The hypoxic tumour microenvironment

Abstract

Cancer progression often benefits from the selective conditions present in the tumour microenvironment, such as the presence of cancer-associated fibroblasts (CAFs), deregulated ECM deposition, expanded vascularisation and repression of the immune response. Generation of a hypoxic environment and activation of its main effector, hypoxia-inducible factor-1 (HIF-1), are common features of advanced cancers. In addition to the impact on tumour cell biology, the influence that hypoxia exerts on the surrounding cells represents a critical step in the tumorigenic process. Hypoxia indeed enables a number of events in the tumour microenvironment that lead to the expansion of aggressive clones from heterogeneous tumour cells and promote a lethal phenotype. In this article, we review the most relevant findings describing the influence of hypoxia and the contribution of HIF activation on the major components of the tumour microenvironment, and we summarise their role in cancer development and progression.

Fig. 1. Tumour stroma and extracellular matrix in hypoxia

. A rapidly growing tumour leads to a reduction in the oxygen supply of the cancer and in tumour stromal cells that are far from the blood vessels. In hypoxia, these cells switch to glycolytic metabolism, which contributes to the acidification of the tumour microenvironment. Produced glycolytic metabolites such as lactate can be utilised by cancer cells and promote tumour growth. The hypoxic microenvironment is also enriched in diverse types of immune cells, and many of them are recruited from the circulation. Cytokine expression by tumour and stromal cells is altered by hypoxia. In particular, hypoxic cancer cells produce signalling molecules that promote the transformation of fibroblasts into CAFs. Together with cancer cells, in hypoxia, CAFs produce an ECM that is stiff and aligned, different from a normoxic ECM, and support cell migration. CAF cancer-associated fibroblasts, ECM extracellular matrix

Fig. 2. HIF regulates interactions of cancer cells with ECM and ECM biosynthesis

. a Regulation of cell–ECM interactions by HIF. HIF was shown to transcriptionally induce ITGA5 and ITGA6 genes encoding integrins α5 and α6. Each integrin α subunit together with a β subunit forms a specific ECM receptor. Integrin α5β1 binds fibronectin and integrin α6β1, or α6β4 binds integrin. In the cell, integrins bind with a multi-component complex named the integrin adhesome. Some proteins of this complex can be involved in signalling cascades, and others interact with the cytoskeleton. As a result of interactions with the ECM, cells undergo alteration of their signalling networks and their motility. b HIF contributes to collagen production. P4HA1, P4HA2, PLOD1, PLOD2, LOX, LOXL2 and LOXL4 are transcriptional targets of HIF that are involved in collagen posttranslational modification. P4HA1/2 and PLOD1/2 catalyse the first step of procollagen molecule modification, which occurs in the ER and allows the formation of the triple-stranded procollagen molecule. Triple-stranded procollagens are exported from the cell and into the extracellular space, where they are modified by proteinases and assembled in collagen fibrils. Subsequently, LOX, LOXL2 and LOXL4 catalyse the crosslinking of collagen fibrils and the formation of a functional collagen fibre. ER endoplasmic reticulum

Fig. 3. Immune checkpoints in the tumour microenvironment

. Effector T cells infiltrating the tumour can become repressed due to the activation of immune checkpoints. The targeting of PD-1 and CTLA-4 checkpoint pathways with specific antibodies is a promising therapeutic approach. In the tumour microenvironment, these pathways can be activated by the following mechanisms. a PD-1 receptor binding to its ligand PD-L1 leads to effector T-cell repression. PD-L1 can be expressed on the surface of cancer cells, MDSCs, DCs, and macrophages, and in these cells, it is directly transactivated by HIF in hypoxia. b Binding of interferon γ secreted by active effector T cells to its receptor on cancer cells results in activation of PD-L1 gene expression and subsequent T-cell repression. c PD-L1 gene expression can be constantly upregulated in cancer cells because of oncogenic mutations and signalling alteration, which leads to effector T cell repression upon interaction with this type of tumour cell. d Antigen-presenting cells express CD80 and CD86 ligands. Upon CD80/86 binding to CTLA-4 receptor on T cells, they become functionally repressed. Hypoxia was shown to induce CTLA-4 expression in T-cells, which potentially could contribute to their repression in the hypoxic tumour microenvironment. Teff effector T-cell, MDSC myeloid-derived suppressor cell, DC dendritic cell, IFNγ interferon gamma, IFN-γ R interferon gamma receptor, APC antigen-presenting cell