Spontaneous generation of germline characteristics in mouse fibrosarcoma cells

It has been noted for a long time that germ-cell development and tumor formation share important similarities1,2,3. For instance, immortalization, invasion, independence, lack of adhesion, migratory behavior, demethylation, and immune evasion are examples of features and processes shared by cancer cells and cells undergoing germ cell/gamete/trophoblast differentiation1,2,3. Indeed, as early as 100 years ago, based on the similarity of the biological features of trophoblasts and cancer cells, Wright (1910) proposed a germinal cell origin of a pediatric sarcoma, i.e.,Willm's tumor (nephroblastoma), and John Beard (1911) postulated that tumors may arise from displaced and activated trophoblasts or even displaced germ cells (GCs)1,2,3. Germ cells can generate gametes (oocytes and spermatocytes), and trophoblastic cells that contribute to the formation of the chorion and the placenta1. Evidence for an association between the processes of germline development and tumor formation comes in two main forms1,2. First, germline tumors are known to occur in testicle or ovary tissues, as observed in ovarian and yolk-sac tumors as well as seminomas, teratomas, and teratocarcinomas1,2,4. Germline tumors can even occur outside of the genitals, as is the case for mediastinal GC and brain GC tumors4. Second, it is well known that germline-related genes, such as the so-called cancer testis (C/T) antigens, are often found to be activated (~40 identified so far) in various tumors (e.g., gastric, lung, liver, renal, and bladder carcinomas as well as melanomas, medulloblastomas, pediatric sarcomas, and germinal tumors1,3,4,5,6,7,8,9. Intriguingly, germline genes are frequently co-expressed in somatic tumors, therefore Lloyd J. Old proposed that the activation of germline genes in tumors might reflects the activation of the silenced gametogenic programme in somatic cells, and that this programmatic acquisition is one of the driving forces of tumorigenesis1,3. We further proposed that the activation of a gametogenic program might reflect the formation of germ cells in somatic tumor cells. Janic et al. reported that germline traits are necessary for tumor growth and that inactivation of germline genes can have tumor-suppressing effects in Drosophila10, which indicated that the acquisition of germline/embryonic traits contributes to tumor malignancy1,3,10,11,12. Therefore, it is essential to determine if cells that function as germ cells are present in somatic cancers. It has reported that germline cells could be generated from somatic cells under special culture condition13,14,15,16. In our previous study, we found that oocyte-like cells can be generated from bone marrow-derived cells by treatment with the carcinogen 3-methycholanthrene17, suggesting the possibility of germ cell formation in carcinogenesis. However, this result may represent an extreme case because bone marrow-derived cells are known for their multipotency; they can differentiate into cells of all three germ layers18,19,20 even female or male germ cells21,22 under certain condition. In order to show that the gametogenesis-like phenomenon is common in tumors, we further investigate whether tumor cells derived from mouse adult somatic tissues are able to undergo germline differentiation.