Tumour Suppressors

Biallelic inactivation of BRCA2 in Fanconi anemia.Howlett, N. G. et al. Science 13 June 2002 [epub ahead of print]

The cancer-predisposition syndrome Fanconi anaemia (FA) can be caused by germ-line mutations in several genes. However, the genes that cause FA subtypes B and D1 have not been identified. Now, Alan D'Andrea and colleagues show that cell lines that are derived from patients with FA-B and -D1 have biallelic mutations in BRCA2, which result in the expression of truncated proteins. This study adds BRCA2 to the common pathway that has already been established for BRCA1 and the six identified FA genes.

Melanoma

Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability.McGill, G. G. et al. Cell 109, 707–718 (2002) [Contents page]

The SCF ligand, its receptor Kit, and the downstream transcription factor Mitf are important for the survival of melanocytes — a pathway that might be involved in the treatment resistance that occurs in melanomas. A microarray-based screen used to identify Mitf transcriptional targets has led to the discovery that the anti-apoptotic gene Bcl2 is directly regulated by Mitf; Bcl2 expression is also essential for melanoma survival. Mitf, in addition to Bcl2, could therefore be a useful theraputic target for melanoma.

Tumour Targeting

A tumor-homing peptide with a targeting specificity for lymphatic vessels.Laakkonen, P. et al. Nature Med. 7, 751–755 (2002)

This study describes a combined ex vivo and in vivo phage selection for peptides that recognize tumour vessels other than blood vessels. Using this screen, the authors isolated a cyclic 9-amino-acid peptide, LyP1, that specifically accumulates in the nuclei of tumour lymphatic cells in mice. LyP1 does not bind all tumour lymphatics, however, indicating that different tumours might have different types of lymphatic vessels. Lymphatic vessels are important routes for tumour metastasis, so LyP1 can be developed as a vehicle for delivering cytotoxic agents that block tumour expansion.

Angiogenesis

Active immunization against the vascular endothelial growth factor receptor Flk1 inhibits tumor angiogenesis and metastasis.Li, Y. et al. J. Exp. Med. 195, 1575–1584 (2002)

The vascular endothelial growth factor receptor-2 (VEGFR2/Flk1) has a crucial role in tumour angiogenesis. Li et al. have developed an immunotherapy approach, using dendritic cells pulsed with soluble VEGFR2, to directly target the blood vessels around the growing tumour cells, which would cut off their oxygen supply. Inhibition of VEGFR2 suppressed tumour angiogenesis and development of metastases, and increased survival in mouse models.