Stromal FAP Expression is Associated with MRI Visibility and Patient Survival in Prostate Cancer

Abstract

Some clinically significant prostate cancers (PCa) are missed by magnetic resonance imaging (MRI). We asked if the tumour stroma in surgically treated localized PCa lesions positive or negative with MRI are different in their cellular and molecular properties, and whether the differences are reflected to the clinical course of the disease. We profiled the stromal and immune cell composition of MRI-classified tumour lesions by applying multiplexed fluorescence immunohistochemistry (mfIHC) and automated image analysis in a clinical cohort of 343 patients (Cohort I). We compared stromal variables between MRI-visible, invisible lesions, and benign tissue and assessed the predictive significance for biochemical recurrence (BCR) and disease-specific survival (DSS) using Cox regression and Log rank analysis. Subsequently, we carried out a prognostic validation of the identified biomarkers in a population-based cohort of 319 patients (Cohort II). MRI true-positive lesions are different from benign tissue and MRI false-negative lesions in their stromal composition. CD163-positive cells (macrophages) and fibroblast activation protein (FAP)-positive cells were more abundant in MRI true-positive than in MRI false-negative lesions or benign areas. In MRI true-visible lesions, a high proportion of stromal FAP-positive cells was associated with PTEN status and increased immune infiltration (CD8+, CD163+), and predicted elevated risk for BCR. High FAP phenotype was confirmed to be a strong indicator of poor prognosis in two independent patient cohorts using also conventional IHC. The molecular composition of the tumour stroma may determine whether early prostate lesions are detectable by MRI and associates with survival after surgical treatment.

Overexpression of Fibroblast Activation Protein (FAP) in stroma of proliferative inflammatory atrophy (PIA) and primary adenocarcinoma of the prostate

“…Prior studies found that FAP mRNA levels correlated with the extent of CD163 mRNA (used as surrogate for M2 macrophage infiltration) across multiple tumor types, 44 and FAP protein and CD163 protein correlated in primary prostatic adenocarcinomas. 16 In the present study, there was a positive correlation between the FAP area fraction and the CD163 area fraction ( Fig. 10A ).…”

“…A prior study indicated that FAP expression was higher in prostate cancer cases with PTEN loss. 16 Also, 25-50% of prostatic adenocarcinomas harbor ERG gene fusions, which denote a specific molecular subtype. We thus evaluated the level of FAP in relation to the status of PTEN and ERG as characterized by IHC.…”

“…Finally, while FAP expression was found to be increased in a region of inflammation in benign prostatic hyperplasia (BPH) in a single case, 9 its expression in benign prostatic tissues has been reported as negative or has not been commented upon and it has not been systematically studied in benign inflammatory lesions of the prostate. 9,13–16…”

“…11,12 In prostate cancer there are conflicting studies regarding FAP expression. 9,[13][14][15][16] Using multiplex immunofluorescence on tissue microarrays (TMAs), increasing FAP levels have been positively associated with higher Gleason score, MRI positivity, biochemical recurrence, and disease progression after prostatectomy. 16 However, a separate recent study found no FAP protein expression in primary tumors using TMAs, but noted high levels of expression in metastatic castration resistant prostate cancer (mCRPC).…”

The roles of proteases in prostate cancer

“…252,253 Recently, several highly prevalent cancers, including prostate cancer, have demonstrated high uptake and image contrast in patients by 68 Ga-FAP-targeted PET-CT 254 and FAP-directed ligands carrying therapeutic payloads have shown promising results in cancer patient trials. [255][256][257] FAP is elevated in the stroma of prostate cancer compared with benign prostate tissue, 258,259 suggesting that imaging agents directed against it may have utility for selecting patients who will benefit from FAP-targeted therapy.…”