Article

Erythropoietin and its receptor in breast cancer: putting together the pieces of the puzzle.

Department of Biomolecular Sciences, Section of Clinical Biochemistry, University Carlo Bo, Urbino, Italy.
The Oncologist (Impact Factor: 4.1). 08/2008; 13(7):761-8. DOI: 10.1634/theoncologist.2008-0110
Source: PubMed

ABSTRACT The expression of erythropoietin (Epo) and the Epo receptor (EpoR) has been detected in healthy tissue as well as in a variety of human cancers, including breast. Functional Epo/EpoR signaling in cancer cells, which contributes to disease initiation/progression, is not completely straightforward and is difficult to reconcile with the clinical practice of preventing/treating anemia in cancer patients with recombinant Epo. Preclinical and clinical investigations have provided contrasting results, ranging from a beneficial role that improves the patient's overall survival to a negative impact that promotes tumor growth progression. A careful gathering of Epo/EpoR biomolecular information enabled us to assemble an unexpected jigsaw puzzle which, via distinct JAK-dependent and JAK-independent mechanisms and different internalization/recycling as well as ubiquitination/degradation pathways, could explain most of the controversies of preclinical and clinical studies. However, until the mechanisms of the contrasting literature data are resolved, this new point of view may shed light on the Epo/EpoR paracrine/autocrine system and function, providing a basis for further studies in order to achieve the highest possible benefit for cancer patients.

0 Bookmarks
 · 
107 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Erythropoietin (EPO) provides an alternative to transfusion for increasing red blood cell mass and treating anemia in cancer patients. However, recent studies have reported increased adverse events and/or reduced survival in patients receiving both EPO and chemotherapy, potentially related to EPO-induced cancer progression. Additional preclinical studies that elucidate the possible mechanism underlying EPO cellular growth stimulation are needed. Using commercial tissue microarray (TMA) of a variety of cancers and benign tissues, EPO and EPO receptor immunohistochemical staining was performed. Furthermore using a panel of human renal cells (Caki-1, 786-O, 769-P, RPTEC), in vitro and in vivo experiments were performed with the addition of EPO in normoxic and hypoxic states to note phenotypic and genotypic changes. EPO expression score was significantly elevated in lung cancer and lymphoma (compared to benign tissues), while EPOR expression score was significantly elevated in lymphoma, thyroid, uterine, lung and prostate cancers (compared to benign tissues). EPO and EPOR expression scores in RCC and benign renal tissue were not significantly different. Experimentally, we show that exposure of human renal cells to recombinant EPO (rhEPO) induces cellular proliferation, which we report for the first time, is further enhanced in a hypoxic state. Mechanistic investigations revealed that EPO stimulates the expression of cyclin D1 while inhibiting the expression of p21cip1 and p27kip1 through the phosphorylation of JAK2 and ERK1/2, leading to a more rapid progression through the cell cycle. We also demonstrate an increase in the growth of renal cell carcinoma xenograft tumors when systemic rhEPO is administered. In summary, we elucidated a previously unidentified mechanism by which EPO administration regulates progression through the cell cycle, and show that EPO effects are significantly enhanced under hypoxic conditions.
    Journal of Hematology & Oncology 09/2013; 6(1):65. · 4.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The aim of this research is to investigate the relationship between anemia and erythropoietin (Epo) and erythropoietin receptor (EpoR) expression. This study also investigated the relationship between Epo and EpoR expression level and the proliferation rate of cancer cells. Methods: 20 samples of breast cancer tissues were divided into two groups; anemic group (from patiens with Hb level < 12) and non-anemic group (from patients with Hb level > 12). All samples were analyzed by using immunofluorescence staining in order to examine Epo and EpoR expression. Proliferation of cancer cells were analyzed by using Hematoxylin-Eosin staining. Results: Anemic breast cancer group represented higher Epo and EpoR expression than the non-anemic group. The results also indicated that in anemic samples expression levels of Epo and EpoR were negatively correlated with the number of cancer cells. In contrast, Epo and EpoR expression levels from non-anemic samples were positively correlated with the number of cancer cells. Conclusion: These results conducted that anemia is a crucial factor of hypoxic condition. Hypoxia led by anemia cause a different control mechanism of Epo and EpoR expression and cancer cell proliferation.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The aim of this research is to investigate the relationship between anemia and erythropoietin (Epo) and erythropoietin receptor (EpoR) expression. This study also investigated the relationship between Epo and EpoR expression level and the proliferation rate of cancer cells. Methods: 20 samples of breast cancer tissues were divided into two groups; anemic group (from patiens with Hb level < 12) and non-anemic group (from patients with Hb level > 12). All samples were analyzed by using immunofluorescence staining in order to examine Epo and EpoR expression. Proliferation of cancer cells were analyzed by using Hematoxylin-Eosin staining. Results: Anemic breast cancer group represented higher Epo and EpoR expression than the non-anemic group. The results also indicated that in anemic samples expression levels of Epo and EpoR were negatively correlated with the number of cancer cells. In contrast, Epo and EpoR expression levels from non-anemic samples were positively correlated with the number of cancer cells. Conclusion: These results conducted that anemia is a crucial factor of hypoxic condition. Hypoxia led by anemia cause a different control mechanism of Epo and EpoR expression and cancer cell proliferation.
    Journal of Experimental and Integrative Medicine. 07/2013; 3(3):199-204.

Full-text

Download
37 Downloads
Available from
May 29, 2014