Several clinical trials in oncology have reported increased mortality or
disease progression associated with
erythropoiesis-stimulating agents. One hypothesis proposes that
erythropoiesis-stimulating agents directly stimulate
tumor proliferation and/or survival through
cell-surface receptors. To test this hypothesis and examine if human
tumors utilize the
erythropoietin receptor pathway, the response of
tumor cells to human recombinant
erythropoietin was investigated in disaggregated
tumor cells obtained from 186 patients with colorectal, breast, lung, ovarian, head and neck, and other
tumors. A cocktail of well characterized
tumor growth factors (
EGF, HGF, and IGF-1) were analyzed in parallel as a positive control to determine whether freshly-isolated
tumor cells were able to respond to
growth factor activation ex vivo. Exposing
tumor cells to the
growth factor cocktail resulted in stimulation of survival and proliferation pathways as measured by an increase in phosphorylation of the downstream signaling
proteins AKT and ERK. In contrast, no activation by human recombinant
erythropoietin was observed in isolated
tumor cells. Though
tumor samples exhibited a broad range of cell-surface expression of EGFR, c-Met, and IGF-1R, no cell-surface
erythropoietin receptor was detected in
tumor cells from the 186
tumors examined (by flow cytometry or Western blot).
Erythropoiesis-stimulating agents did not act directly upon isolated
tumor cells to stimulate pathways known to promote proliferation or survival of human
tumor cells isolated from primary and metastatic
tumor tissues.