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Functional EpoR pathway utilization is not detected in primary tumor cells isolated from human breast, non-small cell lung, colorectal, and ovarian tumor tissues.

Patterson SD, Rossi JM, Paweletz KL, Fitzpatrick VD, Begley CG, Busse L, Elliott S, McCaffery I - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences, Amgen Inc., Thousand Oaks, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Levels of EpoR, IGF-1R, c-Met, and EGFR in freshly-derived tumor cell populations from human tumor tissues.Tumors were disaggregated with dispase (0.34U/mL) and EpoR levels determined by flow cytometry. Cell-surface receptor levels are expressed as a ratio to the appropriate isotype control to allow comparison of relative levels of receptor between tissues. On each plot, the negative EpoR control cell-line (HT29) is shown for comparison (n = 44 determinations). Data shown for tumors from (a) colorectal (n = 46), (b) breast (n = 34), (c) non-small cell lung (n = 41), (d) ovarian (n = 35).
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pone.0122149.g006: Levels of EpoR, IGF-1R, c-Met, and EGFR in freshly-derived tumor cell populations from human tumor tissues.Tumors were disaggregated with dispase (0.34U/mL) and EpoR levels determined by flow cytometry. Cell-surface receptor levels are expressed as a ratio to the appropriate isotype control to allow comparison of relative levels of receptor between tissues. On each plot, the negative EpoR control cell-line (HT29) is shown for comparison (n = 44 determinations). Data shown for tumors from (a) colorectal (n = 46), (b) breast (n = 34), (c) non-small cell lung (n = 41), (d) ovarian (n = 35).

Mentions: A wide range of cell-surface expression of EGFR, c-Met, and IGF-1R was observed among the tumor tissues that were analyzed, whereas in no case were significant levels of EpoR detectable on the cell-surface of the tumor cells from each of these tissues that were above the negative control cell-line or isotype control (Figs. 6 and 7). Significant levels of EpoR were not detected in the small cohorts of tumor tissues from metastatic tissues or from patients that had been previously treated with chemotherapy (Figs. 7B and 7C). The lack of EpoR expression suggested that EpoR was not induced in tumor cells during disease progression and was also not induced in response to treatment.


Functional EpoR pathway utilization is not detected in primary tumor cells isolated from human breast, non-small cell lung, colorectal, and ovarian tumor tissues.

Patterson SD, Rossi JM, Paweletz KL, Fitzpatrick VD, Begley CG, Busse L, Elliott S, McCaffery I - PLoS ONE (2015)

Levels of EpoR, IGF-1R, c-Met, and EGFR in freshly-derived tumor cell populations from human tumor tissues.Tumors were disaggregated with dispase (0.34U/mL) and EpoR levels determined by flow cytometry. Cell-surface receptor levels are expressed as a ratio to the appropriate isotype control to allow comparison of relative levels of receptor between tissues. On each plot, the negative EpoR control cell-line (HT29) is shown for comparison (n = 44 determinations). Data shown for tumors from (a) colorectal (n = 46), (b) breast (n = 34), (c) non-small cell lung (n = 41), (d) ovarian (n = 35).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4373902&req=5

pone.0122149.g006: Levels of EpoR, IGF-1R, c-Met, and EGFR in freshly-derived tumor cell populations from human tumor tissues.Tumors were disaggregated with dispase (0.34U/mL) and EpoR levels determined by flow cytometry. Cell-surface receptor levels are expressed as a ratio to the appropriate isotype control to allow comparison of relative levels of receptor between tissues. On each plot, the negative EpoR control cell-line (HT29) is shown for comparison (n = 44 determinations). Data shown for tumors from (a) colorectal (n = 46), (b) breast (n = 34), (c) non-small cell lung (n = 41), (d) ovarian (n = 35).
Mentions: A wide range of cell-surface expression of EGFR, c-Met, and IGF-1R was observed among the tumor tissues that were analyzed, whereas in no case were significant levels of EpoR detectable on the cell-surface of the tumor cells from each of these tissues that were above the negative control cell-line or isotype control (Figs. 6 and 7). Significant levels of EpoR were not detected in the small cohorts of tumor tissues from metastatic tissues or from patients that had been previously treated with chemotherapy (Figs. 7B and 7C). The lack of EpoR expression suggested that EpoR was not induced in tumor cells during disease progression and was also not induced in response to treatment.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences, Amgen Inc., Thousand Oaks, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus