Therapies targeting a tumor's blood supply have been proposed to have an undesirable side effect: promoting metastasis. Mechanistic insights into this controversial caveat are provided by two recent papers.

Cooke et al. (Cancer Cell 21, 66–81) examined the contribution of pericytes, the cells that wrap around and support blood vessels, to cancer progression in people with and in mouse models of breast cancer. Although pericyte ablation did not affect primary tumor growth, it increased metastasis in mouse models, and lower pericyte coverage of blood vessels correlated with poor prognosis in humans with breast cancer. The authors unraveled a mechanism by which, in the absence of pericytes, tumor blood vessel function is affected, leading to decreased perfusion and hypoxia. Hypoxia-activated signaling pathways involving the oncogenic Met receptor then trigger a phenotypic adaptation that drives tumor cell invasion and metastasis. The authors also report that drugs that target pericytes through inhibition of platelet-derived growth factor receptor may help drive hypoxia-driven metastatic spread, and they suggest that combining these drugs with Met inhibitors may prevent unsought clinical complications.

Other promalignant effects of drug-induced hypoxia are deciphered in a recent report (Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.1018866109). In mice, Conley et al. show that antiangiogenic drugs targeting blood vessels can also induce hypoxia. In this case, low oxygen concentrations trigger signaling pathways that lead to the expansion of a tumor cell population with stem-like properties. These tumor-initiating cells have previously been shown to have metastatic features and may be responsible for therapeutic resistance and relapse.

Further work is needed to clarify the effects of tumor vessel-targeting drugs, but both reports support the hypothesis that one of their potential effects, hypoxia, can promote adaptations in cancers that result in increased malignancy. Perhaps making life hard for tumors may end up making them harder to kill.