Insights into the stem cell origin of human cancers by studying a registry of bone marrow and other organ transplant recipients who later developed solid cancers

Abstract

11010 Background: The existence of cancer stem cells (CSCs) in solid cancers has been presumed based on properties of self- renewal, multipotency and embryonal markers exhibited by tumor cell subpopulations in vitro. But the in vivo existence for CSCs is still unproven. Because of isolated reports of tumors of donor origin arising in transplant recipients and because of the stem cell implications of this finding, we studied a registry of transplant recipients who later developed solid cancers to investigate this issue. Methods: We studied 165 renal, 25 heart, 25 liver, 10 lung and 55 bone marrow transplant recipients. The solid cancers arising in these patients included skin, soft tissue, lung, liver, kidney, breast and others. 48% of these transplants were from different sex donors. We created a tissue microarray (TMA) consisting of the secondary solid cancers, adjacent normal tissues and control cancers from non-transplant patients. We conducted XY chromosome FISH and, in selected cases, microsatellite marker, ploidy and gene rearrangement studies. Results: Approximately 12% of the solid cancers arising in non-sex matched transplant recipients were of donor origin. The majority of these were in patients receiving a bone marrow transplant and were secondary cancers. This was seen in both female as well as male recipients. The numbers may actually have been higher than observed because some cancers of male origin spontaneously lost the Y chromosome. Conversely in some donor organs where primary solid cancers arose, the cancers were recipient in origin in 8% of the cases. In selected cases, microsatellite marker studies confirmed the FISH results of donor v. recipient origin. Ploidy and gene rearrangement studies excluded lymphocytic fusion or donor-recipient chimerism as mechanisms to explain the findings. Conclusions: Our studies suggest that solid cancers arising in transplant recipients can take origin from stem cells that are derived from either the transplanted organ (usually bone marrow) or the host. In either case these stem cells do not initially reside in the organ where the cancer developed. These observations could explain the rareness of transformation, tumor dormancy, local recurrence and distal metastasis. No significant financial relationships to disclose.