Metastasis

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Yin, J. J. et al. Proc. Natl Acad. Sci. USA 100, 10954–10959 (2003)

Yin et al. have developed a reproducible model of osteoblastic metastases by inoculating nude mice with ZR-75-1 human breast cancer cells, which secrete endothelin-1 (ET-1). Treatment of these mice with an ET-receptor antagonist markedly decreased metastases and tumour burden in bone. As ZR-75-1 cells do not express ET-1 receptor, the authors propose that the effects of ET-1 in this model are mediated through osteoblasts.

Tumorigenesis

TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Brugarolas, J. B. et al. Cancer Cell 4, 147–158 (2003)

Tuberous sclerosis complex (TSC) — a hereditary cancer syndrome caused by mutations in TSC1 or TSC2 — is characterized by highly vascular tumours. The TSC1–TSC2 complex negatively regulates mammalian target of rapamycin (mTOR) and HIF. Brugarolas et al. found increased levels of Hif and its target Vegf in TSC2−/− mouse embryonic fibroblasts (MEFs). The mTOR antagonist rapamycin normalises Hif levels in Tsc2−/− MEFs, but only partially inhibits Vegf expression, indicating that TSC2 regulates VEGF through mTOR-dependent and -independent pathways.

Epigenetics

Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases. Paz, M. F. et al. Hum. Mol. Genet. 12, 2209–2219 (2003)

Tumour-suppressor genes are often silenced in tumours by hypermethylation of the CpG islands within the genes. To find out which genes were silenced in colon cancer, the authors knocked out two key DNA methyltransferase genes — DNMT1 and DNMT3b — in a colon cancer cell line. Loss of hypermethylated CpG islands induced the reactivation of many known tumorigenesis-associated genes, such as the cadherin family member FAT and the homeobox genes LMX1 and DUX4. They also found other genes, including a calcium-channel subunit that had not previously been shown to have a role in tumorigenesis.

Antisense therapy

Pharmacologic inactivation of kinase suppressor of ras-1 abrogates Ras-mediated pancreatic cancer. Xing, H. R. et al. Nature Med. 7 Sept 2003 (doi:10.1038/nm927)

The growth of pancreatic cancer, for which there is no effective therapy, is RAS-dependent. Xing et al. used an antisense oligonucleotide to the kinase suppressor of RAS-1 (KSR1) to prevent growth of established human pancreatic xenografts in nude mice, without any toxic effects.