Targeting hypoxic tumour cells to overcome metastasis

Abstract

The microenvironment within solid tumours can influence the metastatic dissemination of tumour cells, and recent evidence suggests that poorly oxygenated (hypoxic) cells in primary tumours can also affect the survival and proliferation of metastatic tumour cells in distant organs. Hypoxic tumour cells have been historically targeted during radiation therapy in attempts to improve loco-regional control rates of primary tumours since hypoxic cells are known to be resistant to ionizing radiation-induced DNA damage. There are, therefore, a number of therapeutic strategies to directly target hypoxic cells in primary (and metastatic) tumours, and several compounds are becoming available to functionally inhibit hypoxia-induced proteins that are known to promote metastasis. This mini-review summarizes several established and emerging experimental strategies to target hypoxic cells in primary tumours with potential clinical application to the treatment of patients with tumour metastases or patients at high risk of developing metastatic disease. Targeting hypoxic tumour cells to reduce metastatic disease represents an important advance in the way scientists and clinicians view the influence of tumour hypoxia on therapeutic outcome.

Figure 1

Targeting tumour hypoxia to overcome metastasis. Functional inhibition of the HIF-1 transcription factor or hypoxia-inducible proteins, such as CAIX, LOX, or CXCR4, can affect multiple steps in the metastatic process. A range of hypoxia-activated cytotoxins are also available to directly target hypoxic cells in primary tumours and in distant tumour metastases.