The role that cancer stem cells may play in the initiation and pathogenesis of cancer has been the focus of intense research in recent years. The ability to self-renew, a characteristic shared by cancer stem cells and normal stem cells residing in somatic tissues and responsible for their maintenance, have led some to suggest that tumorigenesis may initiate in normal stem cells (13
). As a result of mutation or microenvironmental influences, these cells may lose regulatory controls that normally keep cell proliferation and differentiation in check, and cancer may develop. Given the stem cell-like potential of fetal microchimeric cells to differentiate into cells of multiple lineages and their persistent presence in women following pregnancy, it is intriguing to speculate that, as a consequence of genetic alterations or changes in their microenvironmental niche, these cells may act like cancer stem cells and give rise to tumors.
The results of one study suggest that fetal microchimerism may be involved in the pathogenesis or progression of cervical cancer (14
). In this study, male cells were found in all cervical cancers tested. Interestingly, 24% (9 of 37) microchimeric cells were found to be cytokeratin-positive, a marker for epithelial cells. While this result suggests that circulating cells of fetal origin may have differentiated and contributed to the development of cervical tumors, the number of tumors examined was very small, and further work needs to be done to draw firm conclusions.
The overall results of the previously cited breast cancer study clearly show a protective role for fetal microchimeric cells (7
). In light of the possibility that these cells may sometimes give rise to tumors, however, it is noteworthy that the incidence of fetal cells in the peripheral blood buffy coat of two breast cancer cases in this study was very high relative to the incidence in other breast tumors and in normal control women. Thus, the two outlying cases had values of 277 and 374 fetal genomes per 106
maternal genomes, whereas the median concentrations for cases and controls were 2, with ranges of (0-375) and (0-78), respectively. Perhaps these two outlier cases are rare cases where fetal cells have transformed and actually contribute to the growth of the tumor.
To investigate the tumor-generating capacity of fetal microchimeric cells, my laboratory is using a mouse model in which the fate of fetal cells that express a GFP reporter transgene can be easily tracked in female mice following pregnancy. We and others have shown that GFP-expressing fetal cells can be detected in multiple organs many months post-partum. We found the highest frequency of fetal cells in the lung. In one experiment, we crossed A/J females to males bearing a CAG/GFP transgene (CAG is a stong, ubiquitously expressed promoter). A/J mice develop lung tumors at a high frequency relative to other mouse strains. In one 8-month old A/J female, we discovered two solid lung tumor lesions in which a majority of the cells fluoresced bright green, indicating their fetal origin (). Unfortunately, we were not able to determine the nature of these cells, but their large number and the gross appearance of the tumors suggest that they are indeed tumor cells and not immune cells recruited to the tumor site. Perhaps the microenvironment of normal lung stem cells contributes to the propensity of the A/J strain to develop lung tumors, and serves in a similar way to convert fetal cells lodged in the lung into cancer stem cells. Spurred on by this intriguing finding, we are continuing our studies and now use a luciferase reporter gene to track fetal cells, thus allowing us to use optical imaging to detect lung tumors containing fetal microchimeric cells in parous female mice.
Figure 1 A. Lungs of A/J female mouse 8 months after she had given birth following mating with a CAG/EGFP male, observed under fluorescent light. Fetally-derived GFP-expressing cells associated with a solid tumor are within the boxed area. Image of this tumor (more ...)