Vessel maturation effects on tumour growth: validation of a computer model in implanted human ovarian carcinoma spheroids.

We analysed measurements of tumour growth, neovascular maturation and function in human epithelial ovarian carcinoma xenografts, studied noninvasively by magnetic resonance imaging. Results suggest that vascular maturation and mature and immature vessel regression occur continuously during tumour neovascularisation. Moreover, in these spheroids, a high tumour growth-rate is associated with monotonic changes in vessel density (VD) and with large proportions of mature blood vessels, whereas a lower tumour growth-rate is associated with fluctuating VD and lower proportions of mature vessels. These results corroborate a mathematical model for tumour dynamics, including vascular maturation and immature and mature vessel regression. The model predicts that rapid tumour growth may result from a high maturation-rate of neo-vasculatures, due to substantial mature VD in the microenvironment, while a slower tumour growth is an outcome of a lower background VD, leading to a lower vessel maturation-rate, larger proportion of immature vessels and, consequently, to regression-driven instabilities. The generality of these results for other tumour types should be validated.

[1]  K. Hirschi,et al.  Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. , 1999, Circulation research.

[2]  Z. Agur,et al.  A computer algorithm describing the process of vessel formation and maturation, and its use for predicting the effects of anti-angiogenic and anti-maturation therapy on vascular tumor growth , 2004, Angiogenesis.

[3]  T. Danielsen,et al.  The constitutive level of vascular endothelial growth factor (VEGF) is more important than hypoxia-induced VEGF up-regulation in the angiogenesis of human melanoma xenografts , 2000, British Journal of Cancer.

[4]  Kenneth J. Hillan,et al.  Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene , 1996, Nature.

[5]  K. Messmer,et al.  Platelet-endothelial interaction in tumor angiogenesis and microcirculation. , 2003, Blood.

[6]  R. Jain,et al.  Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: mammary fat pad versus cranial tumors. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[7]  Michal Neeman,et al.  In Vivo Prediction of Vascular Susceptibility to Vascular Endothelial Growth Factor Withdrawal Magnetic Resonance Imaging of C6 Rat Glioma in Nude Mice , 1999 .

[8]  N. Ferrara,et al.  Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. , 1989, Biochemical and biophysical research communications.

[9]  Y. Dor,et al.  Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. , 2001, American journal of physiology. Cell physiology.

[10]  M. Neeman,et al.  Dynamic remodeling of the vascular bed precedes tumor growth: MLS ovarian carcinoma spheroids implanted in nude mice. , 1999, Neoplasia.

[11]  Z. Agur,et al.  The growth law of primary breast cancer as inferred from mammography screening trials data. , 1998, British Journal of Cancer.

[12]  Syed Mohsin,et al.  Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer , 2003, The Lancet.

[13]  E. Keshet,et al.  Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis , 1992, Nature.

[14]  Laurent Capelle,et al.  Continuous growth of mean tumor diameter in a subset of grade II gliomas , 2003, Annals of neurology.

[15]  N. Ferrara,et al.  Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. 1989. , 2012, Biochemical and biophysical research communications.

[16]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[17]  Lieve Moons,et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele , 1996, Nature.

[18]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[19]  G. Breier,et al.  Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. , 1992, Development.

[20]  R. Kerbel.  Tumor angiogenesis: past, present and the near future. , 2000, Carcinogenesis.

[21]  H. Augustin,et al.  Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. , 2000, Cancer research.

[22]  N. Ferrara,et al.  Molecular and biological properties of the vascular endothelial growth factor family of proteins. , 1992, Endocrine reviews.

[23]  Michael D Feldman,et al.  Tumor vessel development and maturation impose limits on the effectiveness of anti-vascular therapy. , 2003, The American journal of pathology.

[24]  D. A. BRUNNING,et al.  European Journal of Cancer , 1966, Nature.

[25]  Thomas N. Sato,et al.  Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. , 1997, Science.

[26]  J. Spratt,et al.  Growth rates of primary breast cancers , 1979, Cancer.

[27]  Peteris Daugulis,et al.  Hopf point analysis for angiogenesis models , 2003 .

[28]  E. Keshet,et al.  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. , 1998, Development.

[29]  M. Neeman,et al.  The role of angiogenesis, vascular maturation, regression and stroma infiltration in dormancy and growth of implanted MLS ovarian carcinoma spheroids , 2004, International Journal of Cancer.

[30]  M. Neeman,et al.  Analysis of subcutaneous angiogenesis by gradient echo magnetic resonance imaging , 1998, Magnetic resonance in medicine.