Modulation of the tumour microenvironment by signalling inhibition as a strategy to improve cytotoxic therapy

Mammalian cells are able to transduce signals via protein pathways, and this enables cells to grow, differentiate and survive in a controlled fashion. This regulation is often lost in cancer, leading to the development of malignant tumours. Cytotoxic therapy such as radiotherapy and chemotherapy are commonly used to treat cancer. Numerous pharmacological drugs have also recently been developed, in an attempt to inhibit the action of these oncogenic proteins and to prevent their aberrant action, or to sensitise cancer cells to cytotoxic therapy. However, little is known about the actions of these inhibitors on the tumour microenvironment, which amongst other components, is comprised of blood vessels. Tumour vasculature is poorly organised, dilated, irregular in distribution and shape, and is less mature than its normal counterpart. The failure of cancer chemotherapy is partly thought to be due to the failure of cytotoxic drug delivery to the tumour. Since effective drug penetration relies in part on an effective blood supply throughout the tumour, the ability to modulate the tumour microenvironment is one possible strategy to help achieve better drug distribution. The inefficient vasculature also results in tumour hypoxia. Clinically, hypoxic tumours are more resistant to radiotherapy, in part because oxygen is required for the maximal fixation of radical species which can cause DNA damage. Increasing oxygen levels within tumours may thus improve the efficiency of radiotherapy. Here, we characterise vascular changes in the tumour microenvironment upon signalling inhibition. After the restriction of oncogenic signalling, tumour vasculature becomes more structurally normal with improved flow, which leads to a corresponding reduction in tumour hypoxia. These changes result in improved chemotherapy drug delivery and the enhancement of radiotherapy which, in turn delays tumour growth. We demonstrate that modulation of the tumour microenvironment in this way is a viable strategy to improve the effectiveness of cytotoxic therapy.EThOS - Electronic Theses Online ServiceGBUnited Kingdo