Case report: EBV-related eye orbits and sinuses lymphohistiocytic infiltration responsive to rituximab in a patient with X lymphoproliferative syndrome type 1.

Background and aims: X lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity due to mutations of SH2D1A, encoding for slam-associated protein (SAP). The clinical phenotype includes severe mononucleosis, hemophagocytic lymphohistiocytosis (HLH), and B-cell lymphomas. Methods: We report the case of a child affected with XLP1 who presented with an incomplete HLH, triggered by Epstein-Barr virus (EBV) and treated with rituximab, involving orbits and paranasal sinuses. Results: The lesion was indistinguishable from lymphoma, complicating diagnosis and treatment. In addition, considering the high incidence of lymphoma in patients with XLP1, histology helped define its nature, driving therapeutic choices. Conclusion: We described an unusual presentation of incomplete HLH in a patient affected with XLP1: an EBV-driven infiltration of the orbits and paranasal sinuses. This led us to a challenging differential diagnosis of lymphoma-associated hemophagocytic syndrome, which can be frequently observed in patients with XLP1. Considering the extremely poor prognosis of this clinical finding, we sought for a prompt diagnosis and managed to obtain it and to immediately establish the right treatment on the basis of the pathological finding.

Cannabidiol Inhibits the Proliferation and Invasiveness of Prostate Cancer Cells.

Prostate cancer is the fifth leading cause of cancer death in men, responsible for over 375,000 deaths in 2020. Novel therapeutic strategies are needed to improve outcomes. Cannabinoids, chemical components of the cannabis plant, are a possible solution. Preclinical evidence demonstrates that cannabinoids can modulate several cancer hallmarks of many tumor types. However, the therapeutic potential of cannabinoids in prostate cancer has not yet been fully explored. The aim of this study was to investigate the antiproliferative and anti-invasive properties of cannabidiol (CBD) in prostate cancer cells in vitro. CBD inhibited cell viability and proliferation, accompanied by reduced expression of key cell cycle proteins, specifically cyclin D3 and cyclin-dependent kinases CDK2, CDK4, and CDK1, and inhibition of AKT phosphorylation. The effects of CBD on cell viability were not blocked by cannabinoid receptor antagonists, a transient receptor potential vanilloid 1 (TRPV1) channel blocker, or an agonist of the G-protein-coupled receptor GPR55, suggesting that CBD acts independently of these targets in prostate cancer cells. Furthermore, CBD reduced the invasiveness of highly metastatic PC-3 cells and increased protein expression of E-cadherin. The ability of CBD to inhibit prostate cancer cell proliferation and invasiveness suggests that CBD may have potential as a future chemotherapeutic agent.

SRF inhibitors reduce prostate cancer cell proliferation through cell cycle arrest in an isogenic model of castrate-resistant prostate cancer.

Castrate-resistant prostate cancer (CRPC) is challenging to treat, despite improvements with next-generation anti-androgens such as enzalutamide, due to acquired resistance. One of the mechanisms of such resistance includes aberrant activation of co-factors of the androgen receptor (AR), such as the serum response factor (SRF), which was associated with prostate cancer progression and resistance to enzalutamide. Here, we show that inhibition of SRF with three small molecules (CCG-1423, CCG-257081 and lestaurtinib), singly and in combination with enzalutamide, reduces cell viability in an isogenic model of CRPC. The effects of these inhibitors on the cell cycle, singly and in combination with enzalutamide, were assessed with western blotting, flow cytometry and ß-galactosidase staining. In the androgen deprivation-sensitive LNCaP parental cell line, a synergistic effect between enzalutamide and all three inhibitors was demonstrated, while the androgen deprivation-resistant LNCaP Abl cells showed synergy only with the lestaurtinib and enzalutamide combination, suggesting a different mechanism of action of the CCG series of compounds in the absence and presence of androgens. Through analysis of cell cycle checkpoint proteins, flow cytometry and ß-galactosidase staining, we showed that all three SRF inhibitors, singly and in combination with enzalutamide, induced cell cycle arrest and decreased S phase. While CCG-1423 had a more pronounced effect on the expression of cell cycle checkpoint proteins, CCG-257081 and lestaurtinib decreased proliferation also through induction of cellular senescence. In conclusion, we show that inhibition of an AR co-factors, namely SRF, provides a promising approach to overcoming resistance to AR inhibitors currently used in the clinic.

Emerging role for the Serum Response Factor (SRF) as a potential therapeutic target in cancer.

INTRODUCTION: The Serum Response Factor (SRF) is a transcription factor involved in three hallmarks of cancer: the promotion of cell proliferation, cell death resistance and invasion and metastasis induction. Many studies have demonstrated a leading role in the development and progression of multiple cancer types, thus highlighting the potential of SRF as a prognostic biomarker and therapeutic target, especially for cancers with poor prognosis. AREAS COVERED: This review examines the role of SRF in several cancers in promoting cellular processes associated with cancer development and progression. SRF co-factors and signaling pathways are discussed as possible targets to inhibit SRF in a tissue and cancer-specific way. Small-molecule inhibitors of SRF, such as the CCGs series of compounds and lestaurtinib, which could be used as cancer therapeutics, are also discussed. EXPERT OPINION: Targeting of SRF and its co-factors represents a promising therapeutic approach. Further understanding of the molecular mechanisms behind the action of SRF could provide a pipeline of novel molecular targets and therapeutic combinations for cancer. Basket clinical trials and the use of SRF immunohistochemistry as companion diagnostics will help testing of these new targets in patients.

Evaluation of a Real-time PCR in Combination with a Cultivation Method for the Detection of Brucella Abortus in Organs of Infected Cattle in Southern Italy.

Introduction: Brucellosis is a widespread zoonosis of great economic importance for livestock farming in many areas of the world. It is a highly infectious disease which is diagnosed using conventional serological and microbiological methods. The aim of this study was to assess the efficiency of a specific real-time PCR in combination with broth cultivation in detecting Brucella spp. in organs of infected cattle, in order to compare the sensitivity of the two approaches and the time needed in them until a correct diagnosis is made. Material and Methods: We examined 67 organs collected from 10 cattle slaughtered following a brucellosis outbreak which occurred in February 2016 in southern Italy. The research was carried out by enrichment broth cultivations in combination with a real-time PCR every week for six weeks. Results: Brucella strains were isolated by cultivation from 44 enrichment broths of organs. All isolates were later identified as Brucella abortus by real-time PCR. Using this method in combination with cultivation made it possible to identify the same percentage of infected animals faster than by cultivation alone. Moreover, the same diagnostic results were obtained, on average two weeks before they would have been using only cultivation. In almost all cases, Brucella was detected by real-time PCR after the first week of cultivation in pre-enrichment Brucella broth, while the bacterial growth was evident usually after 2 or 3 weeks. Conclusion: Real-time PCR has allowed results to be obtained faster than in the classical microbiological method, reducing the response times to identify positive animals by half.

Inhibition of Serum Response Factor Improves Response to Enzalutamide in Prostate Cancer.

Castrate-resistant prostate cancer (CRPC) is challenging to treat with the androgen receptor (AR), the main target and key focus of resistance. Understanding the mechanisms of AR interaction with co-regulators will identify new therapeutic targets to overcome AR resistance mechanisms. We previously identified the serum response factor (SRF) as a lead target in an in vitro model of CRPC and showed that SRF expression in tissues of CRPC patients was associated with shorter survival. Here, we tested SRF inhibition in vitro and in vivo to assess SRF as a potential target in CRPC. Inhibition of SRF with the small-molecule inhibitor CCG1423 resulted in enhanced response to enzalutamide in vitro and reduced tumour volume of LuCaP 35CR, a CRPC patient-derived xenograft model. Nuclear localisation of AR post-CCG1423 was significantly decreased and was associated with decreased α-tubulin acetylation in vitro and decreased prostate specific antigen (PSA) levels in vivo. SRF immunoreactivity was tested in metastatic tissues from CRPC patients to investigate its role in enzalutamide response. Kaplan-Meier curves showed that high SRF expression was associated with shorter response to enzalutamide. Our study supports the use of SRF inhibitors to improve response to enzalutamide.

Sub-Toxic Concentrations of Ionic Liquids Enhance Cell Migration by Reducing the Elasticity of the Cellular Lipid Membrane.

Cell migration is a universal and crucial mechanism for life. It is required in a series of physiological processes, in wound repair and immune response and is involved in several pathological conditions, including cancer and virus dissemination. Among the several biochemical and biophysical routes, changing cell membrane elasticity holds the promise to be a universal strategy to alter cell mobility. Due to their affinity with cell membranes, ionic liquids (ILs) may play an important role. This work focuses on the effect of subtoxic amounts of imidazolium-ILs on the migration of the model cancer cell line MDA-MB-231. Here we show that ILs are able to enhance cell mobility by reducing the elasticity of the cellular lipid membrane, and that both mobility and elasticity can be tuned by IL-concentration and IL-cation chain length. This biochemical-physical mechanism is potentially valid for all mammalian cells, and its impact in bionanomedicine and bionanotechnology is discussed.

Clinical Phenotype, Immunological Abnormalities, and Genomic Findings in Patients with DiGeorge Spectrum Phenotype without 22q11.2 Deletion.

BACKGROUND: The phenotype of early embryonic fourth branchial arch defects encompasses a wide spectrum of clinical conditions including DiGeorge syndrome (DGS), velocardiofacial syndrome, and conotruncal anomaly face syndrome. The majority of the patients have a 22q11.2 deletion. However, in 6% to 17% of patients, the identification of a genetic cause remains unknown through fluorescence in situ hybridization. In these patients, the clinical features and the immunological abnormalities are not well defined. OBJECTIVE: To describe the main genomic abnormalities, clinical features, and immunological abnormalities of a cohort of patients resembling the 22q11.2 deletion phenotype in the absence of 22q11.2 locus alterations. METHODS: Eleven patients from unrelated nonconsanguineous families with suspected 22q11.2 deletion syndrome (22q11.2DS) according to Tobias criteria were enrolled. Array-comparative genomic hybridization was performed in 10 patients. A phenotypic and immunological assessment was performed in all patients. RESULTS: The majority of patients had a phenotype overlapping with 22q11.2DS and immunological abnormalities suggestive of abnormalities in T-cell development, being severe in 2 of them. Most subjects suffered from recurrent infections. Clinically overt autoimmune manifestations were identified in 2 (18%) subjects. New pathogenic or likely pathogenic genomic regions associated with 22q11.2DS features were identified. CONCLUSION: Patients with a DGS-like phenotype share the same features of the classical 22q11.2DS associated with other rare genomic alterations. Severe forms of immunodeficiency may also be observed in this group.

Novel Strategies for Cancer Treatment: Highlights from the 55th IACR Annual Conference.

While conventional cancer treatments, such as surgery, radiotherapy and chemotherapy, have been combined for decades in an effort to treat cancer patients, the emergence of novel fields of cancer research have led to a renewed interest in combining conventional treatments with more innovative approaches. The realisation that cancer progression is not exclusively due to changes in the cancer epithelial cells, but also involves changes in the tumour microenvironment, has opened new avenues for combination treatments. Here we discuss the use of combination therapies presented at the 55th Irish Association for Cancer Research (IACR) Annual Conference, highlighting examples of novel therapeutic strategies which, combined with conventional therapies, may greatly enhance not only the overall outcome for patients, but also the quality of life for cancer survivors. Among the novel treatment strategies, immune metabolism, epigenetic therapies and physical exercise are presented. In addition, novel technologies in the field of precision medicine, which will be useful to discover new therapeutics and to stratify patients for combination treatments, are also discussed.

Innovative Technologies Changing Cancer Treatment.

Conventional therapies for cancer such as chemotherapy and radiotherapy remain a mainstay in treatment, but in many cases a targeted approach is lacking, and patients can be vulnerable to drug resistance. In recent years, novel concepts have been emerging to improve the traditional therapeutic options in cancers with poor survival outcomes. New therapeutic strategies involving areas like energy metabolism and extracellular vesicles along with advances in immunotherapy and nanotechnology are driving the next generation of cancer treatments. The development of fields such as theranostics in nanomedicine is also opening new doors for targeted drug delivery and nano-imaging. Here we discuss the use of innovative technologies presented at the Irish Association for Cancer Research (IACR) Annual Meeting, highlighting examples of where new approaches may lead to promising new treatment options for a range of cancer types.

Role of serum response factor expression in prostate cancer biochemical recurrence.

BACKGROUND: Up to a third of prostate cancer patients fail curative treatment strategies such as surgery and radiation therapy in the form of biochemical recurrence (BCR) which can be predictive of poor outcome. Recent clinical trials have shown that men experiencing BCR might benefit from earlier intervention post-radical prostatectomy (RP). Therefore, there is an urgent need to identify earlier prognostic biomarkers which will guide clinicians in making accurate diagnosis and timely decisions on the next appropriate treatment. The objective of this study was to evaluate Serum Response Factor (SRF) protein expression following RP and to investigate its association with BCR. MATERIALS AND METHODS: SRF nuclear expression was evaluated by immunohistochemistry (IHC) in TMAs across three international radical prostatectomy cohorts for a total of 615 patients. Log-rank test and Kaplan-Meier analyses were used for BCR comparisons. Stepwise backwards elimination proportional hazard regression analysis was used to explore the significance of SRF in predicting BCR in the context of other clinical pathological variables. Area under the curve (AUC) values were generated by simulating repeated random sub-samples. RESULTS: Analysis of the immunohistochemical staining of benign versus cancer cores showed higher expression of nuclear SRF protein expression in cancer cores compared with benign for all the three TMAs analysed (P < 0.001, n = 615). Kaplan-Meier curves of the three TMAs combined showed that patients with higher SRF nuclear expression had a shorter time to BCR compared with patients with lower SRF expression (P < 0.001, n = 215). Together with pathological T stage T3, SRF was identified as a predictor of BCR using stepwise backwards elimination proportional hazard regression analysis (P = 0.0521). Moreover ROC curves and AUC values showed that SRF was better than T stage in predicting BCR at year 3 and 5 following radical prostatectomy, the combination of SRF and T stage had a higher AUC value than the two taken separately. CONCLUSIONS: SRF assessment by IHC following RP could be useful in guiding clinicians to better identify patients for appropriate follow-up and timely treatment.

The role of epithelial-mesenchymal transition drivers ZEB1 and ZEB2 in mediating docetaxel-resistant prostate cancer.

Docetaxel is the main treatment for advanced castration-resistant prostate cancer; however, resistance eventually occurs. The development of intratumoral drug-resistant subpopulations possessing a cancer stem cell (CSC) morphology is an emerging mechanism of docetaxel resistance, a process driven by epithelial-mesenchymal transition (EMT). This study characterised EMT in docetaxel-resistant sublines through increased invasion, MMP-1 production and ZEB1 and ZEB2 expression. We also present evidence for differential EMT across PC-3 and DU145 in vitro resistance models as characterised by differential migration, cell colony scattering and susceptibility to the CSC inhibitor salinomycin. siRNA manipulation of ZEB1 and ZEB2 in PC-3 and DU145 docetaxel-resistant sublines identified ZEB1, through its transcriptional repression of E-cadherin, to be a driver of both EMT and docetaxel resistance. The clinical relevance of ZEB1 was also determined through immunohistochemical tissue microarray assessment, revealing significantly increased ZEB1 expression in prostate tumours following docetaxel treatment. This study presents evidence for a role of ZEB1, through its transcriptional repression of E-cadherin to be a driver of both EMT and docetaxel resistance in docetaxel-resistant prostate cancer. In addition, this study highlights the heterogeneity of prostate cancer and in turn emphasises the complexity of the clinical management of docetaxel-resistant prostate cancer.

Abnormal cell-clearance and accumulation of autophagic vesicles in lymphocytes from patients affected with Ataxia-Teleangiectasia.

Ataxia-Teleangiectasia (A-T) is a neurodegenerative disorder due to mutations in ATM gene. ATM in the nucleus ensures DNA repair, while its role in the cytosol is still poorly clarified. Abnormal autophagy has been documented in other neurodegenerative disorders, thus we evaluated whether alteration in this process may be involved in the pathogenesis of A-T by analyzing the autophagic vesicles and the genes implicated in the different stages of autophagy. Through transmission electron microscopy (TEM) and immunofluorescence analysis we observed an accumulation of APs associated with a LC3 puncta pattern, and a reduced number of ALs. We also documented an increased expression of genes involved in AP and lysosome biogenesis and function, and a decrease of Vps18 expression, involved in their vesicular trafficking and fusion. mTORC1-controlled proteins were hyperphosphorylated in A-T, in keeping with an increased mTOR inhibitory influence of autophagy. Betamethasone is able to promote the degradation of SQSTM1, a biomarker of autophagy. Collectively, our results indicate that in cells from A-T patients, the APs maturation is active, while the fusion between APs and lysosomes is inappropriate, thus implying abnormalities in the cell-clearance process. We also documented a positive effect of Betamethasone on molecules implicated in autophagosome degradation.

Relationship between serum response factor and androgen receptor in prostate cancer.

BACKGROUND: Serum response factor (SRF) is an important transcription factor in castrate-resistant prostate cancer (CRPC). Since CRPC is associated with androgen receptor (AR) hypersensitivity, we investigated the relationship between SRF and AR. MATERIALS AND METHODS: Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry. RESULTS: To investigate AR involvement in SRF response to androgen, AR expression was down-regulated using siRNA. This resulted in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in AR-negative PC346 DCC cells, which was only restored following AR over-expression. Next, SRF expression was down-regulated by siRNA, resulting in AR increased transcriptional activity in castrate-resistant LNCaP Abl cells but not in the parental LNCaP. This negative feedback loop in the resistant cells was confirmed by immunohistochemistry which showed a negative correlation between AR and SRF expression in CRPC bone metastases and a positive correlation in androgen-naïve prostatectomies. Cell proliferation was next assessed following SRF inhibition, demonstrating that SRF inhibition is more effective than AR inhibition in castrate-resistant cells. CONCLUSION: Our data support SRF as a promising therapeutic target in combination with current treatments.

Commercialized biomarkers: new horizons in prostate cancer diagnostics.

Limitations with current clinical tools available for diagnosis and prognosis of prostate cancer (PCa) have resulted in overdiagnosis and costly overtreatment, which is affecting the outcomes and quality of life of men. The biotech industry is investing significant resources into developing more specific biomarkers for PCa detection and patient stratification that would greatly advance the decision-making processes behind PCa management and treatment. In this review, we focus on those biomarkers that have been translated into commercial tests available to clinicians. Since these tests aim to fill specific gaps during the decision-making process of PCa management, we have grouped them based on the clinical question they claim to address, that is, improved PCa screening, false-negative biopsy dilemma, prognostic tests following a positive biopsy and tests predicting relapse/metastases after surgery. We evaluate each test with respect to its development, platform, clinical validation, biomatrix, regulatory approval status and cost.

Spindle assembly checkpoint protein expression correlates with cellular proliferation and shorter time to recurrence in ovarian cancer.

Ovarian carcinoma (OC) is the most lethal of the gynecological malignancies, often presenting at an advanced stage. Treatment is hampered by high levels of drug resistance. The taxanes are microtubule stabilizing agents, used as first-line agents in the treatment of OC that exert their apoptotic effects through the spindle assembly checkpoint. BUB1-related protein kinase (BUBR1) and mitotic arrest deficient 2 (MAD2), essential spindle assembly checkpoint components, play a key role in response to taxanes. BUBR1, MAD2, and Ki-67 were assessed on an OC tissue microarray platform representing 72 OC tumors of varying histologic subtypes. Sixty-one of these patients received paclitaxel and platinum agents combined; 11 received platinum alone. Overall survival was available for all 72 patients, whereas recurrence-free survival (RFS) was available for 66 patients. Increased BUBR1 expression was seen in serous carcinomas, compared with other histologies (P = .03). Increased BUBR1 was significantly associated with tumors of advanced stage (P = .05). Increased MAD2 and BUBR1 expression also correlated with increased cellular proliferation (P < .0002 and P = .02, respectively). Reduced MAD2 nuclear intensity was associated with a shorter RFS (P = .03), in ovarian tumors of differing histologic subtype (n = 66). In this subgroup, for those women who received paclitaxel and platinum agents combined (n = 57), reduced MAD2 intensity also identified women with a shorter RFS (P < .007). For the entire cohort of patients, irrespective of histologic subtype or treatment, MAD2 nuclear intensity retained independent significance in a multivariate model, with tumors showing reduced nuclear MAD2 intensity identifying patients with a poorer RFS (P = .05).

The role of transcription factors in prostate cancer and potential for future RNA interference therapy.

INTRODUCTION: Prostate cancer is a leading cause of cancer-related death in men and current treatments offer only a modest survival benefit in advanced stages of the disease. RNA interference (RNAi) is a therapeutic option that has received great attention in recent years with the potential to treat a variety of disorders, including prostate cancer. Transcription factors are cellular proteins that can up-regulate or down-regulate the transcription of genes and offer promising therapeutic targets. AREAS COVERED: This review will focus on transcription factors that have been identified as key molecules in drug resistance, disease progression and metastases in prostate cancer, which may offer potential as therapeutic targets for RNAi in the future. EXPERT OPINION: By identifying therapeutically viable transcription factor targets in prostate cancer, it is hoped that treatment strategies using RNAi will augment the effect of current chemotherapy regimens, slow disease progression and reduce metastases in prostate cancer, resulting in disease regression.

The analysis of serum response factor expression in bone and soft tissue prostate cancer metastases.

BACKGROUND: Castration-resistant prostate cancer (CRPC) represents a challenge to treat with no effective treatment options available. We recently identified serum response factor (SRF) as a key transcription factor in an in vitro model of castration resistance where we showed that SRF inhibition resulted in reduced cellular proliferation. We also demonstrated an association between SRF protein expression and CRPC in a cohort of castrate-resistant transurethral resections of the prostate (TURPS). The mechanisms regulating the growth of CRPC bone and visceral metastases have not been explored in depth due to the paucity of patient-related material available for analysis. In this study, we aim to evaluate SRF protein expression in prostate cancer (PCa) metastases, which has not previously been reported. METHODS AND RESULTS: We evaluated the nuclear tissue expression profile of SRF by immunohistochemistry in 151 metastatic sites from 42 patients who died of advanced PCa. No relationship between SRF nuclear expression and the site of metastasis was observed (P = 0.824). However, a negative association between SRF nuclear expression in bone metastases and survival from (a) diagnosis with PCa (P = 0.005) and (b) diagnosis with CRPC (P = 0.029) was seen. These results demonstrate that SRF nuclear expression in bone metastases is associated with survival, with patients with the shortest survival showing high SRF nuclear expression and patients with the longest survival having low SRF nuclear expression. CONCLUSION: Our study indicates that SRF is a key factor determining patients' survival in metastatic CRPC and therefore may represent a promising target for future therapies.

Identification of transcription factors associated with castration-resistance: is the serum responsive factor a potential therapeutic target?

BACKGROUND: Advanced prostate cancer is treated by hormone ablation therapy. However, despite an initial response, the majority of men relapse to develop castration-resistant disease for which there are no effective treatments. We have previously shown that manipulating individual proteins has only minor alterations on the resistant phenotype so we hypothesize that targeting the central transcription factors (TFs) would represent a better therapeutic approach. METHODS: We have undertaken a transcriptomic analysis of gene expression differences between the androgen-dependent LNCaP parental cells and its castration-resistant Abl and Hof sublines, revealing 1,660 genes associated with castration-resistance. Using effective bioinformatic techniques, these transcriptomic data were integrated with TF binding sites resulting in a list of TFs associated with the differential gene expression observed. RESULTS: Following validation of the gene-chip results, the serum response factor (SRF) was chosen for clinical validation and functional analysis due to its recent association with prostate cancer progression. SRF immunoreactivity in prostate tumor samples was shown for the first time to be associated with castration-resistance. SRF inhibition by siRNA and the small molecule inhibitor CCG-1423 resulted in decreased proliferation. CONCLUSION: SRF is a key TF by which resistant cells survive with depleted levels of androgens representing a target for therapeutic manipulation.

Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes.

BACKGROUND: Hormone-refractory prostate cancer remains hindered by inevitable progression of resistance to first-line treatment with docetaxel. Recent studies suggest that phenotypic changes associated with cancer may be transferred from cell-to-cell via microvesicles/exosomes. Here we aimed to investigate phenotypic changes associated with docetaxel-resistance in order to help determine the complexity of this problem and to assess the relevance of secreted exosomes in prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: Docetaxel-resistant variants of DU145 and 22Rv1 were established and characterised in terms of cross-resistance, morphology, proliferation, motility, invasion, anoikis, colony formation, exosomes secretion their and functional relevance. Preliminary analysis of exosomes from relevant serum specimens was also performed. Acquired docetaxel-resistance conferred cross-resistance to doxorubicin and induced alterations in motility, invasion, proliferation and anchorage-independent growth. Exosomes expelled from DU145 and 22Rv1 docetaxel-resistant variants (DU145RD and 22Rv1RD) conferred docetaxel-resistance to DU145, 22Rv1 and LNCap cells, which may be partly due to exosomal MDR-1/P-gp transfer. Exosomes from prostate cancer patients' sera induced increased cell proliferation and invasion, compared to exosomes from age-matched controls. Furthermore, exosomes from sera of patients undergoing a course of docetaxel treatment compared to matched exosomes from the same patients prior to commencing docetaxel treatment, when applied to both DU145 and 22Rv1 cells, showed a correlation between cellular response to docetaxel and patients' response to treatment with docetaxel. CONCLUSIONS/SIGNIFICANCE: Our studies indicate the complex and multifaceted nature of docetaxel-resistance in prostate cancer. Furthermore, our in vitro observations and preliminary clinical studies indicate that exosomes may play an important role in prostate cancer, in cell-cell communication, and thus may offer potential as vehicles containing predictive biomarkers and new therapeutic targets.