Tumour Hypoxia Affects the Responsiveness of Cancer Cells to Chemotherapy and Promotes Cancer Progression

Abstract

A solid tumour forms an organ-like structure that is comprised of cancer cells as well as stroma cells (fibroblasts, inflammatory cells) that are embedded in an extracellular matrix and are nourished by vascular network. However, tumoral microenvironment is heterogeneous due to the abnormal vasculature network and high proliferation rate of cancer cells. Because of these features, some regions are starved from oxygen, a phenomenon called hypoxia. Transient hypoxia is associated with inadequate blood flow while chronic hypoxia is the consequence of the increased oxygen diffusion distance due to tumour expansion. Both types of hypoxia are correlated with poor outcome for patients. Moreover, hypoxia also enhances chemoresistance of cancer cells. Firstly, the delivery of drugs in hypoxic area and cellular uptake of it are affected by hypoxia or associated acidity. Secondly, some chemotherapeutic drugs require oxygen to generate free radicals that contribute to cytotoxicity. Last, hypoxia induces cellular adaptations that compromise the effectiveness of chemotherapy. In response to nutrient deprivation due to hypoxia, the rate of proliferation of cancer cells decreases but chemotherapeutic drugs are more effective against proliferating cells. On the other hand, hypoxia induces adaptation by post-translational and transcriptional changes that promote cell survival and resistance to chemotherapy. Through these changes, hypoxia promotes angiogenesis, shift to glycolytic metabolism, expression of ABC transporters, cell survival by inducing the expression of genes encoding growth factors and the modulation of apoptotic process. The aim of this review is to provide a description of known hypoxia-induced mechanisms of chemoresistance at a cellular level.