Exosome proteomic analyses identify inflammatory phenotype and novel biomarkers in African American prostate cancer patients

Abstract

African American men face a stark prostate cancer (PCa)‐related health disparity, with the highest incidence and mortality rates compared to other races. Additional and innovative measures are warranted to reduce this health disparity. Here, we focused on the identification of a novel serum exosome‐based “protein signature” for potential use in the early detection and better prognosis of PCa in African American men. Nanoparticle tracking analyses showed that compared to healthy individuals, exosome concentration (number/ml) was increased by ~3.2‐fold (P ˂ 0.05) in the sera of African American men with PCa. Mass spectrometry‐based proteomic analysis of serum exosomes identified seven unique and fifty‐five overlapping proteins (up‐ or downregulated) in African Americans with PCa compared to healthy African Americans. Furthermore, ingenuity pathway analyses identified the inflammatory acute‐phase response signaling as the top pathway associated with proteins loaded in exosomes from African American PCa patients. Interestingly, African American PCa E006AA‐hT cells secreted exosomes strongly induced a proinflammatory M2‐phenotype in macrophages and showed calcium response on sensory neurons, suggesting a neuroinflammatory response. Additionally, proteomic analyses showed that the protein Isoform 2 of Filamin A has higher loading (2.6‐fold) in exosomes from African Americans with PCa, but a lesser loading (0.6‐fold) was observed in exosomes from Caucasian men with PCa compared to race‐matched healthy individuals. Interestingly, TCGA and Taylor's dataset as well as IHC analyses of PCa tissue showed a lower Filamin A expression in tissues of PCa patients compared with normal subjects. Overall, these results support the usefulness of serum exosomes to noninvasively detect inflammatory phenotype and to discover novel biomarkers associated with PCa in African American men.

Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer

“…Khan et al reported that survivin, an oncoprotein associated with chemoresistance, is overexpressed in patient-derived exosomes and acts as a diagnostic and prognostic marker of PCa [71]. More interestingly, exosomes isolated from serum of African American men with PCa are a wealthy source of biomarkers for early detection and monitoring PCa patients [72]. In addition, exosomes isolated from urine can be utilized as a sentinel to monitor PCa stages and reduce the number of unnecessary biopsies [73].…”

Proteomic Analysis of Exosomes for Discovery of Protein Biomarkers for Prostate and Bladder Cancer

“…Therefore, there is an urgent need for additional PCa biomarkers for highly specific monitoring of disease progression and treatment response, including noninvasive exosomal biomarkers from biofluids (e.g., urine and plasma/serum). We reviewed recent proteomic studies of exosomes from urine, plasma/serum, and cell culture media for PCa protein biomarker discovery [ 19 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ]. A summary of these studies is provided in Table 2 .…”

“…Only two studies were reported for proteomic discovery of PCa exosomal protein biomarkers from patient plasma/serum ( Table 2 ). With ExoQuick or UC, ~300 [ 92 ] and ~100 proteins [ 86 ] were identified with ~32% and ~70% annotated as exosomal proteins, respectively. The highest number of exosomal proteins in plasma/serum reported so far was 2238 using immunoaffinity isolation with only 5 µL of plasma [ 61 ]; however, the GO term analysis showed that only 18.4% were annotated as exosomal proteins, suggesting issues with exosomal purity.…”

“…Using UC for exosome isolation and label-free MS analysis, Panigrahi et al identified 134 proteins in serum samples from African American men ( n = 8) and Caucasian men ( n = 8) with PCa and healthy individuals. Filamin A was found to be a potential biomarker, specifically in African Americans, for discrimination of PCa from healthy individuals, while no Filamin A expression changes were observed for Caucasian men [ 86 ]. Turay et al performed another proteomic analysis of nine healthy controls and 12 PCa patients (four Caucasian, four African American, and four Hispanic) with identification of ~300 proteins [ 92 ].…”

No association between three polymorphisms (rs1800629, rs361525 and rs1799724) in the tumor necrosis factor-α gene and susceptibility to prostate cancer: a comprehensive meta-analysis

“…The incidence and mortality of PCA are correlated with increasing age, and the average age at the time of diagnosis is over 66 years in some regions. Additionally, there is also evidence of an association between ethnicity and PCA; for example, the incidence rate in African-American men is 158.3 newly diagnosed cases/100,000, which is higher than that in White men, and their mortality is about twice that of White men according to Panigrahi et al [3]. Several factors may contribute to this disparity, such as differences in diet, habits/ customs, and genetic/environmental factors.…”