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Stromal microenvironment is a key determinant of tumour biology
Lenos KJ, Miedema DM, Lodestijn SC et al. Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer. Nat Cell Biol 2018;20:1193–1202.
Cancer stem cells (CSCs) drive solid tumour expansion and confer resistance to chemotherapy. The stem cell hierarchy is well defined in homoeostasis, but in cancer the plasticity of differentiated cells is less clear. Human colon cancer cell lines were injected subcutaneously into mice and lineage tracing introduced. Tumour growth was modelled stochastically and loss of clonogenicity used as a measure of intrinsic or environmental pressure; simultaneous loss of clonogenicity is driven by the environment and random loss driven by an intrinsic process. Lack of an intrinsic hierarchy was shown within individual clones. RNA sequencing of cells from xenograft edges showed enrichment of proliferative genes but no increase in CSC markers. Retransplantation of the tumour centre led to increased growth, revealing a difference between those CSC marker positive cells throughout the tumour and functional CSCs at the tumour edge. The edge cells were also enriched for stromal markers. Coculture of cancer cells with primary fibroblasts encouraged growth, suggesting that cancer-associated fibroblasts (CAFs) secrete key oncogenic factors. Osteopontin was the most abundantly expressed factor. When this was overexpressed in cancer cell lines, there was accelerated growth and less variation in clone sizes. When xenografts were treated with chemotherapy, there was an increase in CSC markers but no difference in clonal dynamics. Colorectal cancer lacks a stem cell hierarchy and stem cell function is defined by the environment. CAFs shape tumour biology and therapies aimed at CSCs are unlikely to be of benefit given cell plasticity but targeting CAF factors may be a new therapeutic strategy.
Differential regulation of non-alcoholic fatty liver disease-induced liver inflammation and tumourigenesis by STAT-1 and STAT-3 signalling
Grohmann M, Wiede F, Dodd GT, et al. Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell 2018;175:1289–1306.
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