Cell adhesion to the extracellular matrix is fundamental to tissue integrity and human health. Integrins are the main cellular adhesion receptors that through multifaceted roles as signalling molecules, mechanotransducers and key components of the cell migration machinery are implicated in nearly every step of cancer progression from primary tumour development to metastasis. Altered integrin expression is frequently detected in tumours, where integrins have roles in supporting oncogenic growth factor receptor (GFR) signalling and GFR-dependent cancer cell migration and invasion. In addition, integrins determine colonization of metastatic sites and facilitate anchorage-independent survival of circulating tumour cells. Investigations describing integrin engagement with a growing number of versatile cell surface molecules, including channels, receptors and secreted proteins, continue to lead to the identification of novel tumour-promoting pathways. Integrin-mediated sensing, stiffening and remodelling of the tumour stroma are key steps in cancer progression supporting invasion, acquisition of cancer stem cell characteristics and drug resistance. Given the complexity of integrins and their adaptable and sometimes antagonistic roles in cancer cells and the tumour microenvironment, therapeutic targeting of these receptors has been a challenge. However, novel approaches to target integrins and antagonism of specific integrin subunits in stringently stratified patient cohorts are emerging as potential ways forward.
Integrin expression and/or function have been implicated in nearly every stage of cancer development from primary tumour formation to cancer cell extravasation and formation of a metastatic niche (parts a – d ). In addition, integrin signalling has been linked to the acquisition of drug resistance (part e ). This fact, together with the vital roles of integrins in cancer, has rendered integrins and integrin-dependent functions attractive therapeutic targets in the fight against cancer (part f ). CAF, cancer-associated fibroblast; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; FAK, focal adhesion kinase; RTK, receptor tyrosine kinase; TGFβ, transforming growth factor-β.The middle panel shows a schematic of integrin-mediated extravasation of circulating tumour cells (CTCs). The mechanisms involved in this process are α3β1 integrin-mediated and α6β1 integrin-mediated cancer cell adhesion to subendothelial laminin, which is required for successful transendothelial migration. β1 integrin is also a prerequisite for tumour cells to fully clear the endothelial layer and invade into the basement membrane (part a ). The presence of fibronectin patches on endothelial cells promotes cancer cell adhesion to the vessel wall in a manner dependent on the integrin activator talin 1 (part b ). Endothelial cells also express integrins. Endothelial α5 integrin directly binds to neuropilin 2 (NRP2), a receptor for vascular endothelial growth factor (VEGF) and the semaphorin family of proteins, on cancer cells, and this interaction promotes cancer cell attachment to the endothelium and subsequent extravasation (part c ). Pre-existing patches of exposed basement membrane can promote CTC arrest on the vascular wall in a mechanism whereby exposed laminin is engaged by α3β1 integrin on the tumour cell (part d ). Features of the blood clotting cascade can promote integrin-mediated cancer cell invasive protrusion and extravasation, such as local recruitment of plasma fibronectin to trigger αvβ3 integrin activation (part e ). MMP, matrix metalloproteinase; MT1, membrane type 1; TKS5, tyrosine kinase substrate with five SH3 domains (also known as SH3PXD2A).
Exercise-dependent regulation of the tumour microenvironment
NK cells, natural killer cells; QOL, quality of life; RCT, randomized controlled trial.
Abstract
The integrity and composition of the tumour microenvironment (TME) is highly plastic, undergoing constant remodelling in response to instructive signals derived from alterations in the availability and nature of systemic host factors. This 'systemic milieu' is directly modulated by host exposure to modifiable lifestyle factors such as exercise. Host exposure to regular exercise markedly reduces the risk of the primary development of several cancers and might improve clinical outcomes following a diagnosis of a primary disease. However, the molecular mechanisms that underpin the apparent antitumour effects of exercise are poorly understood. In this Opinion article, we explore the putative effects of exercise in reprogramming the interaction between the host and the TME. Specifically, we speculate on the possible effects of exercise on reprogramming 'distant' tissue microenvironments (those not directly involved in the exercise response) by analysing how alterations in the systemic milieu might modulate key TME components to influence cancer hallmarks.
The central nervous system orchestrates the initiation as well as the integration of the exercise response through a feedforward 'central command' response involving coordination of the respiratory and cardiovascular systems (for example, increased respiration and cardiac output) to maintain organ perfusion pressure and increase the delivery of oxygen and nutrients (for example, increased glucose output and free fatty acid mobilization) to metabolically active skeletal muscle for ATP re-synthesis. The exercise response (light blue boxes) therefore involves the integration of multiple organ systems, including the lungs, heart, liver, vascular system, adipose tissue and skeletal muscle. Feedback from type III and type IV afferents in the skeletal muscle, as well as feedback from changes in baroreceptor resetting and chemoreceptor sensing and activation in response to changes in mean arterial pressure, partial pressure of O 2 ( p O 2 ), partial pressure of CO 2 ( p CO 2 ), pH and body temperature (grey boxes), further regulates the exercise response. Reductions in blood glucose levels during exercise promote the release of adrenaline and cortisol from the adrenal gland and glucagon from the pancreas, which collectively delay exercise-induced hypoglycaemia. Adapted with permission from Ref. 28 , Elsevier.
Prolonged exposure to physical inactivity is associated with elevated circulating concentrations of numerous growth factors and hormones — a pro-tumorigenic milieu (blue boxes). By contrast, host exposure to acute bouts of exercise stimulates inter-organ signalling achieved by the secretion of hormones, cytokines and growth factors into the host systemic milieu from various tissues and organs (for example, skeletal muscle, heart, bone, liver and adipose tissue), which can subsequently regulate multiple highly integrated homeostatic control circuits that operate at the cellular, tissue and whole-organismal levels (purple boxes). Over time, chronic exercise-induced perturbation of inter-organ signalling promotes physiological adaptation across homeostatic control circuits (establishment of a higher homeostatic 'set point') that, in concert, stimulates the reprogramming of the systemic milieu, potentially characterized by alterations in the availability (reservoir), mobilization, recruitment, retention and function of specific cell types and/or molecules (green boxes), potentially altering their availability and composition in 'distant' tumour microenvironments (TMEs). Exercise-induced alterations in the systemic milieu influence key regulatory mechanisms in the TME, such as angiogenesis, immune regulation and metabolism, thus having a cumulative antitumorigenic effect (ochre box). In addition to activating the secretion of numerous factors from skeletal muscle, during acute exercise, blood flow is redirected to the metabolically active skeletal muscle that paradoxically occurs in conjunction with increased tumour blood perfusion and reduced tumour hypoxia. As such, this represents an alternative mechanism of exercise regulation of the TME (red box). CRP, C-reactive protein; IGF1, insulin-like growth factor 1; IL-6, interleukin 6; MCT1, monocarboxylate transporter 1; NK cell, natural killer cell; TAM, tumour-associated macrophage.
