title: Functional EpoR pathway utilization is not detected in primary tumor cells isolated from human breast, non-small cell lung, colorectal, and ovarian tumor tissues.
abstract: 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.
authors: Department of Medical Sciences, Amgen Inc., Thousand Oaks, California, United States of America.
authors: Scott D
authors: SD
authors: Patterson
authors: Department of Molecular Sciences, Amgen Inc., Thousand Oaks, California, United States of America.
authors: John M
authors: JM
authors: Rossi
authors: Department of Molecular Sciences, Amgen Inc., Thousand Oaks, California, United States of America.
authors: Katherine L
authors: KL
authors: Paweletz
authors: Department of Molecular Sciences, Amgen Inc., Thousand Oaks, California, United States of America.
authors: V Dan
authors: VD
authors: Fitzpatrick
authors: Department of Oncology Research, Amgen Inc., Thousand Oaks, California, United States of America.
authors: C Glenn
authors: CG
authors: Begley
authors: Department of Molecular Sciences, Amgen Inc., Thousand Oaks, California, United States of America.
authors: Leigh
authors: L
authors: Busse
authors: Department of Oncology Research, Amgen Inc., Thousand Oaks, California, United States of America.
authors: Steve
authors: S
authors: Elliott
authors: Department of Molecular Sciences, Amgen Inc., Thousand Oaks, California, United States of America.
authors: Ian
authors: I
authors: McCaffery
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D000068817:Epoetin Alfa / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D019073:HT29 Cells; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017467:Receptors, Erythropoietin; D004815:Epidermal Growth Factor; D000068817:Epoetin Alfa; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases