Extracellular vesicles (EVs) are small lipid membrane vesicles that are secreted from almost all kinds of cells into the extracellular space. EVs are widely accepted to be involved in various cellular processes; in particular, EVs derived from cancer cells have been reported to play important roles in modifying the tumor microenvironment and promoting tumor progression. In addition, EVs derived from cancer cells encapsulate various kinds of tumor-specific molecules, such as proteins and RNAs, which contribute to cancer malignancy. Therefore, the unveiling of the precise mechanism of intercellular communication via EVs in cancer patients will provide a novel strategy for cancer treatment. Furthermore, a focus on the contents of EVs could promote the use of EVs in body fluids as clinically useful diagnostic and prognostic biomarkers. In this review, we summarize the current research knowledge on EVs as biomarkers and therapeutic targets and discuss their potential clinical applications.

Substantial geographical differences in prostate cancer (PCa) incidence and mortality exist, being lower among Asian (ASI) men compared with Caucasian (CAU) men. We prospectively compared PCa prevalence in CAU and ASI men from specific populations with low penetrance of prostate-specific antigen screening. Prostate glands were prospectively obtained during autopsy from men who died from causes other than PCa in Moscow, Russia (CAU), and Tokyo, Japan (ASI). Prostates were removed en-block and analyzed in toto. We compared across the 2 populations PCa prevalence, number and Gleason score (GS) of tumour foci, pathological stage, spatial location, and tumor volume using χ², Mann–Whitney–Wilcoxon tests, and multiple logistic regression. All statistical tests were two-sided. Three hundred twenty prostates were collected, 220 from CAU men and 100 from ASI mean. The mean age was 62.5 in CAU men and 68.5 years in ASI men (P < .001). PCa prevalences of 37.3% in CAU men and 35.0% in ASI men were observed (P = .70). Average tumor volume was 0.303cm³. In men aged greater than 60 years, PCa was observed in more than 40% of prostates, reaching nearly 60% in men aged greater than 80 years. GS 7 or greater cancers accounted for 23.1% and 51.4% of all PCa in CAU and ASI men, respectively, (P = .003). When adjusted for age and prostate weight, ASI men still had a greater probability of having GS 7 or greater PCa (P = .03). PCa is found on autopsy in a similar proportion of Russian and Japanese men. More than 50% of cancers in ASI and nearly 25% of cancers in CAU men have a GS of 7 or greater. Our results suggest that the definition of clinically insignificant PCa might be worth re-examining.

Bone metastasis is an incurable complication of breast cancer. In advanced stages, patients with estrogen-positive tumors experience a significantly higher incidence of bone metastasis (>87%) compared to estrogen-negative patients (<56%). To understand the mechanism of this bone-tropism of ER⁺ tumor, and to identify liquid biopsy biomarkers for patients with high risk of bone metastasis, the secreted extracellular vesicles and cytokines from bone-tropic breast cancer cells are examined in this study. Both exosomal miR-19a and Integrin-Binding Sialoprotein (IBSP) are found to be significantly upregulated and secreted from bone-tropic ER⁺ breast cancer cells, increasing their levels in the circulation of patients. IBSP is found to attract osteoclast cells and create an osteoclast-enriched environment in the bone, assisting the delivery of exosomal miR-19a to osteoclast to induce osteoclastogenesis. Our findings reveal a mechanism by which ER⁺ breast cancer cells create a microenvironment favorable for colonization in the bone. These two secreted factors can also serve as effective biomarkers for ER⁺ breast cancer to predict their risks of bone metastasis. Furthermore, our screening of a natural compound library identifies chlorogenic acid as a potent inhibitor for IBSP-receptor binding to suppress bone metastasis of ER⁺ tumor, suggesting its preventive use for bone recurrence in ER⁺ patients.

Background: The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables. Methods: The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements. Results: ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects. Conclusions: A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor. Impact: Interaction of PTEN and ERG pathways warrants further studies. Cancer Epidemiol Biomarkers Prev; 22(12); 2333–44. ©2013 AACR.

Progress in cancer treatment has improved the survival of patients with advanced-stage cancers. Consequently, the clinical courses of patients are prolonged and often accompanied by morbidity due to bone metastases. Skeletal-related events (SREs), such as pathological fractures and spinal paralysis, cause impairment in activities of daily life and quality of life (QOL). To avoid serious SREs causing impairment in QOL and survival, early diagnosis and a prophylactic approach are required. It is necessary to initiate a bone management program concurrently with the initiation of cancer treatment to prevent complications of bone metastasis. In addition, the requirement of a multidisciplinary approach through a cancer board focusing on the management of bone metastases and involving a team of specialists in oncology, palliative care, radiotherapy, orthopedics, nuclear medicine, radiology, and physiatrists has been emphasized. In the cancer board, a strong focus is placed on the prevention of complications due to bone metastases and on reductions in the high morbidity, hospitalization rate, and overall costs associated with advanced-stage cancers. Recent reports suggest the usefulness of such approaches. The multidisciplinary approach through a cancer board would improve QOL and prognosis of patients, leading to new or continued systemic therapy for primary cancers.