Cell proliferation, drug distribution and therapeutic effects in relation to the vascular system of solid tumours

In this perspective, the authors summarise some properties of the solid tumour micro-environment that have been explored during the last 55 years. It is well established that the concentrations of nutrients, including oxygen, decrease with increasing distance from tumour blood vessels, and that low extracellular pH is found in nutrient-poor regions. Cell proliferation is dependent on nutrient metabolites and decreases in regions distal from patent blood vessels. Proliferating cells cause migration of neighbouring cells further from blood vessels where they may die, and their breakdown products pass into regions of necrosis. Anticancer drugs reach solid tumours via the vascular system and establish concentration gradients such that drug concentration within tumours may be quite variable. Treatment with chemotherapy such as doxorubicin or docetaxel can kill well-nourished proliferating cells close to blood vessels, thereby interrupting migration toward necrotic regions and lead to re-oxygenation and renewed proliferation of distal cells, as can occur with radiotherapy. This effect leads to the paradox that cancer treatment can rescue cells that were destined to die in the untreated tumour. Renewed and sometimes accelerated repopulation of surviving tumour cells can counter the effects of cell killing from repeated treatments, leading to tumour shrinkage and regrowth without changes in the intrinsic sensitivity of cells to the administered treatment. Strategies to prevent these effects include the combined use of chemotherapy with agents that selectively kill hypoxic tumour cells, including inhibitors of autophagy, since this is a process that may allow recycling of cellular macromolecules from dying cells and improve their survival.