Effects of erythropoietin and stem cell factor on normal and cancer cells: implication for supportive therapy in oncological patients

Abstract

The ability of erythropoietin (Epo) to promote the production of red cells is currently exploited to treat chemotherapy-induced anemia. However, the expression of Epo receptor (EpoR) in a variety of cancer cells suggests that Epo-based supportive therapy can negatively affect the clinical outcome. In line with this hypothesis, some clinical trials have questioned the benefit of Epo administration in patients affected by different tumors, including breast cancer. In this study we directly determined the effect of Epo on cancer mammospheres, whose tumorigenic activity was validated through the establishment of xenografts in immunocompromized SCID mice. Our preliminary data showed that EpoR was expressed in both, undifferentiated mammospheres and in differentiated primary breast cancer cells. The presence of Epo increased the expansion and survival of tumor mammospheres and differentiated primary breast cancer cells. More importantly, Epo was able to considerably protect both, differentiated and undifferentiated breast cancer cells, from death induced by many antineoplastic drugs. Accordingly, we observed that Epo increased the expression of its receptor, induced activation of AKT/PKB and MAPKs and increased the expression of Bcl-xL in breast cancer cells. Thus, the use of Epo may promote the survival and growth of tumorigenic breast cancer cells by counteracting the cytotoxic effects of chemotherapy suggesting the need for alternative therapeutic options in cancer patients. In a comprehensive investigation, 81/120 tumor types examined did not yield any sample positive for c-kit expression, suggesting that the use of Stem Cell Factor (SCF) should be safe in many of the most common malignancies. 1 To determine the possible oncogenic effect of SCF, we compared the pro-tumor activity of Epo and SCF on breast cancer, the major cancer type in women. Among this, we tested the potential protective effects of SCF in preventing hematopoietic cell death during chemotherapy in vivo. Our data are showing that Epo increased the expansion and survival of tumor mammospheres and differentiated primary breast cancer cells. More importantly, Epo was able to considerably protect both, differentiated and undifferentiated breast cancer cells, from death induced by many antineoplastic drugs possibly through increased expression of the anti-apoptotic protein Bcl-xL. SCF, on the contrary, can not exert any pro-tumor activity, since the majority of cancer cells tested, particularly breast cancer, resulted negative for c-kit expression. In in vitro experiments performed on primary human erythroid progenitors we found that SCF is able to prevent apoptosis of erythroid progenitors induced by promising new anticancer agents and in vivo SCF restores the density of bone marrow cells to the level of controls in mice treated with Cisplatin or 5-Fluorouracil (5-FU). In peripheral blood analysis we observe an increase in the levels of all mature blood cells upon SCF administration. Therefore, taken together our experiments demonstrate that SCF protects the hematopoietic system from chemotherapy-induced damage in vivo and outline a protocol for a potential clinical application of SCF to prevent chemotherapy-induced cytotoxicity.