Leukaemia: Adding e for survival
Nature Reviews Cancer 12, 4 (01 April 2012) | doi:10.1038/nrc3249
The ability of cancer cells to manage increased levels of reactive oxygen species (ROS) seems to be crucial for their survival. Maintaining levels of glutathione (GSH) is an important part of this process, and new data indicate that the cysteine that is required to generate GSH can be provided by stromal cells through the uptake and conversion of cystine.
Chronic lymphocytic leukaemia (CLL) cells removed from patients are, like many cancer cells, difficult to grow in culture and have high rates of apoptosis. Previous experiments have shown that CLL cells are dependent on GSH for survival, and, when cultured ex vivo, GSH levels decline rapidly. To investigate the contribution of bone marrow stromal cells to the survival of CLL cells, Peng Huang and colleagues co-cultured CLL cells isolated from patients with bone marrow stromal cell lines. Co-culture increased the survival of CLL cells, and this was associated with higher levels of GSH in the CLL cells compared with the levels in CLL cells cultured in the absence of stromal cells. The addition of the GSH precursor N-acetylcysteine to CLL cells cultured in the absence of stromal cells also increased CLL cell viability and, conversely, the addition of β-phenylethyl isothiocynate (PEITC), which depletes GSH, prevented the stromal cell-mediated increase in CLL cell viability.
targeting the leukaemia–stromal cell interaction through metabolic pathways ... could improve the sensitivity of leukaemia cells to standard chemotherapy treatments
The use of transwell co-culture systems, where the two cell populations are separated by a membrane, indicated that the stromal cells provide a soluble factor that increases GSH levels in the CLL cells. Fractionation of culture media from the stromal cells suggested that the molecules in question resided in a low-molecular-mass fraction of less than 3000 kDa. Indeed, increased levels of cysteine, a thiol-containing compound that is rate limiting for GSH synthesis, were present in this fraction.
Cysteine is not a stable compound, and most cells take up cystine (via the cystine transporter Xc) and convert it to cysteine. The authors found that CLL cells have low expression levels of the active subunit of Xc and take up low levels of radioactive cystine. However, stromal cells are able to take up cystine and convert it to cysteine for use by the CLL cells: removal of cystine from the medium prevented the increase in GSH levels in CLL cells in the presence of stromal cells. Importantly, CLL cells cultured with stromal cells showed increased sensitivity to chemotherapy agents, such as oxaliplatin, when PEITC or Xc inhibitors were added to the culture medium. Moreover, the use of an Xc inhibitor in Tcl1-transgenic mice, which develop a CLL-like disease, reduced the levels of GSH in the leukaemia cells and the numbers of leukaemia cells in the peritoneum in all of the four mice tested.
These data indicate that targeting the leukaemia-stromal cell interaction through metabolic pathways, such as the provision of cysteine by the stromal cells, could improve the sensitivity of leukaemia cells to standard chemotherapy treatments.
ORIGINAL RESEARCH PAPER
- Zhang, W. et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nature Cell Biol. 19 Feb 2012 (doi:10.1038/ncb2432) | Article |