Curcumin and its anti-colorectal cancer potential: From mechanisms of action to autophagy.

Colorectal cancer (CRC) development and progression, one of the most common cancers globally, is supported by specific mechanisms to escape cell death despite chemotherapy, including cellular autophagy. Autophagy is an evolutionarily highly conserved degradation pathway involved in a variety of cellular processes, such as the maintenance of cellular homeostasis and clearance of foreign bodies, and its imbalance is associated with many diseases. However, the role of autophagy in CRC progression remains controversial, as it has a dual function, affecting either cell death or survival, and is associated with cellular senescence in tumor therapy. Indeed, numerous data have been presented that autophagy in cancers serves as an alternative to cell apoptosis when the latter is ineffective or in apoptosis-resistant cells, which is why it is also referred to as programmed cell death type II. Curcumin, one of the active constituents of Curcuma longa, has great potential to combat CRC by influencing various cellular signaling pathways and epigenetic regulation in a safe and cost-effective approach. This review discusses the efficacy of curcumin against CRC in vitro and in vivo, particularly its modulation of autophagy and apoptosis in various cellular pathways. While clinical studies have assessed the potential of curcumin in cancer prevention and treatment, none have specifically examined its role in autophagy. Nonetheless, we offer an overview of potential correlations to support the use of this polyphenol as a prophylactic or co-therapeutic agent in CRC.

Agarose spot migration assay to measure the chemoattractant potential of extracellular vesicles: applications in regenerative medicine and cancer metastasis.

BACKGROUND: The recruitment of effector cells is one of the novel functions described for extracellular vesicles (EVs) that needs further study. For instance, cell recruitment by mesenchymal stromal cell derived-EVs (MSC-EVs) is one of the features by which MSC-EVs may induce regeneration and ameliorate tissue injury. On the other hand, increasing evidence suggests that cancer EVs play an important role in the preparation of the pre-metastatic niche (PMN) by recruiting their primary tumour cells. Understanding and measuring the potential of MSC-EVs or cancer-EVs to induce cell migration and recruitment is essential for cell-free therapeutic approaches and/or for a better knowledge of cancer metastasis, respectively. In this context, classical in vitro migration assays do not completely mimic the potential situation by which EVs exert their chemotactic capacity. RESULTS: We adapted an agarose spot migration assay as an in vitro system to evaluate the cell recruitment capacity of locally delivered or localized EVs. Cell migration was tracked for 12 h or 48 h, respectively. Thereafter, endpoint migration images and time-lapse videos were analysed to quantify several parameters aiming to determine the migration of cells to either MSC-EV or pro-metastatic EV. The number of cells contained inside the agarose spots, the migration distance, the area occupied by cells, the directionality of the cell movement, and the Euclidean distance were measured. This multi-parametric evaluation revealed the potential of different MSC-EV preparations to recruit endothelial cells and to detect an enhanced recruitment capacity of highly metastatic PC3-derived EVs (PC3-EVs) compared to low-metastatic LNCaP-EVs in a tumour cell-specific manner. CONCLUSIONS: Overall, this agarose spot migration assay may offer a diversity of measurements and migration settings not provided by classical migration assays and reveal its potential use in the EV field in two different contexts with recruitment in common: regeneration and cancer metastasis.

Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers.

Urological cancer encompasses a diverse range of tumors, including bladder, prostate, renal, upper urinary tract, and germ cell tumors [...].

Curcumin: A therapeutic strategy for colorectal cancer?

Colorectal cancer (CRC) is the second cause of cancer death worldwide. The metastatic disease is mainly treated with aggressive therapies consisting on combinations of cytotoxic chemotherapy plus anti-EGFR or anti-VEGF drugs. In spite of the improvements in clinical outcomes achieved in the last decade, these are the result of multiple new combinations using the existing therapeutic options and the introduction of regorafenib and TAS-102 in second or later lines of treatment. As immunotherapies are limited to less than 5% of CRC patients harboring tumors with deficient mismatch repair, there is an urgent need of finding new drugs to increase our patients' survival opportunities. Among all the natural products that are candidates to be used for the treatment of CRC cancer, curcumin (the golden spice) is in the spotlight. Used for centuries in the Ayurveda medicine, its demonstrated anticancer properties and low toxicity profile made it the focus of hundreds of preclinical and clinical investigations. So far we know that it can be combined with most of the aforementioned drugs in a safe and synergistic way. Regretfully, its poor bioavailability has been one of the main issues for its successful introduction in the clinic. Nevertheless, a plethora of new formulations with a huge increase in bioavailability are under study with promising results. In this review we discuss the possibility of incorporating curcumin in the treatment of CRC; specifically, we review preclinical and clinical data supporting its possible combination with current therapies as well as new formulations under clinical study. It is time for the golden spice revolution.

Nomogram based on baseline clinicopathological characteristics for predicting bladder cancer-specific survival to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

PURPOSE: To develop a risk score based on a prognostic model and a nomogram integrating baseline clinicopathological variables to predict bladder cancer-specific survival (BCSS) to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) patients. METHODS: We retrospectively identified a consecutive sample of 247 MIBC patients treated with cisplatin-based NAC-plus-cystectomy in two Spanish hospitals between 2000 and 2019. Age at MIBC diagnosis, sex, histology, lymphovascular invasion, previous non-MIBC, hydronephrosis, and clinical TNM were included in the initial Cox regression model. A risk score was computed based on the final prognostic model and a nomogram was used to estimate BCSS at 2 and 5 years. RESULTS: Median age was 66 years; 89% were males; 83% had pure urothelial carcinoma; 16.2% had previous non-MIBC. Clinical stage was T2N0, T3-4aN0, and Tx-4N + in 24%, 57%, and 19% of patients, respectively. Complete pathological response was seen in 29.4% and downstaging to non-MIBC (ypT1, ypTa, ypTis) in 12.5% of patients. Overall 5-year BCSS was 59%. Four prognostic factors were identified: variant histology, previous non-MIBC, female sex and hydronephrosis. By adding the points attributed to each of these factors, we categorized patients in three groups: low-risk (0 points); intermediate-risk (1-9 points); high-risk (≥ 10 points). Five-year BCSS was 72%, 53%, and 15%, respectively (p < 0.0001). CONCLUSION: We developed a nomogram and risk score based on four baseline clinicopathological characteristics to predict BCSS to NAC-plus-cystectomy in MIBC patients. If validated in prospective studies, this nomogram can be useful for selecting patients likely to benefit from NAC.

Curcumin: A Novel Way to Improve Quality of Life for Colorectal Cancer Patients?

Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women. Treatment of metastatic CRC consists of highly toxic chemotherapeutic drug combinations that often negatively affect patient quality of life (QoL). Moreover, chemotherapy-induced toxicity and chemotherapy resistance are among the most important factors limiting cancer treatment and can lead to the interruption or discontinuation of potentially effective therapy. Several preclinical studies have demonstrated that curcumin acts through multiple cellular pathways and possesses both anti-cancer properties against CRC and the capacity to mitigate chemotherapy-related side effects and overcome drug resistance. In this review article, we suggest that the addition of curcumin to the standard chemotherapeutic treatment for metastatic CRC could reduce associated side-effects and overcome chemotherapy resistance, thereby improving patient QoL.

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.

Moving towards Personalized Medicine in Muscle-Invasive Bladder Cancer: Where Are We Now and Where Are We Going?

Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the recommended treatment, with the highest level of evidence, for patients with muscle-invasive bladder cancer (MIBC). However, only a minority of patients receive this treatment, mainly due to patient comorbidities, the relatively small survival benefit, and the lack of predictive biomarkers to select those patients most likely to benefit from this multimodal approach. In addition, adjuvant chemotherapy has been recommended for patients with high-risk MIBC, although randomized trials have not provided conclusive evidence on the impact of this approach. At present, however, this situation is changing, largely due to our improved knowledge of the molecular biology of bladder cancer, which has enabled us to identify new prognostic and predictive biomarkers that can be used to select the most appropriate treatment for each patient. Moreover, new active treatments, especially immunotherapy, have shown promising results in the neoadjuvant setting. In addition, the gene expression profile of bladder tumors can be used to classify them into different subtypes, which correlate with specific clinical-pathological characteristics and with treatment response or resistance. Therefore, the main objective for the near future is to introduce these translational breakthroughs into routine clinical practice in order to personalize treatment for each patient.

Microbiota and Resveratrol: How Are They Linked to Osteoporosis?

Osteoporosis (OP), which is characterized by a decrease in bone density and increased susceptibility to fractures, is closely linked to the gut microbiota (GM). It is increasingly realized that the GM plays a key role in the maintenance of the functioning of multiple organs, including bone, by producing bioactive metabolites such as short-chain fatty acids (SCFA). Consequently, imbalances in the GM, referred to as dysbiosis, have been identified with a significant reduction in beneficial metabolites, such as decreased SCFA associated with increased chronic inflammatory processes, including the activation of NF-κB at the epigenetic level, which is recognized as the main cause of many chronic diseases, including OP. Furthermore, regular or long-term medications such as antibiotics and many non-antibiotics such as proton pump inhibitors, chemotherapy, and NSAIDs, have been found to contribute to the development of dysbiosis, highlighting an urgent need for new treatment approaches. A promising preventive and adjuvant approach is to combat dysbiosis with natural polyphenols such as resveratrol, which have prebiotic functions and ensure an optimal microenvironment for beneficial GM. Resveratrol offers a range of benefits, including anti-inflammatory, anti-oxidant, analgesic, and prebiotic effects. In particular, the GM has been shown to convert resveratrol, into highly metabolically active molecules with even more potent beneficial properties, supporting a synergistic polyphenol-GM axis. This review addresses the question of how the GM can enhance the effects of resveratrol and how resveratrol, as an epigenetic modulator, can promote the growth and diversity of beneficial GM, thus providing important insights for the prevention and co-treatment of OP.

Chemotactic signaling pathways in prostate cancer: Implications in the tumor microenvironment and as potential therapeutic targets.

Prostate cancer (PCa) stands as a significant global health concern, ranking among the leading causes of cancer deaths in men. While there are several treatment modalities for localized PCa, metastatic castration-resistant PCa (mCRPC) remains incurable. Despite therapeutic advancements showing promise in mCRPC, their impact on overall survival has been limited. This chapter explores the process by which tumors form, reviews our current understanding of PCa progression to mCRPC, and addresses the challenges of boosting anti-tumor immune responses in these tumors. It specifically discusses how chemotactic signaling affects the tumor microenvironment and its role in immune evasion and cancer progression. The chapter further examines the rationale of directly or indirectly targeting these pathways as adjuvant therapies for mCRPC, highlighting recent pre-clinical and clinical studies currently underway. The discussion emphasizes the potential of targeting specific chemokines and chemokine receptors as combination therapies with mainstream treatments for PCa and mCRPC to maximize long-term survival for this deadly disease.

E-learning pills on immunotherapy in urothelial carcinoma: The E-PIMUC program for continuing medical education.

Background: The high incidence and mortality rates of urothelial carcinoma mean it remains a significant global health concern. Its prevalence is notably pronounced in industrialized countries, with Spain registering one of the highest incidences in Europe. Treatment options are available for various stages of bladder cancer. Moreover, the management landscape for this disease has been significantly transformed by the rapid advances in immunotherapy. Healthcare professionals who diagnose, treat, and follow up with bladder cancer patients need comprehensive training to incorporate these advances into their clinical practice. To bridge these knowledge gaps, we set up the E-PIMUC program to educate healthcare professionals on bladder cancer management and specifically immunotherapy. Methods: E-PIMUC used an innovative microlearning methodology comprising bitesize learning pills that support efficient acquisition of specialized expertise. We used a mixed methods, quantitative and qualitative approach to assess the success of the E-PIMUC program. Data collection encompassed pre-post testing, participation metrics, satisfaction surveys, and self-perceived performance assessments. Results: A total of 751 healthcare professionals enrolled in the program. Of these, 81.0% actively engaged with the content and 33.2% passed all tests and were awarded the course certificate and professional credits. The course received satisfaction ratings of 94.3% to 95.1% and significantly improved the declarative knowledge of participants who had a range of professional profiles (p < 0.001). Participants reported increased confidence in applying immunotherapy principles in their practice (average improvement of 1.4 points). Open-ended responses also underscored participants' perceived benefits, including expanded knowledge and enhanced patient interaction skills. Conclusion: The E-PIMUC program provided effective, comprehensive, cutting-edge training on bladder cancer management, particularly on the use of immunotherapy in this area of oncology. The high participation rates, positive satisfaction scores, substantial knowledge enhancement, and improved self-perceived performance, are all testament to the program's success. E-PIMUC was endorsed by regulatory bodies as a trusted educational resource in urothelial carcinoma management. What is more, complementary initiatives brought together patients and medical experts to foster a holistic, patient-centered approach to the complexities of bladder cancer care.

Dual inhibition of MEK and PI3Kß/δ-a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer.

Background: Docetaxel remains the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). However, resistance frequently emerges as a result of hyperactivation of the PI3K/AKT and the MEK/ERK pathways. Therefore, the inhibition of these pathways presents a potential therapeutic approach. In this study, we evaluated the efficacy of simultaneous inhibition of the PI3K/AKT and MEK/ERK pathways in docetaxel-resistant mCRPC, both in vitro and in vivo. Methods: Docetaxel-sensitive and docetaxel-resistant mCRPC cells were treated with selumetinib (MEK1/2 inhibitor), AZD8186 (PI3Kß/δ inhibitor) and capivasertib (pan-AKT inhibitor) alone and in combination. Efficacy and toxicity of selumetinib+AZD8186 were tested in docetaxel-resistant xenograft mice. CRISPR-Cas9 generated a PTEN-knockdown docetaxel-resistant cell model. Changes in phosphorylation of AKT, ERK and downstream targets were analyzed by Western blot. Antiapoptotic adaptations after treatments were detected by dynamic BH3 profiling. Results: PI3K/AKT and MEK/ERK pathways were hyperactivated in PTEN-wild-type (wt) docetaxel-resistant cells. Selumetinib+AZD8186 decreased cell proliferation and increased apoptosis in PTEN-wt docetaxel-resistant cells. This observation was further confirmed in vivo, where docetaxel-resistant xenograft mice treated with selumetinib+AZD8186 exhibited reduced tumor growth without additional toxicity. Conclusion: Our findings on the activity of selumetinib+AZD8186 in PTEN-wt cells and in docetaxel-resistant xenograft mice provide an excellent rationale for a novel therapeutic strategy for PTEN-wt mCRPC patients resistant to docetaxel, in whom, unlike PTEN-loss patients, a clinical benefit of treatment with single-agent PI3K and AKT inhibitors has not been demonstrated. A phase I-II trial of this promising combination is warranted.

Development and Independent Validation of a Prognostic Gene Expression Signature Based on RB1, PTEN, and TP53 in Metastatic Hormone-sensitive Prostate Cancer Patients.

BACKGROUND: Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC). OBJECTIVE: To study the clinical implications of TSG mRNA expression in mHSPC patients. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective biomarker study in mHSPC patients. TSGlow status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSGwt for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis. RESULTS AND LIMITATIONS: A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSGlow (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSGlow was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSGlow patients, while a significant benefit was observed for ADT + D in the TSGwt group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART. CONCLUSIONS: TSGlow expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted. PATIENT SUMMARY: The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.

Curcumin as a hepatoprotective agent against chemotherapy-induced liver injury.

Despite significant advances in cancer therapeutics, chemotherapy remains the cornerstone of treatment for many tumors. Importantly, however, chemotherapy-induced toxicity, including hepatotoxicity, can lead to the interruption or discontinuation of potentially effective therapy. In recent years, special attention has been paid to the search for complementary therapies to mitigate chemotherapy-induced toxicity. Although there is currently a lack of specific interventions to mitigate or prevent hepatotoxicity in chemotherapy-treated patients, the polyphenol compound curcumin has emerged as a potential strategy to overcome this adverse effect. Here we review, firstly, the molecular and physiological mechanisms and major risk factors of chemotherapy-induced hepatotoxicity. We then present an overview of how curcumin has the potential to mitigate hepatotoxicity by targeting specific molecular mechanisms. Hepatotoxicity is a well-described side effect of cytotoxic drugs that can limit their clinical application. Inflammation and oxidative stress are the most common mechanisms involved in hepatotoxicity. Several studies have shown that curcumin could prevent and/or palliate chemotherapy-induced liver injury, mainly due to its anti-inflammatory, antioxidant, antifibrotic and hypolipidemic properties. Further clinical investigation using bioavailable curcumin formulations is warranted to demonstrate its efficacy as an hepatoprotective agent in cancer patients.

Predictive signature of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer integrating mRNA expression, taxonomic subtypes, and clinicopathological features.

Background and objective: Neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression. Material and methods: From 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method. Results: LASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02). Conclusions: We have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing.

Natural bioactive compounds: a potential therapeutic strategy to sensitize bladder cancer to cisplatin treatment?

Bladder cancer (BC) is the tenth most common cancer, and its incidence is steadily rising worldwide, with the highest rates in developed countries. Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the standard therapy for patients with muscle-invasive bladder cancer. However, less than 50% of patients initially respond to this treatment and nearly all of them eventually develop resistance, which is an important barrier to long-term survival. Therefore, there is an urgent need to understand the mechanisms of cisplatin resistance in BC and develop ways to counteract them. Several preclinical studies have demonstrated that naturally derived bioactive compounds, such as phytochemicals and flavonoids, can enhance the antitumor activity of cisplatin, with minimal side effects, by targeting different pathways involved in cisplatin sensitivity and resistance. However, their poor bioavailability has been one of the main problems for their successful introduction into clinical practice. At present, however, many new formulations with greatly increased bioavailability are under study in several clinical trials with encouraging results.

Neoadjuvant therapy for muscle-invasive bladder cancer: Current clinical scenario, future perspectives, and unsolved questions.

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the standard treatment for patients with muscle-invasive bladder cancer (MIBC). However, the implementation of NAC is lower than desirable mainly due to its limited impact on overall survival, patients' comorbidities and the lack of predictive biomarkers to select those patients most likely to benefit from NAC. In the last decade, improved molecular MIBC characterisation, the identification of potential predictive and prognostic biomarkers as well as the incorporation of new effective therapies with a better toxicity profile, such as immunotherapy, has changed the treatment paradigm for MIBC. Therefore, the main goal for the near future is to introduce these clinical and translational advances into routine clinical practice to personalise treatment for each patient and increase the opportunity to implement bladder preservation strategies. The present review focuses on the current status of NAC in MIBC, unsolved questions and future therapeutic approaches.

Lipid Metabolism and Epigenetics Crosstalk in Prostate Cancer.

Prostate cancer (PCa) is the most commonly diagnosed malignant neoplasm in men in the Western world. Localized low-risk PCa has an excellent prognosis thanks to effective local treatments; however, despite the incorporation of new therapeutic strategies, metastatic PCa remains incurable mainly due to disease heterogeneity and the development of resistance to therapy. The mechanisms underlying PCa progression and therapy resistance are multiple and include metabolic reprogramming, especially in relation to lipid metabolism, as well as epigenetic remodelling, both of which enable cancer cells to adapt to dynamic changes in the tumour. Interestingly, metabolism and epigenetics are interconnected. Metabolism can regulate epigenetics through the direct influence of metabolites on epigenetic processes, while epigenetics can control metabolism by directly or indirectly regulating the expression of metabolic genes. Moreover, epidemiological studies suggest an association between a high-fat diet, which can alter the availability of metabolites, and PCa progression. Here, we review the alterations of lipid metabolism and epigenetics in PCa, before focusing on the mechanisms that connect them. We also discuss the influence of diet in this scenario. This information may help to identify prognostic and predictive biomarkers as well as targetable vulnerabilities.

Macrophages as a Therapeutic Target in Metastatic Prostate Cancer: A Way to Overcome Immunotherapy Resistance?

Prostate cancer (PC) is the most common malignancy and the fifth cause of cancer death in men. The treatment for localized or locally advanced stages offers a high probability of cure. Even though the therapeutic landscape has significantly improved over the last decade, metastatic PC (mPC) still has a poor prognosis mainly due to the development of therapy resistance. In this context, the use of immunotherapy alone or in combination with other drugs has been explored in recent years. However, T-cell directed immune checkpoint inhibitors (ICIs) have shown limited activity with inconclusive results in mPC patients, most likely due to the highly immunosuppressive PC tumor microenvironment (TME). In this scenario, targeting macrophages, a highly abundant immunosuppressive cell type in the TME, could offer a new therapeutic strategy to improve immunotherapy efficacy. In this review, we summarize the growing field of macrophage-directed immunotherapies and discuss how these could be applied in the treatment of mPC, focusing on their combination with ICIs.

Prognostic Impact of CD36 Immunohistochemical Expression in Patients with Muscle-Invasive Bladder Cancer Treated with Cystectomy and Adjuvant Chemotherapy.

Neoadjuvant chemotherapy followed by a cystectomy is the standard treatment in muscle-invasive bladder cancer (MIBC). However, the role of chemotherapy in the adjuvant setting remains controversial, and therefore new prognostic and predictive biomarkers are needed to improve the selection of MIBC patients. While lipid metabolism has been related to several biological processes in many tumours, including bladder cancer, no metabolic biomarkers have been identified as prognostic in routine clinical practice. In this multicentre, retrospective study of 198 patients treated with cystectomy followed by platinum-based adjuvant chemotherapy, we analysed the immunohistochemical expression of CD36 and correlated our findings with clinicopathological characteristics and survival. CD36 immunostaining was positive in 30 patients (15%) and associated with more advanced pathologic stages (pT3b-T4; p = 0.015). Moreover, a trend toward lymph node involvement in CD36-positive tumours, especially in earlier disease stages (pT1-T3; p = 0.101), was also observed. Among patients with tumour progression during the first 12 months after cystectomy, disease-free survival was shorter in CD36-positive tumours than in those CD36-negative (6.51 months (95% CI 5.05-7.96) vs. 8.74 months (95% CI 8.16-9.32); p = 0.049). Our results suggest an association between CD36 immunopositivity and more aggressive features of MIBC and lead us to suggest that CD36 could well be a useful prognostic marker in MIBC.