Abstract 4072: Embryonic rest hypothesis of cancer development revisited: functional gonadotropic hormone receptors are expressed by normal and malignant hematopoietic cells and functional erythropoietin receptor is expressed by germline-derived tumors

Background: The existence in adult tissues of developmentally early stem cells with broader specification potential may suggest the presence of embryonic primordial germ cell (PGC) remnants in post-natal organs. To support this small, quiescent stem cells (VSELs) that express several markers of PGCs reside in adult murine bone marrow (BM) (Leukemia 2010;24:1450), and like PGCs, are kept quiescent by erasure of imprinting on paternally imprinted genes (Leukemia 2009;23:2042). As reported hematopoietic stem/progenitor cells (HSPCs) can become specified from a population of migrating PGCs isolated from embryos (Blood 1995;86:463) as well as from adult bone marrow VSELs (Leukemia 2011;25,1278). In support of this intriguing possibility, HSPCs and PGCs are both highly migratory populations of stem cells, and specification of the first primitive HSPCs in yolk sac blood islands as well as the origin of definitive HSPCs in the aorta-gonado-mesonephros region are chronologically and anatomically correlated with the developmental migration of PGCs in extra- and intra-embryonic tissues on their way to the genital ridges. Hypothesis: Based on these observations, we have hypothesized that PGC-derived cells as well as HSPCs share some common receptors, and we tested the expression of gonadotropic hormone receptors (GHR) and erythropoietin receptor (EpoR) on HSPCs and PGC-derived cells, respectively. Materials and Methods. We employed RT-PCR studies to evaluate the expression of GHR on normal and malignant HSPCs, whereas we evaluated the expression of EpoR on teratocarcinoma and ovarian cancer cell lines. The functionality of these receptors was tested by chemotaxis, adhesion, and proliferation assays, and we performed signal transduction studies employing specific ligands for gonadal receptors to stimulate HSPCs and erythropoietin (EPO) to stimulate germline-derived cells. Results. We observed the expression of functional FSH, LH, PRL, estrogen, and androgen receptors on normal murine and human HSPCs and in leukemia cell lines. At the same time, we observed the presence of functional EpoRs on murine and human teratocarcinoma cells and ovarian cancer cell lines. Conclusions. Our data provide further evidence for the existence of a developmental link between germline and hematopoiesis and shed new light on the developmental hierarchy of the stem cell compartment in adult tissues and possibility that some malignancies may develop from embryonic remnants. These observations also have important practical implications: i) pituitary gonadal hormones could be employed in selected cases of BM failure to stimulate hematopoiesis and ii) EPO treatment (e.g., because of anemia after chemotherapy) should be avoided in patients with germline malignancies. Citation Format: Malwina Suszynska, Katarzyna Mierzejewska, Agata Poniewierska-Baran, Ahmed Abdelbasit Ismail, Gabriela Schneider, Pranesh Gunjal, Janina Ratajczak, Sham S. Kakar, Magda Kucia, Mariusz Z. Ratajczak. Embryonic rest hypothesis of cancer development revisited: functional gonadotropic hormone receptors are expressed by normal and malignant hematopoietic cells and functional erythropoietin receptor is expressed by germline-derived tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4072. doi:10.1158/1538-7445.AM2015-4072