Human melanoma mortality is associated with the growth of metastasis in selected organs including the lungs, liver, and brain. In this study, we examined the consequences of overexpression of pigment epitheliumderived factor (PEDF), a neurotrophic factor and potent angiogenesis inhibitor, on both melanoma primary tumor growth and metastasis development. PEDF overexpression by melanoma cells greatly inhibited subcutaneous tumor formation and completely prevented lung and liver metastasis in immunocompromised mice after tail vein injection of metastatic human melanoma cell lines. Whereas the effects of PEDF on primary tumor xenografts appear mostly associated with inhibition of the angiogenic tumor response, abrogation of melanoma metastasis appears to depend on direct PEDF effects on both migration and survival of melanoma cells. PEDF-mediated inhibition of melanoma metastases could thus have a major impact on existing therapies for melanoma.

1a,25-Dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ) has antitumor activity in addition to its classical action on calcium metabolism and bone tissue biology. It is thought to regulate the expression of multiple target genes and thus modulate processes critical for tumor growth and metastases. Here we show that 1a,25(OH) 2 D 3 differentially regulates the expression of Id1 and Id2 genes, members of a family of transcriptional regulators of cell proliferation and differentiation. 1a,25(OH) 2 D 3 induced epithelial differentiation in SW480-ADH human colon carcinoma cell line by promoting expression of the proteins implicated in adherent junction formation, including E-cadherin, and by inhibiting b-catenin transcriptional activity. 1a,25(OH) 2 D 3 activated the human Id1 gene promoter and rapidly induced Id1 RNA and protein. Ectopic overexpression of Id1 was not sufficient to induce E-cadherin, which was critical for the morphological changes induced by 1a,25(OH) 2 D 3 in SW480-ADH cells. Conversely, Id2 transcription rate, RNA and protein levels were decreased by 1a,25(OH) 2 D 3 . Id2 downregulation by 1a,25(OH) 2 D 3 mediated the antiproliferative effect of 1a,25(OH) 2 D 3 on SW480-ADH cells. In addition, we showed that 1a,25(OH) 2 D 3 changed the levels of the inducer of angiogenesis, vascular endothelial growth factor and the potent antiangiogenic factor thrombospondin-1, leading to a balanced change in the angiogenic potential of SW480-ADH human colon carcinoma cells.

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Preceded by three decades of intense basic research on tumour angiogenesis, we are assisting to the translation of anti-antiangiogenic therapies as medical oncologists are increasingly using pioneering anti-angiogenic drugs in combination with standard treatments. While basic knowledge in the field of angiogenesis is reaching maturity and our level of understanding of the complex process of vessel development and growth in health and disease has been enriched at the molecular and cellular levels, the translation of this knowledge to the clinic is still in its infancy. Identifying the most suitable drugs, and the optimal dosage and schedule, as well as monitoring patients' responses to anti-angiogenic therapy, remain challenging issues that currently limit the benefit of this new therapeutic approach in cancer. This review will focus on a comprehensive description of the experimental assays in which angiogenesis research has been founded and how the different assays complement and provide relevant information for the task of characterising the angiogenic properties of diverse tumours, giving us a variety of tools to follow up tumour angiogenesis in research models. Following up tumour angiogenesis in patients and their response to antiangiogenic therapy is a more challenging task that will benefit in the near future from the use of non-invasive imaging methods as well as molecular and cellular biomarkers of angiogenesis suitable for clinical oncology. As both the design of the anti-angiogenic therapies and monitoring of the response are improved in the coming years to properly tailor them to the angiogenic profile of every patient, we hope to achieve increasing response and benefit of including antiangiogenic drugs as standard in cancer therapy.