Multiple Tumor Types Could Originate From Bone Marrow-derived Cells

It was thought that tumors originated from transformation of their tissue-specific stem cells. However, bone marrow-derived cells which may possess an unexpected degree of plasticity and often reside in other tissues, might also represent a potential source of malignancy. To study what bone marrow-derived cells play a role in the formation of tumors, the bone marrow-derived cells from mouse were treated with 3-methycholanthrene till getting malignant transformation.Here we show that after treated the BMDCs with 3-methycholane (MCA), the cells showed morphological changes, rapid growth, loss of contact inhibition, anchorage independence and formed tumors in immune-deficient mice. Two of these primary tumors were excised from the mice and injected into secondary mice. Then the two out of two injections formed secondary tumor so that the tumors had the abilities of self-renewal.These findings suggested that the transformed cells had possessed all characteristics of malignant transformed cells. Therefore, the transformed BMDCs had become cancer cells.It was thought that tumors originated from transformation of their tissue-specific stem cells. However, the discovery of multi-potent progenitor cells with the capacity for self-renewal (that is, stem cells) outside the haematopoietic system raises the possibility that cancer stem cells could arise from other tissue stem cells and initiate other cancer types, including solid cancers. Bone marrow-derived cells (BMDCs) may possess an unexpected degree of plasticity and often reside in other tissues. Moreover, Houghton JM et al. found that gastric cancers could originate from bone marrow-derived sources. We doubted whether bone marrow-derived cells might also represent a potential source of multiple tumor types.The experiments showed that the transformed BMDCs differentiated spontaneously to epithelial tumor cells, blood vessel endothelial tumor cells, glial tumor cells, neuronal tumor cells and muscular tumor cells in vitro. Moreover, the transformed BMDCs also produced various tumor types in vivo, including muscular tumor, blood vessel endothelial tumor, tumor of fibroblast, epithelial tumor, neural tumor and tumor of poor differentiation.The transformed BMDCs might give rise to many types of tumors in vitro and in vivo. That is, these findings suggest that many types oftumors may originate from marrow-derived sources.Many researches had shown that cancer stem cells, which form only a small proportion of the total tumor cell population, are the only tumor cells with the capacity to keep tumors growing. Moreover, the experiments here showed that the clonal frequency of the transformed BMDCs in semi-solid medium containing 2.7 % methyl cellulose was only 18 out of 4000. It means that not all of the transformed BMDCs had the ability of propagation. Therefore, animal implant and in vitro studies showed that the transformed BMDCs could give rise to multiple tumor types, suggesting that there were either multi-potent cancer stem cells or the mixtures of committed progenitor cells with restricted potential, in the transformed BMDCs. We determined whether a multi-potent cancer stem cell presented in the transformed cells to take responsible for these tumor types. The transformed BMDCs were serially diluted into expansion medium in 96-well plates so that only a single cell was expanded. Clonal transformed BMDCs were gotten from the single cell in order to study their self-renewal and differentiation.Our experiments revealed that there seemed to exist multi-potent stem cells in the transformed BMDCs because the transformed BMDCs at the single cell level could self-renew and differentiate into various types of tumors cells in vitro. The clone transformed BMDCs could express the markers associated with multipotency and could form teratoma containedthree germ layers in vivo.In conclusion, these findings further supported that various tissues tumors might originate from bone marrow-derived sources. Multipotent tumor stem cells were involved in the transformed BMDCs contributing to the various tumor types. For the first time, we show that teratoma also can originate from adult cells/adult stem cells. The BMDCs seemed to obtain some properties of embryonic cell during the course of transformation and long culture. The concepts will help us to better understand cancer origin and develop the studies of cancer stem cells.In previous studies showed that the transformed BMDCs could give rise to neural tumor cells in vitro and in vivo. Moreover, the transformed BMDCs could spontaneous form neural stem cell-like sphere in culture. Therefore, we doubted whether the sphere contain neural stem cells.Then we examined the spheres' ability of self-renewal, differentiation and formation of neural tumor. The expressions of marker on the spheres also were studied. The studies showed that the sphere could produce neural cancer cells, express the specific markers of neural stem cells and formed neural tumors in nude mice. Even, the spheres could form mature teratoma which is the teratoma of brain tissue.Therefore, these findings suggest that the spheres might be consist of neural tumor stem cells. Moreover, these results further confirmed that BMDCs might be a source of neural tumor. At the same time, our experiments provide a new way to get neural tumor stem cells. Furthermore, that the spheres could form mature teratoma of brain tissue will provide a possible mode for the study of brain development.