The OCT-3/4 transcription factor is known to determine cell fate — it is required for embryonal stem-cell self renewal and its altered expression results in different cell fates. However, Sharon Gidekel and colleagues now report in Cancer Cell that it can also determine the oncogenic potential of germ-cell tumours and could be a useful therapeutic target.

As tumours are thought to be maintained by tumour stem cells, the role of OCT-3/4 in maintaining the stem-cell fate of germ cells led the authors to investigate whether it might also be expressed in germ-cell tumours. In the adult male, the expression of OCT-3/4 is restricted to type A spermatogonia, but it was also found to be expressed in all 45 germ-cell tumours that were tested. The expression was particularly high in the pre-malignant cells, so it might contribute to germ-cell neoplasia from an early stage. It was not expressed in any of 182 non-germ-cell tumours.

But what effect does it actually have on tumorigenicity? The authors used several lines of engineered embryonic stem (ES) cells that expressed from 0–150% of wild-type OCT-3/4. These were injected subcutaneously into mice and the incidence of tumour formation was determined. Mice that were injected with wild-type cells developed tumours at an incidence of 83%, but this decreased to only 4.3% if OCT-3/4 was not expressed. Upregulating OCT-3/4 also increased the proportion of tumours with primitive neural and malignant-appearing tissues, further confirming that it influences cell fate.

Another question was whether OCT-3/4 is required to maintain the malignant phenotype. In one engineered ES cell line, the only copy of OCT-3/4 was under the tetracycline promoter, so could be controlled by doxycycline. When OCT-3/4 expression was switched off after tumours were established, the tumours regressed significantly — in one-third of tumours, the malignant component disappeared completely — so OCT-3/4 does seem to be required for tumour maintenance, which makes it an interesting therapeutic target.

To confirm its function as an oncogene, the authors next transfected Swiss 3T3 fibroblasts with OCT-3/4 or RAS. Interestingly, OCT-3/4 transfected cells had a similar ability to grow in the absence of anchorage — a hallmark of cancer cells — as RAS-transfected cells, and they formed more invasive tumours than RAS-transfected cells when injected into immunodeficient mice.

So, OCT-3/4 seems to act as a dose-dependent oncogene and determines the specific cell fate of arising tumours. What is left to be determined is the mechanism by which this transcription factor acts.