Clinical oncology is hampered by lack of tools to accurately assess a patient's response to pathway-targeted therapies. Serum and tumor cell surface proteins whose abundance, or change in abundance in response to therapy, differentiates patients responding to a therapy from patients not responding to a therapy could be usefully incorporated into tools for monitoring response. Here, we posit and then verify that proteomic discovery in in vitro tissue culture models can identify proteins with concordant in vivo behavior and further, can be a valuable approach for identifying tumor-derived serum proteins. In this study, we use stable isotope labeling of amino acids in culture (SILAC) with proteomic technologies to quantitatively analyze the gefitinib-related protein changes in a model system for sensitivity to EGF receptor (EGFR)-targeted tyrosine kinase inhibitors. We identified 3,707 intracellular proteins, 1,276 cell surface proteins, and 879 shed proteins. More than 75% of the proteins identified had quantitative information, and a subset consisting of 400 proteins showed a statistically significant change in abundance following gefitinib treatment. We validated the change in expression profile in vitro and screened our panel of response markers in an in vivo isogenic resistant model and showed that these were markers of gefitinib response and not simply markers of phospho-EGFR downregulation. In doing so, we also were able to identify which proteins might be useful as markers for monitoring response and which proteins might be useful as markers for a priori prediction of response.
[Show abstract][Hide abstract] ABSTRACT: Anterior gradient 2 (AGR2) is associated with metastatic progression in prostate cancer cells as well as other normal and malignant tissues. We investigated AGR2 expression in patients with metastatic prostate cancer.
Blood was collected from 44 patients with metastatic prostate cancer separated as: castration sensitive prostate cancer (CSPC, n = 5); castration resistant prostate cancer (CRPC, n = 36); and neuroendocrine-predominate CRPC defined by PSA ≤ 1 ng/ml in the presence of wide-spread metastatic disease (NE-CRPC, n = 3). AGR2 mRNA levels were measured with RT-PCR in circulating tumor cell (CTC)-enriched peripheral blood. Plasma AGR2 levels were determined via ELISA assay. AGR2 expression was modulated in prostate cancer cell lines using plasmid and viral vectors.
AGR2 mRNA levels are elevated in CTCs and strongly correlated with CTC enumeration. Plasma AGR2 levels are elevated in all sub-groups. AGR2 levels vary independently to PSA and change in some patients in response to androgen-directed and other therapies. Plasma AGR2 levels are highest in the NE-CRPC sub-group. A correlation between AGR2, chromagranin A (CGA), and neuron-specific enolase (NSE) expression is demonstrated in prostate cancer cell lines.
We conclude that AGR2 expression is elevated at the mRNA and protein level in patients with metastatic prostate cancer. In particular, we find that AGR2 expression is associated features consistent with neuroendocrine, or anaplastic, prostate cancer, exemplified by an aggressive clinical phenotype without elevation in circulating PSA levels. Further studies are warranted to explore the mechanistic and prognostic implications of AGR2 expression in this patient population. Prostate 73: 306–315, 2013.
The Prostate 02/2013; 73(3). DOI:10.1002/pros.22569 · 3.57 Impact Factor
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