Abstract
Although hypoxia is known to contribute to several aspects of tumour progression, relatively little is known about the effects of hypoxia on cancer-associated myofibroblasts (CAMs), or the consequences that conditional changes in CAM function may have on tumour development and metastasis. To investigate this issue in the context of gastric cancer, a comparative multiomic analysis was performed on populations of patient-derived myofibroblasts, cultured under normoxic or hypoxic conditions. Data from this study reveal a novel set of CAM-specific hypoxia-induced changes in gene expression and secreted proteins. Significantly, these signatures are not observed in either patient matched adjacent tissue myofibroblasts (ATMs) or non-cancer associated normal tissue myofibroblasts (NTMs). Functional characterisation of different myofibroblast populations shows that hypoxia-induced changes in gene expression not only enhance the ability of CAMs to induce cancer cell migration, but also confer pro-tumorigenic (CAM-like) properties in NTMs. This study provides the first global mechanistic insight into the molecular changes that contribute to hypoxia-induced pro-tumorigenic changes in gastric stromal myofibroblasts.
Highlights
Gastric cancer remains a leading cause of cancer death worldwide [1]
This study provides novel evidence that hypoxia induces differences in the functional effects that gastric cancer-associated myofibroblasts (CAMs) and normal tissue myofibroblasts (NTMs) exert on cancer cell migration and proliferation
This study shows that patient-derived gastric cancer-associated myofibroblasts (CAMs) exhibit unique changes in gene expression and protein secretion in response to hypoxic conditions
Summary
It is clear that many tumours develop as a result of complex reciprocal interactions between cancer cells and neighbouring cells within the tumour microenvironment These include fibroblasts, myofibroblasts, endothelial cells, and immune cells, which together contribute to the formation of a specialised extracellular matrix, and soluble paracrine factors [2,3] which support the growth and metastasis of gastric tumours. Gastric cancer-associated myofibroblasts (CAMs) secrete factors that increase the migration, invasion, and proliferation of cancer cells, when compared to either adjacent tissue myofibroblasts (ATMs), or normal tissue myofibroblasts (NTMs) [5]. This tumour-promoting phenotype is maintained, at least in part, due to a robust CAM-specific DNA methylation signature [6].
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