMed  CAS  Google Scholar 

  • Kano MR, Komuta Y, Iwata C, Oka M, Shirai YT, Morishita Y, Ouchi Y, Kataoka K, Miyazono K (2009) Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-beta receptor inhibitor on extravasation of nanoparticles from neovasculature. Cancer Sci 100:173–180

    Article  PubMed  CAS  Google Scholar 

  • Klein D, Demory A, Peyre F, Kroll J, Augustin HG, Helfrich W, Kzhyshkowska J, Schledzewski K, Arnold B, Goerdt S (2008) Wnt2 acts as a cell type-specific, autocrine growth factor in rat hepatic sinusoidal endothelial cells cross-stimulating the VEGF pathway. Hepatology 47:1018–1031

    Article  PubMed  CAS  Google Scholar 

  • Klein D, Demory A, Peyre F, Kroll J, Géraud C, Ohnesorge N, Schledzewski K, Arnold B, Goerdt S (2009) Wnt2 acts as an angiogenic growth factor for non-sinusoidal endothelial cells and inhibits expression of stanniocalcin-1. Angiogenesis 12:251–265

    Article  PubMed  CAS  Google Scholar 

  • Klein D, Weißhardt P, Kleff V, Jastrow H, Jakob HG, Ergün S (2011) Vascular wall-resident cd44+ multipotent stem cells give rise to pericytes and smooth muscle cells and contribute to new vessel maturation. PLoS One 6:e20540

    Article  PubMed  CAS  Google Scholar 

  • Lee S (2010) What tumor vessels can tell us. Pigment Cell Melanoma Res 23:309–311

    Article  PubMed  Google Scholar 

  • Lin MI, Sessa WC (2004) Antiangiogenic therapy: creating a unique “window” of opportunity. Cancer Cell 6:529–531

    PubMed  CAS  Google Scholar 

  • Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000

    Article  PubMed  Google Scholar 

  • Mulder K, Scarfe A, Chua N, Spratlin J (2011) The role of bevacizumab in colorectal cancer: understanding its benefits and limitations. Expert Opin Biol Ther 11:405–413

    Article  PubMed  CAS  Google Scholar 

  • Nehls V, Denzer K, Drenckhahn D (1992) Pericyte involvement in capillary sprouting during angiogenesis in situ. Cell Tissue Res 270:469–474

    Article  PubMed  CAS  Google Scholar 

  • Neskey DM, Ambesi A, Pumiglia KM, McKeown-Longo PJ (2008) Endostatin and anastellin inhibit distinct aspects of the angiogenic process. J Exp Clin Cancer Res 27:61

    Article  PubMed  Google Scholar 

  • Nicosia RF, Villaschi S (1999) Autoregulation of angiogenesis by cells of the vessel wall. Int Rev Cytol 185:1–43

    Article  PubMed  CAS  Google Scholar 

  • Ozerdem U, Stallcup WB (2003) Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis 6:241–249

    Article  PubMed  CAS  Google Scholar 

  • Passman JN, Dong XR, Wu SP, Maguire CT, Hogan KA, Bautch VL, Majesky MW (2008) A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells. Proc Natl Acad Sci USA 105:9349–9354

    Article  PubMed  CAS  Google Scholar 

  • Puthillath A, Patel A, Fakih MG (2009) Targeted therapies in the management of colorectal carcinoma: role of bevacizumab. Onco Targets Ther 2:1–15

    PubMed  CAS  Google Scholar 

  • Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D (2006) Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem 13:1845–1857

    Article  PubMed  CAS  Google Scholar 

  • Raza A, Franklin MJ, Dudek AZ (2010) Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol 85:593–598

    Article  PubMed  CAS  Google Scholar 

  • Sato Y (2003) Molecular diagnosis of tumor angiogenesis and anti-angiogenic cancer therapy. Int J Clin Oncol 8:200–206

    Article  PubMed  CAS  Google Scholar 

  • Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G (2005) PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7:870–879

    Article  PubMed  CAS  Google Scholar 

  • Tigges U, Hyer EG, Scharf J, Stallcup WB (2008) FGF2-dependent neovascularization of subcutaneous Matrigel plugs is initiated by bone marrow-derived pericytes and macrophages. Development 135:523–532

    Article  PubMed  CAS  Google Scholar 

  • Tilki D, Kilic N, Sevinc S, Zywietz F, Stief CG, Ergun S (2007) Zone-specific remodeling of tumor blood vessels affects tumor growth. Cancer 110:2347–2362

    Article  PubMed  CAS  Google Scholar 

  • Virgintino D, Girolamo F, Errede M, Capobianco C, Robertson D, Stallcup WB, Perris R, Roncali L (2007) An intimate interplay between precocious, migrating pericytes and endothelial cells governs human fetal brain angiogenesis. Angiogenesis 10:35–45

    Article  PubMed  Google Scholar 

  • Wesseling P, Schlingemann RO, Rietveld FJ, Link M, Burger PC, Ruiter DJ (1995) Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: an immuno-light and immuno-electron microscopic study. J Neuropathol Exp Neurol 54:304–310

    Article  PubMed  CAS  Google Scholar 

  • Zengin E, Chalajour F, Gehling UM, Ito WD, Treede H, Lauke H et al (2006) Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development 133:1543–1551

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Mohamed Benchellal for his excellent technical assistance.

Conflict of interest

The authors state that there are no personal or institutional conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Diana Klein.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 12753 kb)

Supplementary material 2 (PDF 20 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weißhardt, P., Trarbach, T., Dürig, J. et al. Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab. Histochem Cell Biol 137, 391–401 (2012). https://doi.org/10.1007/s00418-011-0898-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-011-0898-8

Keywords

Navigation