The tumour microenvironment (TME), which includes extracellular matrix proteins, other non-cancerous cell types and the cytokines they produce, is increasingly being identified as playing a key role in tumour progression. As such, in vitro oncology studies are now employing more sophisticated co-culture systems.
One such area of study is the effect the TME has on the cancer stem-like population. Two recent papers demonstrate, through co-culture experiments, that cells present in the TME promote “stemness” within cancer cell lines through the production of certain cytokines.
Ning and colleagues investigated the effects of macrophages on ovarian cancer stem-like cells (OCSLC) derived from the SKOV3 ovarian cancer cell line, and vice versa. When co-cultured with OCSLCs, THP‑1 monocytes differentiated into the M2 phenotype resulting in increased secretion of IL‑8, amongst other cytokines, and an increase in the expression of phosphorylated STAT3, an oncogenic gene associated with poor prognosis in ovarian cancer.
SKOV3 cells co-cultured with THP‑1 cells were observed to have an increased sphere and colony forming efficiency and increased cancer stem cell marker expression, suggesting the co-culture increased the stemness of these cells. These effects were mimicked by IL‑8 treatment of SKOV3 cells, or overexpression of STAT3, and abrogated through the use of IL‑8 neutralising antibodies or the knockdown of STAT3.
Rodrigues and colleagues also observed an increase in stemness of lung carcinoma cells upon co-culture with TME cells. They initially observed an increase in malignancy of their cell line, RenG2, through serial in vivo transplantation, and the resultant cell lines (DRenG2 and DDRenG2) from these tumours gained the capacity to form spheres in low adherence cultures, identifying potential cancer stem-like cells within these lines.
To ascertain whether this enhanced malignancy was due to fibroblast cells within the TME, the original RenG2 cell line was co-cultured in vitro with primary abdominal fibroblasts. As with the in vivo transplantation, the RenG2 cells acquired the capacity for sphere growth upon this co-culture, suggesting a dedifferentiation into a more stem-like cell had occurred.
Analysis of the conditioned media from these co-cultures showed increases in IL‑6, G‑CSF and Activin A. The addition of the relevant neutralising antibodies to these co-cultures completely abrogated the previously acquired sphere forming capacity.
Taken together, both these papers suggest crosstalk between cells in the TME and the tumour results in an increase in the stem-like population of the tumour, ultimately promoting tumour progression. They suggest that in vitro studies in which the TME is better represented, are more physiological when testing novel therapeutics. In addition, these studies will likely reveal potential novel therapeutic targets.