Angiogenesis
Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Orimo, A. et al. Cell 121, 335–348 (2005)
Weinberg and colleagues have identified how carcinoma-associated fibroblasts (CAFs) contribute to the tumour microenvironment using a tumour xenograft model. CAFs express abnormally high levels of stromal-cell-derived factor 1 (SDF1). SDF1 production helps recruit endothelial progenitor cells, thereby promoting tumour angiogenesis, as well as directly stimulating cell growth by interacting with its cognate receptor, CXCR4, on carcinoma cells. Inhibiting SDF1–CXCR4 signalling would therefore be an excellent therapeutic target.
Cancer Vaccines
Peripheral tolerance prevents a reaction against normal self antigens but probably causes the poor response of patients to antitumour vaccines. In the Erbb2-N mouse model of breast cancer, cyclophosphamide treatment in combination with an ERBB2-targeted vaccine produces tumour protection in 10–30% of vaccinated mice. Cylophosphamide acheives this by inhibiting the host's CD4+CD25+ regulatory T cells. High-avidity ERBB2-specific CD8+ T cells are not deleted as previously thought, and can be recruited to illict a potent antitumour response.
Tumorigenesis
Protein farnesyltransferases in embryogenesis, adult homeostasis, and tumour development. Mijimolle, N. et al. Cancer Cell 7, 313–324 (2005)
Protein farnesyltransferase (FTase) modifies proteins with a carboxy-terminal CaaX motif, enabling protein–protein interactions or association with membranes. FTase inhibitors have been developed to prevent the activation of proteins, such as RAS, at the membrane. This paper demonstrates that FTase is essential for embryogenesis, but is dispensible in the adult. Moreover, a lack of FTase does not prevent RAS-induced tumorigenesis, but does inhibit tumour progression.
Therapeutics
Signal transducer and activator of transcription 3 (STAT3) is constitutively active in many human cancers. This paper shows that derivatives of indirubin, a herbal constituent of traditional Chinese medicine, inhibit STAT3 signalling in human breast and prostate cancer cells. One derivative also inhibited the kinase SRC, which activates STAT3, indicating that the antitumour activity of these compounds is due, in part, to inhibition of this signalling pathway.
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In Brief. Nat Rev Cancer 5, 417 (2005). https://doi.org/10.1038/nrc1640
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DOI: https://doi.org/10.1038/nrc1640