Incorporation of Bone Marrow Derived Cells in Colonic Adenoma.

Bone marrow contains stem cells that can engraft in various distant organs. These observations prompted us to investigate the cellular origin of post-transplant solid tumor neoplasias found in women having received a bone marrow transplant at our facility. In women having received bone marrow transplantation from male siblings we found colonic adenomas post-transplant. Presence of donor-derived cells were examined using a combination of immunohistochemistry for cells expressing the pan-leukocyte antigen, CD45, and the colonocyte antigen, cytokeratin 20, in conjunction with fluorescent in situ hybridization for X and Y chromosomes. Confocal microscopy was used to evaluate for evidence of cell fusion. In these cases, recipients of gender-mismatched transplants showed evidence of Y-chromosome positive, cytokeratin positive cells within the adenomas. The male cells accounted for 1 to 4% of the adenoma cells in histologic section. Confocal microscopy permitted evaluation of entire nuclei (Z-stack steps of 0.25 microns) and demonstrated no male cell with more than one X chromosome. A total of 40 male cells expressing cytokeratin were found throughout the adenomas. When considering how bone marrow derived cells incorporate into colonic adenomas, two possibilities should be regarded. First, bone marrow derived cells may migrate to neoplasias due to upregulation of tumor growth factors, which also act as inflammatory cytokines and chemokines, such as stromal derived factor 1 (SDF-1). Up- or down-regulating SDF-1 has profound effects on recruiting circulating bone marrow stem/progenitor cells for engraftment as end-organ epithelia. SDF-1 staining of the colonic adenomas found in our patients demonstrated intense, patchy SDF-1 expression compared to normal colonic epithelia. Second, roving donor-derived bone marrow cells may have engulfed the recipient adenoma cells. A donor scavenger cell could have phagocytosed an apoptotic adenoma cell. In these situations the fusion of nuclear material should result in a multiplicity of sex chromosomes (XXY or XXXY). However, as noted, the donor-derived epithelial cells within the adenomas demonstrated no extra X chromosomes. In the liver, where cell fusion has been demonstrated in severe disease stress states, it has been postulated that 28% of donor-derived hepatocytes are due to reduction division, resulting in diploid daughter cells. Based on the probability of binomial distribution, the chance that we would find 40 out of 40 diploid donor-derived epithelial cells amidst a background fusion resolution rate of 28% is one in 1x10e22. Thus, direct differentiation, rather then absolutely complete and perfect resolution of every fusion event is the most likely explanation of our current findings.