Anterior gradient 2 (AGR2): blood-based biomarker elevated in metastatic prostate cancer associated with the neuroendocrine phenotype.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
University of Southern California, Los Angeles, California 90033, USA.
Kian
K
Kani
Paymaneh D
PD
Malihi
Yuqiu
Y
Jiang
Haiying
H
Wang
Yixin
Y
Wang
Daniel L
DL
Ruderman
David B
DB
Agus
Parag
P
Mallick
Mitchell E
ME
Gross
D000230:Adenocarcinoma / Q000378:metabolism* / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D053379:Chromogranin A / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009088:Mucoproteins; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000473:pathology*; D015513:Oncogene Proteins; D010641:Phenotype; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000556:secondary*; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
C502296:AGR2 protein, human; D014408:Biomarkers, Tumor; D053379:Chromogranin A; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D012333:RNA, Messenger; D017430:Prostate-Specific Antigen; D010751:Phosphopyruvate Hydratase