Abstract
BackgroundProstate cancer (PCa) is among the most commonly diagnosed malignancies in men. Although 5-year survival in patients with localised disease reaches nearly 100%, metastatic disease still remains incurable. Therefore, there is a need for markers indicating metastatic dissemination.MethodsEGFR overexpression (EGFRover) was tracked in 1039 primary tumours, circulating tumour cells from 39 d’Amico high-risk patients and metastatic samples from 21 castration-resistant PCa cases. EGFR status was compared to clinical parameters and multiple molecular factors were assessed using immunohistochemistry and gene ontology analysis. The functional aspect of EGFR was evaluated by plating PC-3 cells on soft and rigid matrices.ResultsEGFRover was found in 14% of primary tumours, where it was associated with shorter metastasis-free survival and was an independent indicator of worse overall survival. EGFRover correlated with a pro-migratory and pro-metastatic phenotype of tumour cells as well as rich collagen fibre content. All circulating tumour cells (detected in 13% of cases) were positive for EGFR, independent of their EMT-related phenotype. EGFRover was more prevalent in castration-resistant bone metastases (29% of patients) and supported growth of human PCa cells on rigid matrices mimicking bone stiffness.ConclusionsEGFRover is a stable, EMT-independent marker of PCa disseminating to rigid organs, preferentially bones.
Highlights
Prostate cancer (PCa) is the second most frequent malignancy in men worldwide.[1]
epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in PCa patients Membranous and membranous/cytoplasmic expression of EGFR with different intensity was evaluated in 1841 primary PCa samples from 1033 patients
EGFR overexpression, found both in primary tumour and circulating tumour cells (CTCs), was an indicator of poor prognosis. It was associated with shorter metastasis-free survival, which has been previously shown to be related with a significant risk of death from PCa.[25]
Summary
Prostate cancer (PCa) is the second most frequent malignancy in men worldwide.[1]. 5-year survival in patients with localised PCa is nearly 100%, metastatic disease still remains incurable.[2,3] there is an urgent need for markers that could help to detect initial stages of tumour dissemination, probability of recurrence and predict preferred sites of metastasis in order to personalise patients’ treatment.Epithelial–mesenchymal transition (EMT) and plasticity are involved in metastatic progression of PCa.[4,5,6] In addition, significant roles for the epidermal growth factor receptor (EGFR) have been suggested in prostate tumorigenesis and progression.[7,8] EGFR expression was previously shown to be associated with high grade, advanced stage and high risk for prostate-specific antigen (PSA) recurrence[9] and bone metastases.[10]. Prostate cancer (PCa) is the second most frequent malignancy in men worldwide.[1] 5-year survival in patients with localised PCa is nearly 100%, metastatic disease still remains incurable.[2,3] there is an urgent need for markers that could help to detect initial stages of tumour dissemination, probability of recurrence and predict preferred sites of metastasis in order to personalise patients’ treatment. METHODS: EGFR overexpression (EGFRover) was tracked in 1039 primary tumours, circulating tumour cells from 39 d’Amico highrisk patients and metastatic samples from 21 castration-resistant PCa cases. All circulating tumour cells (detected in 13% of cases) were positive for EGFR, independent of their EMT-related phenotype. EGFRover was more prevalent in castration-resistant bone metastases (29% of patients) and supported growth of human PCa cells on rigid matrices mimicking bone stiffness. CONCLUSIONS: EGFRover is a stable, EMT-independent marker of PCa disseminating to rigid organs, preferentially bones
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