Beyond genetics: driving cancer with the tumour microenvironment behind the wheel

Abstract

Cancer has long been viewed as a genetic disease of cumulative mutations. This notion is fuelled by studies showing that ageing tissues are often riddled with clones of complex oncogenic backgrounds coexisting in seeming harmony with their normal tissue counterparts. Equally puzzling, however, is how cancer cells harbouring high mutational burden contribute to normal, tumour-free mice when allowed to develop within the confines of healthy embryos. Conversely, recent evidence suggests that adult tissue cells expressing only one or a few oncogenes can, in some contexts, generate tumours exhibiting many of the features of a malignant, invasive cancer. These disparate observations are difficult to reconcile without invoking environmental cues triggering epigenetic changes that can either dampen or drive malignant transformation. In this Review, we focus on how certain oncogenes can launch a two-way dialogue of miscommunication between a stem cell and its environment that can rewire downstream events non-genetically and skew the morphogenetic course of the tissue. We review the cells and molecules of and the physical forces acting in the resulting tumour microenvironments that can profoundly affect the behaviours of transformed cells. Finally, we discuss possible explanations for the remarkable diversity in the relative importance of mutational burden versus tumour microenvironment and its clinical relevance.

Fig. 1 |. Crosstalk between transformed cells and the microenvironment induces the cancer stem cell state.

Components of the tumour microenvironment crosstalk with the transformed epithelial cell, driving its epigenetic reprogramming towards a cancer stem cell (CSC) state. a, Non-transformed epithelial cells compete with transformed cells, for example, by extrusion physical forces. In colorectal cancer initiation, the release of bone morphogenic proteins from transformed cells inhibits the stem cell function of healthy epithelium. b, The release of immunomodulatory cytokines such as interleukin-33 (IL-33) from transformed cells stimulates immune cells, including macrophages and regulatory T cells (T_reg cells) to produce cytokines such as transforming growth factor-β (TGFβ) and the interleukin IL-1β, which bind to their respective receptors and reprogram transformed cells towards malignancy. c, TGFβ stimulates the release of angiogenic factors that drive vessel formation to increase the supply of nutrients. This also increases tissue concentration of the peptide hormone leptin, which cooperates with oncogenic RAS to drive malignancy. Notably, expression of the leptin receptor (LEPR) in transformed cells is stimulated by TGFβ. d, Cancer-activated fibroblasts (CAFs) also secrete cytokines that support CSC formation. e, In addition, CAFs as well as transformed cells themselves contribute to the remodelling of the extracellular matrix (ECM), for example through the release of metalloproteinases or by exerting physical forces. ECM remodelling affects tissue stiffness, basement membrane integrity and invasion, which collectively drive malignant transformation and progression. f, Finally, nerves have been shown to contribute to tumorigenesis. Transformed cells secrete axonogenic factors and de novo innervation facilitates tumour growth, for example, by promoting CD8⁺ T cell exhaustion. EMT, epithelial–mesenchymal transition; TGFβR, TGFβ receptor; IL1RL1, IL-1 receptor-like 1 (receptor for IL-33, also known as ST2).

Fig. 2 |. Epigenetic changes drive tumorigenesis and progression.

Pathways involved in the epigenetic reprogramming of the cancer stem cell. Numerous external factors — including receptor–ligand interactions, physical forces, hypoxia or nutrient deprivation, and other stresses — influence malignant progression. Activation of cell surface receptors — such as frizzled, transforming growth factor-β (TGFβ) receptor (TGFβR) or the interleukin IL-1β receptor IL-1R, the leptin receptor LEPR or the epidermal growth factor (EGF) receptor EGFR — signal through β-catenin, SMAD family members or MAPK signalling. These pathways regulate transcription through the modulation of transcription factors and chromatin accessibility by modulating the methylation pattern of tumour-suppressor genes (TSGs), topology-associated domains (TADs) or cancer-driver genes. Together, these processes lead to altered transcriptional output, mediated in part by upregulation of the transcriptional regulators SRY (sex-determining region Y)-box 9 (SOX9) or Runt-related transcription factor (RUNX). Mechanical forces are also sensed and transduced to alter transcriptional regulation through Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ) signalling. Increases in extracellular viscosity are transduced through actin–ezrin, leading to increased sodium influx by Na⁺/H⁺ exchanger (NHE) and cell swelling. The increased sodium uptake through NHE activates calcium channel transient receptor potential cation channel subfamily V member 4 (TRPV4), calcium intake, cell contractility and invasive behaviour. Stresses encountered in the tumour microenvironment can affect tumorigenesis and progression. Hypoxia-mediated effects on argonaut 2 (AGO2) inhibits microRNA (miRNA) processing. Hypoxia, starvation or other environmental stresses affect translation through inhibition of mTOR signalling, resulting in phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E) binding protein-1 (EIF4EBP1) and through phosphorylation of eIF2α, allowing eIF2A-dependent translation initiation. APC, adenomatous polyposis coli; TCF, T cell factor.

Fig. 3 |. The balance between mutations and the tumour microenvironment drives tumorigenesis and progression.

Neither external insults (left) nor mutagenesis (right) are enough to initiate a malignancy. Carcinomas are caused by a combination of external factors driving reprogramming of the epithelial cell in combination with a genetic oncogenic mutation. ECM, extracellular matrix.