The Role of Erythropoietin Signaling in Human Cancer
Abstract
Hypoxia in solid tumors emanates from a structural and functionally disturbed vascular supply. Intratumoral oxygen levels are associated with poor prognosis, treatment resistance and cancer metastases, yet mechanisms for such phenomenon remain poorly understood. The major objective of this dissertation was to test whether or not erythropoietin (Epo), a hypoxia inducible cytokine, plays a role in astrocytoma treatment resistance and progression. The specific aims of this dissertation were to: 1) Determine whether or not hypoxia regulates the expression of Epo and EpoR (erythropoietin receptor) in astrocytomas. 2) Examine if Epo treatment results in treatment resistance in astrocytomas against chemotherapy. 3) Evaluate if Epo signaling promotes invasiveness in human astrocytomas. We examined the expression of erythropoietin and its receptor using immunohistochemistry in human glioma and head and neck tumor biopsies. We also established several in vitro cell death and cell invasion assays to examine the effects of Epo signaling on human malignant astrocytoma and head and neck cancer cell lines. In addition, we developed primers to measure baseline and hypoxia-inducible Epo and EpoR mRNA expression in cancer cells with quantitative RT-PCR. Collectively, this work answers key questions that provide insight into how hypoxia promotes cancer malignancy. Human cancers express Epo as well as functional EpoR. Expression of these proteins is most pronounced in hypoxic tumor regions and in invasive tumor margins. This work demonstrates that recombinant human Epoetin-alpha can directly stimulate the invasiveness of human cancer cells through Matrigel (TRADENAME). Epo also promotes tyrosine phosphorylation in human glioma cell lines. Hypoxia upregulates the expression of both Epo and EpoR in cancer cell lines and also promotes invasiveness.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2004
- Accession Number
- ADA435552
Entities
People
- Ahmed Mohyeldin
Organizations
- Uniformed Services University of the Health Sciences