Precancerous stem cells identified
drug targets for use in the fight against cancer.
Cancer stem cells (CSCs) are believed to be a subset of cells found in tumours which differ from other stem cells in that they will cause a cancer to form if as few as 100 are injected into laboratory animals. CSCs were first identified in leukaemia and have since been discovered in breast, brain, colon and prostate cancers. They are tricky to isolate due to their instability and have so far been found resistant to treatment. The source of these stems cells had been a mystery, until a team of scientists, led by Dr Jian-Xin Gao, of the Ohio State University Medical Center, identified a new set of cells dubbed 'precancerous stem cells' (pCSCs). These cells share some characteristics with cancer stem cells, but respond to distinct cell signals that determine whether they grow into cancer or cancer stem cells, lie inactive or are destroyed by the immune system. The new research, which will be published in the 21 March edition of PLoS ONE, describes the discovery of these pCSCs. "These hybrid cells are very complex. They have properties of normal and abnormal stem cells, and do not always lead to cancer - only some of the time, and under very specific conditions," said Gao. The cells were identified during investigations in to cancer growths in mice. Several of the cell lines they identified from the tumours carried a unique surface protein signature and neither of the Sca-1 or c-kit markers exhibited by bone marrow stem cells. While they exhibited none of the lineage markers exhibited by most cancer cells they did exhibit stem cell like structure. The cells were isolated and injected into three different groups of mice; one comprised of severe immune deficient mice; a second group with immune systems that had been knocked out by radiation and partially restored by an infusion of bone marrow cells; and a third group of normal, healthy mice. The results showed that the strength of the immune system affected whether the mice got cancer or not. The mice with healthy or recovering immune systems survived with no cancer growth. Instead, the pCSCs created various benign cells that died on receiving signals to differentiate further. In mice with impaired immune systems, the pCSCs developed into solid tumours and developed additional mutations in different cell types as they spread. "First, it appears that pCSCs require some sort of signal, or cue, from their immediate environment that directs them to become benign or malignant. Second, it seems clear that they can be detected and eliminated by a robust immune system when they are actively developing into cancer cells," Gao continued. The study showed that the progression of pCSCs to cancer cells was accompanied by the up-regulation of c-kit and Sca-1 genes. The pCSCs exclusively express embryonic stem cell genes including POUF1/Oct-4, TDGF!/Cripto and Zfp42/REX1, which may confer the capability of benign differentiation. These genes were undetectable in the CSC lines established in the study. The piwil2 gene, which has been detected in various tumour cells of human and animal cancer cell lines, was stably expressed in the pCSCs. The researchers believe that the expression of piwil2 may contribute to the development of pCSCs and CSCs because the knocking-down of piwil2 mRNA led to the contained pCSC proliferation in vitro.
