Background - It is known that tumor cell heterogeneity is responsible for tumor progression, including metastatic progression, but tumor cells can also sometimes revert in vitro to a non tumor phenotype and later convert to a transformed phenotype again. Probably, many tumors, including secondary lesions, can contain quiescent reverted cells. The question is whether these reverted cells can be a source of dormant metastasis as described in experimental and clinical settings. Methods - A high cloning efficiency method allowed us to obtain a revertant clone collection, which was examined using the following methods: soft agar assay, density-dependent inhibition method, tumorigenicity in vivo, Northern blot, Western immunoprecipitation blot, etc. Results - We have shown that many murine tumors, including several spontaneous sarcomas, the methylcholantrene-induced sarcoma B6-4, and the JB6 and PDV skin carcinomas, can revert to a non tumor phenotype. There are two types of non tumor revertant clones: one which cannot grow in vivo because of a change in its immunological properties and the other which cannot grow because of a change in its growth characteristics. The latter type also could not grow in soft agar, acquired a dependence on peptide growth factors, and exhibited a reduced expression of c-jun. It is very important to know whether such revertants can revert back to a transformed phenotype at different times. When inoculated in syngeneic animals, these transformed cells showed recurrence in 2-5 months, similar to that dormant metastasis. Conclusions - Spontaneous reversions of tumor cells may play an important role in the dormant metastatic process. The cause of this frequent spontaneous transient reversions appears to be of an epigenic nature and remains to be clarified
