Direct and indirect contribution of bone marrow-derived cells to cancer.

Stromal-epithelial interactions may control the growth and initiation of cancers. Here we not only test the hypothesis that bone marrow derived cells may effect development of cancers arising from other tissue cells by forming tumor stroma, but also that sarcomas may arise by transformation of stem cells from the bone marrow and epithelial cancers may arise by transdifferentiation of bone marrow stem cells to epithelial cancers. Lethally irradiated female FVB/N mice were restored with bone marrow (BM) transplants from a male transgenic mouse carrying the polyoma middle T-oncoprotein under the control of the mouse mammary tumor virus promoter (MMTV-PyMT) and followed for development of lesions. Eight of 8 lethally irradiated female FVB/N recipient mice, restored with BM transplants from a male MMTV-PyMT transgenic mouse, developed Ychromosome negative (Y−) cancers of various organs surrounded by Y+ stroma. One of the female FVB/N recipient mice also developed fibrosarcoma and one a diploid breast adenocarcinoma (BCA) containing Ychromosomes. In contrast, only 1 of 12 control female mice restored with normal male bone marrow developed a tumor (lymphoma) during the same time period.. These results indicate not only that the transgenic bone marrow derived stromal cells may indirectly contribute to development of tumors in recipient mice, but also that sarcomas may arise by transformation of bone marrow stem cells and that breast cancers arise by transdifferentiation of bone marrow stem cells, presumably by mesenchymal-epithelial transition.