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.

About The Interconnection Between Erythropoietin, Mononuclears And Colon Carcinoma Cells

“…In our hands EPO did not affect cell proliferation of PBMC and both types of malignant colon cells. This observation is in line with those by Neuman et al [16] who did not detect any effect of EPO on the number of polymorphonuclears and monocytes in dialysis patients and by Patterson et al [17] who did not obtain any proliferation of tumor cells from 186 patients with various cancers under the effect of EPO. The authors concluded that there are not EPO receptors at least on the tumor cells examined.…”

Multi-organ signaling mobilizes tumor-associated erythroid cells expressing immune checkpoint molecules

“…Consistent with these clinical observations, cell culture and animal model studies detected EPOR expression in and direct EPO actions on cancer cells, proposing a role for EPO signaling in promoting their viability, proliferation, metastatic potential, therapy resistance and stemness (11)(12)(13)(14)(15)(16). Evidence against a direct effect of EPO on cancer cells also exists (17,18), leaving the mechanism for EPO function in cancer still under debate.…”

MiRNA-323-5p Promotes U373 Cell Apoptosis by Reducing IGF-1R

“…IGF-1R is an important receptor widely expressed at cell surfaces; it regulates the growth, proliferation, and apoptosis of cells through its combination with its ligands in target insulin-like growth factor (IGF) receptor proteins [ 20 ]. At present, relatively few researchers are focused on whether target insulin-like growth factor (IGF) receptor proteins coordinate with microRNA to regulate cell growth and apoptosis [ 21 , 22 ]. This article indicated that the over-expression of miRNA-323-5p reduced IGF-1R level.…”