Effect of haemopoietic growth factors on cancer cell lines and their role in chemosensitivity

Abstract

The recombinant growth factors (GFs) erythropoietin (Epo) and granulocyte-macrophage colony stimulating factor (GM-CSF) have important roles in the management of cancer patients. However, the effects of these GFs at a cellular level are not well understood. We examined the effect of GFs alone, and in combination with cytotoxic chemotherapy, in a panel of seven cell lines. Flow cytometric analysis showed varying levels of receptor expression, which correlated with phosphorylated MAPK expression. Additionally, there were also concomitant increases in BCL-2 protein levels in those cells with high levels of MAPK activation. Although culturing cells with Epo or GM-CSF did not alter cell viability by themselves, GF pretreatment in cell lines expressing higher receptor levels resulted in a reduced magnitude of cell kill following exposure to cytotoxic IC 50 concentrations of cisplatin. Subsequent co-culture with either the MEK inhibitor U0126 or the GM-CSF antagonist E21R negated this induced resistance to cytotoxic chemotherapy, confirming the importance of the GF receptor as well as MAPK in mediating these effects. These results suggest that the use of GFs during chemotherapy may be detrimental in those cancers expressing higher levels of the specific receptor. Conversely, our results also suggest that GFs are safe to use in chemotherapeutic regimens if the cancer cells do not overexpress the particular receptor.

Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma

“…The recent clinical trials and the accumulating data regarding previously unappreciated EPO-mediated functions in cancer cells demonstrate the need to increase our understanding of the role of EPO in tumor progression. However, these findings should not absolutely preclude the use of EPO in cancer patients, since the available data suggest that EPO may affect only certain types of cancer (Liu et al, 2004).…”

“…In addition, relatively high doses of EPO (10-250 U/ml) were required to detect proliferation effects. A more recent study found no proliferation effect due to EPO or GM-CSF in leukemic, renal cell carcinoma and colorectal adenocarcinoma cell lines (Liu et al, 2004). The analysis was performed using lower doses of EPO (0-20 U/ml) and it suggested that the proliferative effects of EPO may be cell type specific.…”

“…Conversely, a recent study did not detect any proliferative effect by EPO on leukemia, renal carcinoma and colorectal adenocarcinoma cell lines (Liu et al, 2004). We serum starved HNSCC cells and treated them with no growth factor, increasing doses of EPO or EGF (10 ng/ml) as a positive control and assessed proliferation by total cell counts via vital dye exclusion.…”

Human recombinant erythropoietin does not promote cancer growth in presence of functional receptors expressed in cancer cells

“…[25][26] Indeed, EPOR activation has been observed in the absence of any modification in growth rate. 27 It may be that EPO-EPOR signaling effects on proliferative and anti-apoptotic pathways are dependent on the biochemical context of each cellular model and therefore must be assessed independently.…”

Effects of Recombinant Erythropoietin in Palliative Treatment of Unselected Cancer Patients

“…However, chemotherapy-induced anemia may only seemingly be similar to tumor-induced anemia (33) because different mechanisms may explain insufficient blood formation after drug toxicity compared with systemic inflammation with hormonal and cytokine alterations explaining cachexia. Besides, effects of hematopoietic growth factors on cancer growth, proliferation, and chemosensitivity are still open questions (38). Therefore, it was deemed interesting to evaluate how alterations in self-reported quality of life (HRQL) and performance status relate to objective evaluations of integrative physiology during progressive disease with and without anemia in patients randomized to erythropoietin treatment (39,40).…”