Projects / Programmes
The role of recombinant human erythropoietin on gene expression and signal transduction in breast cancer
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| P320 |
Natural sciences and mathematics |
Nucleic acids, protein synthesis |
| B220 |
Biomedical sciences |
Genetics, cytogenetics |
breast cancer, chemotherapy, anemia, erythropoietin, rHuEpo, differential gene expression, Epo signal transduction
Researchers (14)
Organisations (3)
Abstract
Treatment of cancer patients with chemotherapy or radiation often results in anemia that additionally reduces the quality of life of cancer patients. To correct this condition, patients receive packed red blood cell transfusions or injections of erythropoietin (Epo), a hormone that promotes red blood cell production. With the development of recombinant human erythropoietin (rHuEpo) in the 1980's, it became the leading drug for the treatment of anemia. Intensive research during the last decade discovered that Epo acts also on many non-hemopoietic organs. The presence of Epo and its receptor (EpoR) has been demonstrated in various tissues and in many types of cancer and cancerous cell-lines. This finding, and insufficient knowledge about the role of EpoR in cancerous tissue, raised a question about the adequacy of the rHuEpo treatment in cancer patients. Recent accomplished clinical studies about the usage of rHuEpo as supportive therapy of cancer patients have pointed out a decreased survival of the cancer patients with solid tumor receiving rHuEpo. Therefore, it is necessary to perform a detailed analysis of the effects of the rHuEpo support therapy in cancer patients, as well as to investigate the molecular mechanisms of action of rHuEpo on cancerous cell.
The present study will include female patients with metastatic breast cancer, planed to undergone chemotherapy treatment. Patients which will develop anemia during chemotherapy will receive rHuEpo or packed red blood cell transfusion. Three samples of blood, urine and fine needle aspiration biopsy will be taken during the study: at enrolment in the study before treatment with chemotherapy, during chemotherapy before and between treatment with rHuEpo/ transfusion. Within the framework of this study we will determine the level of serum Epo, analyze the global gene expression and transfer of the Epo signal in signaling pathways, and attempt to elucidate the action of rHuEpo on cancerous cells on the molecular and cellular level. This research will give groundwork for new guidelines in the usage of rHuEpo as a support therapy in cancer patients treated with chemotherapy.
Significance for science
The research project is designed to provide integral and detailed answers to important molecular questions regarding the mechanisms of action of recombinant human erythropoietin (rHuEpo) on the signalling transduction and on the regulation of genes in cancerous tissue.
This is the first study addressing the mechanism of contemporary rHuEpo and chemotherapy treatment on the level of endogenous Epo in breast or bladder cancer patients. The Epo analysis with isoelectric focusing (IEF) was established enabling the semi quantification of several samples. We are at the moment the only laboratory in Slovenia enabling the analysis of Epo with IEF.
During research the mechanisms of rHuEpo action was studied in details in vitro, on several breast and bladder cancer cell lines. The RT-qPCR determined genes differentially expressed during acute and chronic rHuEpo treatment. These are genes involved in signalization and cell cycle.
Colony formation test confirmed the effect of rHuEpo on the formation and number of colonies. The use of rHuEpo in cells showed, that rHuEpo has two modes of action depending on the exposure time. This effect could not be confirmed with MTT and Wst-1, t-1.
rHuEpo neuro-protection effects was confirmed on several breast cancer and neuronal cell lines. It was previously shown that rHuEpo acts in tissue-protective manner during mechanical injury of neurons. Its protective role is also suspected in several neurodegenerative diseases. rHuEpo act as neuroprotectant in neuronal damage as well as in different neuronal diseases. It is hypothesized that the protection role is mediated through hetero receptor EpoR-betaCR.
Significance for the country
Novel findings, resulting from the proposed research not only deepen our knowledge about the mechanisms of rHuEpo action on cancer tissue, but also enable to establish the model system of the EpoR action. Conducted research was presented at several international meetings and in SCI cited scientific papers.
The analysis of Epo with isoelectric focusing (IEF) was established in the home laboratory enabling the analysis of Epo in blood and urine samples. At the moment we are the only laboratory in Slovenia enabling analysis of Epo with this methodology. IEF enables to detect Epo misuse in sport, as well as semi quantification of co treatment with chemotherapy in rHuEpo on the level of endogenous Epo and indirectly also on the kidney function. IEF was used for the first time for the analysis of Epo profile in cancer patients.
The research will be done in collaboration with physicians at the Institute of Oncology, informed in full with the results and findings of the presented study. A direct cooperation of researchers and physicians enables fast transfer of research findings and knowledge from laboratories to clinical practice; what in the end affects also the quality and efficacy of treatment of cancer patients.
Most important scientific results
Annual report
2008,
2009,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2008,
2009,
final report,
complete report on dLib.si
