[Mechanisms of cancer angiogenesis].

The early stages of tumor growth are independent of blood vessels. When a tumor reaches a volume of approximately 2 mm3, it requires an oxygen and nutrient supply, like other tissues. Satisfaction of the metabolic demands of tumor tissue occurs through neovascularization, which is also called tumor angiogenesis. The best-characterized mechanism of new vessel formation is endothelial cell sprouting. This three-step process involves dilation of a preexisting vessel and basement membrane degradation as well as endothelial cell proliferation and migration, which lead to the restoration of vessel continuity. Eventually, a new vascular basement membrane is deposited and proliferating pericytes are recruited to stabilize the newly formed vessels. Other examples of tumor neovascularization are intussusceptive and glomerular angiogenesis. Since endothelial cell recruitment, proliferation, and migration is not required, they proceed faster and at lower energetic costs. These types of angiogenesis predominate in the colon, stomach, thymus, and skin cancers as well as gliosarcomas mulitiforme. Moreover, tumors can also be fed by co-opting host vessels or by forming "pseudovessels" in angiogenesis mimicry. All the processes mentioned in this review are not mutually exclusive; on the contrary, they are closely connected in many cases.Therefore, effective anticancer therapies should not only focus on diminishing the activity of proangiogenic factors targeted during vessel sprouting, but include the great variety of vessel factors.

[1]  P. Meltzer,et al.  Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. , 1999, The American journal of pathology.

[2]  K. Alitalo,et al.  Molecular regulation of angiogenesis and lymphangiogenesis , 2007, Nature Reviews Molecular Cell Biology.

[3]  M. Hendrix,et al.  Alternative vascularization mechanisms in cancer: Pathology and therapeutic implications. , 2007, The American journal of pathology.

[4]  J. Folkman,et al.  Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. , 1977, Microvascular research.

[5]  M. Shindoh,et al.  Understanding tumor endothelial cell abnormalities to develop ideal anti‐angiogenic therapies , 2008, Cancer science.

[6]  F. Bussolino,et al.  Integrins: a flexible platform for endothelial vascular tyrosine kinase receptors. , 2007, Autoimmunity Reviews.

[7]  D. Ribatti.  The involvement of endothelial progenitor cells in tumor angiogenesis , 2004, Journal of cellular and molecular medicine.

[8]  G. Davis,et al.  An alpha 2 beta 1 integrin-dependent pinocytic mechanism involving intracellular vacuole formation and coalescence regulates capillary lumen and tube formation in three-dimensional collagen matrix. , 1996, Experimental cell research.

[9]  E. Koivunen,et al.  Cell-surface association between matrix metalloproteinases and integrins: role of the complexes in leukocyte migration and cancer progression. , 2006, Blood.

[10]  S. Paku,et al.  First steps of tumor-related angiogenesis. , 1991, Laboratory investigation; a journal of technical methods and pathology.

[11]  J. Rao,et al.  Expression Pattern of the Novel Gene EG-1 in Cancer , 2004, Clinical Cancer Research.

[12]  Dian Feng,et al.  Heterogeneity of the Angiogenic Response Induced in Different Normal Adult Tissues by Vascular Permeability Factor/Vascular Endothelial Growth Factor , 2000, Laboratory Investigation.

[13]  M. Hendrix,et al.  Angiogenesis: Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma , 2003, Nature Reviews Cancer.

[14]  C. Rüegg,et al.  Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis , 2003, Cellular and Molecular Life Sciences CMLS.

[15]  Koichi Hattori,et al.  Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? , 2002, Nature Reviews Cancer.

[16]  Ruslan Hlushchuk,et al.  Intussusceptive angiogenesis: Its emergence, its characteristics, and its significance , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

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

[18]  H. Ishikura,et al.  Pathophysiology of Tumor Neovascularization , 2005, Vascular health and risk management.

[19]  P. Carmeliet,et al.  Molecular mechanisms of blood vessel growth. , 2001, Cardiovascular research.

[20]  R. Kalluri.  Basement membranes: structure, assembly and role in tumour angiogenesis , 2003, Nature reviews. Cancer.

[21]  S. Rafii,et al.  Circulating endothelial precursors: mystery, reality, and promise. , 2000, The Journal of clinical investigation.

[22]  E. Manseau,et al.  Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery. , 2001, The American journal of pathology.

[23]  J. Rundhaug,et al.  Matrix metalloproteinases and angiogenesis , 2005, Journal of cellular and molecular medicine.

[24]  Erwin G. Van Meir,et al.  Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: a new world of angiogenesis research. , 2001, The American journal of pathology.

[25]  A Vacca,et al.  New non-angiogenesis dependent pathways for tumour growth. , 2003, European journal of cancer.

[26]  Arjan W. Griffioen,et al.  Tumour vascularization: sprouting angiogenesis and beyond , 2007, Cancer and Metastasis Reviews.

[27]  K. Alitalo,et al.  VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia , 2003, The Journal of cell biology.

[28]  S. George,et al.  Matrix metalloproteinase control of capillary morphogenesis. , 2008, Critical reviews in eukaryotic gene expression.