Endogenous ether lipids differentially promote tumor aggressiveness by regulating the SK3 channel.

SK3 channels are potassium channels found to promote tumor aggressiveness. We have previously demonstrated that SK3 is regulated by synthetic ether lipids, but the role of endogenous ether lipids is unknown. Here, we have studied the role of endogenous alkyl- and alkenyl-ether lipids on SK3 channels and on the biology of cancer cells. Experiments revealed that the suppression of alkylglycerone phosphate synthase or plasmanylethanolamine desaturase 1, which are key enzymes for alkyl- and alkenyl-ether-lipid synthesis, respectively, decreased SK3 expression by increasing micro RNA (miR)-499 and miR-208 expression, leading to a decrease in SK3-dependent calcium entry, cell migration, and matrix metalloproteinase 9-dependent cell adhesion and invasion. We identified several ether lipids that promoted SK3 expression and found a differential role of alkyl- and alkenyl-ether lipids on SK3 activity. The expressions of alkylglycerone phosphate synthase, SK3, and miR were associated in clinical samples emphasizing the clinical consistency of our observations. To our knowledge, this is the first report showing that ether lipids differentially control tumor aggressiveness by regulating an ion channel. This insight provides new possibilities for therapeutic interventions, offering clinicians an opportunity to manipulate ion channel dysfunction by adjusting the composition of ether lipids.

Variable effects of periprostatic adipose tissue on prostate cancer cells: Role of adipose tissue lipid composition and cancer cells related factors.

BACKGROUND: Periprostatic adipose tissue (PPAT) is likely to modulate prostate cancer (PCa) progression. We analyzed the variations in the effect of PPAT on cancer cells, according to its fatty acid (FA) composition and tumor characteristics. METHODS: The expression of markers of aggressiveness Ki67 and Zeb1, and epigenetic marks that could be modified during PCa progression, was analyzed by immunohistochemistry on a tissue-micro-array containing 59 pT3 PCa, including intra-prostatic areas and extra-prostatic foci in contact with PPAT belonging to the same tumor. In addition, we cocultivated PC3 and LNCaP cell lines with PPAT, which were then analyzed for FA composition. RESULTS: Although the contact between PPAT and cancer cells led overall to an increase in Ki67 and Zeb1, and a decrease in the epigenetic marks 5MC, 5HMC, and H3K27ac, these effects were highly heterogeneous. Increased proliferation in extra-prostatic areas was associated with the international society of uropathology score. PC3 and LNCaP cocultures with PPAT led to increased Ki67, Zeb1 and H3K27me3, but only for PPAT associated with aggressive PCa. PC3 proliferation was correlated with high 20.2 n-6 and low 20.5n-3 in PPAT. CONCLUSIONS: These results suggest that the effects of PPAT on cancer cells may depend on both PCa characteristics and PPAT composition, and could lead to propose nutritional supplementation.

Potassium and Calcium Channel Complexes as Novel Targets for Cancer Research.

The intracellular Ca2+ concentration is mainly controlled by Ca2+ channels. These channels form complexes with K+ channels, which function to amplify Ca2+ flux. In cancer cells, voltage-gated/voltage-dependent Ca2+ channels and non-voltage-gated/voltage-independent Ca2+ channels have been reported to interact with K+ channels such as Ca2+-activated K+ channels and voltage-gated K+ channels. These channels are activated by an increase in cytosolic Ca2+ concentration or by membrane depolarization, which induces membrane hyperpolarization, increasing the driving force for Ca2+ flux. These complexes, composed of K+ and Ca2+ channels, are regulated by several molecules including lipids (ether lipids and cholesterol), proteins (e.g. STIM), receptors (e.g. S1R/SIGMAR1), and peptides (e.g. LL-37) and can be targeted by monoclonal antibodies, making them novel targets for cancer research.

Porocarcinomas with PAK1/2/3 fusions: a series of 12 cases.

AIMS: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2-fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions. METHODS AND RESULTS: Five patients were male and the median age was 79 years (ranges: 59-95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases. CONCLUSION: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement.

Micro-ultrasound-guided biopsies versus systematic biopsies in the detection of prostate cancer: a systematic review and meta-analysis.

PURPOSE: The diagnosis of prostate cancer (PCa) still relies on the performance of both targeted (TB) and systematic biopsies (SB). Micro-ultrasound (mUS)-guided biopsies demonstrated a high sensitivity in detecting clinically significant prostate cancer (csPCa), which could be comparable to that of magnetic resonance imaging (MRI)-TB, but their added value has not been compared to SB yet. METHODS: We conducted a systematic review and meta-analysis, based on Medline, EMBASE, Scopus, and Web of Science, in accordance with PRISMA guidelines, to compare mUS-guided biopsies to SB. RESULTS: Based on the literature search of 2957 articles, 15 met the inclusion criteria (2967 patients). Most patients underwent mUS-guided biopsies, followed by MRI-TB and SB. Respectively 5 (n = 670) and 4 (n = 467) studies, providing raw data on SB, were included in a random-effect meta-analysis of the detection rate of csPCa, i.e. Gleason Grade Group (GGG) ≥ 2 or non-csPCa (GGG = 1). Overall, PCa was detected in 56-71% of men, with 31.3-49% having csPCa and 17-25.4% having non-csPCa. Regarding csPCa, mUS-guided biopsies identified 196 and SB 169 cases (Detection Ratio (DR): 1.18, 95% CI 0.83-1.68, I2 = 69%), favoring mUS-guided biopsies; regarding non-csPCa, mUS-guided biopsies identified 62 and SB 115 cases (DR: 0.55, 95% CI 0.41-0.73, I2 = 0%), also favoring mUS-guided biopsies by decreasing unnecessary diagnosis. CONCLUSION: Micro-ultrasound-guided biopsies compared favorably with SB for the detection of csPCa and detected fewer non-csPCa than SB. Prospective trials are awaited to confirm the interest of adding mUS-guided biopsies to MRI-TB to optimize csPCa detection without increasing overdiagnosis of non-csPCa.

What is the ideal combination therapy in de novo, oligometastatic, castration-sensitive prostate cancer?

PURPOSE: To review current evidence regarding the management of de novo, oligometastatic, castration-sensitive prostate cancer (PCa). METHODS: A literature search was conducted on PubMed/Medline and a narrative synthesis of the evidence was performed in August 2022. RESULTS: Oligometastatic disease is an intermediate state between localized and aggressive metastatic PCa defined by ≤ 3-5 metastatic lesions, although this definition remains controversial. Conventional imaging has limited accuracy in detecting metastatic lesions, and the implementation of molecular imaging could pave the way for a more personalized treatment strategy. However, oncological data supporting this strategy are needed. Radiotherapy to the primary tumor should be considered standard treatment for oligometastatic PCa (omPCa). However, it remains to be seen whether local therapy still has an additional survival benefit in patients with de novo omPCa when treated with the most modern systemic therapy combinations. There is insufficient evidence to recommend cytoreductive radical prostatectomy as local therapy; or stereotactic body radiotherapy as metastasis-directed therapy in patients with omPCa. Current data support the use of intensified systemic therapy with androgen deprivation therapy (ADT) and next-generation hormone therapies (NHT) for patients with de novo omPCa. Docetaxel has not demonstrated benefit in low volume disease. There are insufficient data to support the use of triple therapy (i.e., ADT + NHT + Docetaxel) in low volume disease. CONCLUSION: The present review discusses current data in de novo, omPCa regarding its definition, the increasing role of molecular imaging, the place of local and metastasis-directed therapies, and the intensification of systemic therapies.

Expanding inclusion criteria for active surveillance in intermediate-risk prostate cancer: a machine learning approach.

PURPOSE: To develop new selection criteria for active surveillance (AS) in intermediate-risk (IR) prostate cancer (PCa) patients. METHODS: Retrospective study including patients from 14 referral centers who underwent pre-biopsy mpMRI, image-guided biopsies and radical prostatectomy. The cohort included biopsy-naive IR PCa patients who met the following inclusion criteria: Gleason Grade Group (GGG) 1-2, PSA < 20 ng/mL, and cT1-cT2 tumors. We relied on a recursive machine learning partitioning algorithm developed to predict adverse pathological features (i.e., ≥ pT3a and/or pN + and/or GGG ≥ 3). RESULTS: A total of 594 patients with IR PCa were included, of whom 220 (37%) had adverse features. PI-RADS score (weight:0.726), PSA density (weight:0.158), and clinical T stage (weight:0.116) were selected as the most informative risk factors to classify patients according to their risk of adverse features, leading to the creation of five risk clusters. The adverse feature rates for cluster #1 (PI-RADS ≤ 3 and PSA density < 0.15), cluster #2 (PI-RADS 4 and PSA density < 0.15), cluster #3 (PI-RADS 1-4 and PSA density ≥ 0.15), cluster #4 (normal DRE and PI-RADS 5), and cluster #5 (abnormal DRE and PI-RADS 5) were 11.8, 27.9, 37.3, 42.7, and 65.1%, respectively. Compared with the current inclusion criteria, extending the AS criteria to clusters #1 + #2 or #1 + #2 + #3 would increase the number of eligible patients (+ 60 and + 253%, respectively) without increasing the risk of adverse pathological features. CONCLUSIONS: The newly developed model has the potential to expand the number of patients eligible for AS without compromising oncologic outcomes. Prospective validation is warranted.

Endemic statistical paradoxes in epidemiologic studies distort knowledge on prostate cancer: mitigation and caution of fallacies in prostate cancer causal epidemiological studies.

PURPOSE OF REVIEW: Many studies on epidemiology of prostate cancer (PCa) are based on a diagnosis of PCa using PSA (prostate-specific antigen) level. However, biases can distort the interpretation of the results, which in turn limits policy and decision making on public health prevention strategies or clinical guidelines. The main confusion is to interpret the posterior probability of the outcome following the exposure as a change in the prevalence of the disease outcome, whereas this change reflects only the predictive values of the PSA test induced by the exposure of interest. RECENT FINDINGS: Many studies report potential causal factors involved in PCa risk. However, the lack of integration of how physiological changes in PSA values are associated with the exposures being investigated, they explain in part contradictory and controversial results on PCa risk factors in the literature. SUMMARY: A strategy to perform case--control studies based on PSA stratification is suggested to avoid misinterpretation related to PSA misclassification. Real data are analysed, and we show that we can exploit the mechanism of selection biases using different modalities of controls recruitment based on biomarker stratification to distinguish real from false causal factors.

Persistent organochlorine pesticides in periprostatic adipose tissue from men with prostate cancer: Ethno-geographic variations, association with disease aggressiveness.

Although several studies have examined the relationship between organochlorine pesticides (OCPs) and prostate cancer (PCa) risk, no data are available concerning the association between OCPs concentrations in periprostatic adipose tissue (PPAT), which reflects cumulative exposure, and PCa aggressiveness. Moreover, no previous study has compared OCPs exposure in two distinct ethno-geographical populations. The objectives were to analyze OCPs in PPAT of PCa patients from either Mainland France or French West Indies in correlation with features of tumor aggressiveness, after adjusting for potential confounders such age, BMI, and polyunsaturated fatty acid (PUFA) content of PPAT. PPAT was analyzed in 160 patients (110 Caucasians and 50 African-Caribbeans), 80 with an indolent tumor (ISUP group 1 + pT2), and 80 with an aggressive tumor (ISUP group more than 3 + pT3). The concentrations of 29 OCPs were measured in PPAT concomitantly with the characterization of PUFA content. Exposure patterns of OCPs differed according to the ethno-geographical origin. Most OCPs were found at higher concentration in Caucasian patients, whereas pp'-DDE content was twice as high in African-Caribbeans. Chlordecone was only detected in PPAT from African-Caribbean patients. Most OCP concentrations were positively correlated with age, and some with BMI. After adjusting for age, BMI, and PUFA composition of PPAT, no significant association was found between OCPs content and risk of aggressive disease, except of mirex which appeared inversely associated with aggressive features of PCa in Caucasian patients. These results highlight a significant ethno-geographic variation in internal exposure to OCPs, which likely reflects differences in consumption patterns. The inverse relationship observed between mirex concentration and markers of PCa aggressiveness need to be further investigated.

Heterogeneity of contemporary grade group 4 prostate cancer in radical prostatectomy specimens.

PURPOSE: The aim was to evaluate the prognostic role of sub-categories of ISUP 4 prostate cancer (PCa) on final pathology, and assess the tumor architecture prognostic role for predicting biochemical recurrence (BCR) after radical prostatectomy. METHODS: From a prospectively-maintained database, we included 370 individuals with ISUP 4 on final pathology. The main outcomes were to evaluate the relationship between different ISUP patterns within the group 4 with pathological and oncological outcomes. Binary logistic regression and Kaplan-Meier estimator were used to evaluate the role of the different categories (3 + 5, 4 + 4, 5 + 3) and tumor architecture (intraductal and/or cribriform) on pathological and oncological outcomes. RESULTS: Among the 370 individuals with ISUP considered for the study, 9, 85 and 6% had grade 3 + 5, 4 + 4 and 5 + 3 PCa, respectively. Overall, 74% had extracapsular extension, while lymph node invasion (LNI) was documented in 9%. A total of 144 patients experienced BCR during follow-up. After adjusting for PSA, pT, grade group, LNI and positive surgical margins (PSM), grade 3 + 5 was a protective factor (HR: 0.30, 95% CI: 0.13,0.68, p = 0.004) in predicting BCR relative to grade 4 + 4. Intraductal or cribriform architecture was correlated with BCR (HR: 5.99, 95% CI: 2.68, 13.4, p < 0.001) after adjusting for PSA, pT, grade group, LNI and PSM. CONCLUSIONS: Patients with tumor grade 3 + 5 had better pathological and prognostic outcomes compared to 4 + 4 or 5 + 3. When accounting for tumor architecture, the sub-stratification into subgroups lost its prognostic role and tumor architecture was the sole predictor of poorer prognosis in terms of biochemical recurrence.

Annual nationwide analysis of costs and post-operative outcomes after radical prostatectomy according to the surgical approach (open, laparoscopic, and robotic).

OBJECTIVE: Annual countrywide data are scarce when comparing surgical approaches in terms of hospital stay outcomes and costs for radical prostatectomy (RP). We aimed to assess the impact of surgical approach on post-operative outcomes and costs after RP by comparing open (ORP), laparoscopic (LRP), and robot-assisted (RARP) RP in the French healthcare system. PATIENTS AND METHODS: Data from all patients undergoing RP in France in 2020 were extracted from the central database of the national healthcare system. Primary endpoints were length of hospital stay (LOS including intensive care unit (ICU) stay if present), complications (estimated by severity index), hospital readmission rates (at 30 and 90 days), and direct costs of initial stay. RESULTS AND LIMITATIONS: A total of 19,018 RPs were performed consisting in ORP in 21.1%, LRP in 27.6%, and RARP in 51.3% of cases. RARP was associated with higher center volume (p < 0.001), lower complication rates (p < 0.001), shorter LOS (p < 0.001), and lower readmission rates (p = 0.004). RARP was associated with reduced direct stay costs (2286 euros) compared with ORP (4298 euros) and LRP (3101 euros). The main cost driver was length of stay. The main limitations were the lack of mid-term data, readmission details, and cost variations due to surgery system. CONCLUSIONS: This nationwide analysis demonstrates the benefits of RARP in terms of post-operative short-term outcomes. Higher costs related to the robotic system appear to be balanced by patient care improvements and reduced direct costs due to shorter LOS.

Grade group 1 prostate cancer on biopsy: are we still missing aggressive disease in the era of image-directed therapy?

PURPOSE: Recently, Eggener et al. reignited a debate consisting to redefine Gleason Grade Group (GGG) 1 prostate cancer (PCa) as a precancerous lesion to reduce overdiagnosis and overtreatment. However, historical cohorts showed that some GGG1-labeled disease at biopsy may be underestimated by the standard PCa diagnostic workup. The aim was to assess whether the risk of adverse features at radical prostatectomy (RP) in selected GGG1 patients still exists in the era of pre-biopsy mpMRI and image-guided biopsies. METHODS: We retrospectively reviewed our data from a European RP dataset to assess in contemporary patients with GGG1 at mpMRI-targeted biopsy the rate of adverse features at final pathology, defined as ≥ pT3a and/or pN+ and/or GGG ≥ 3. RESULTS: A total of 419 patients with cT1-T2 cN0 GGG1-PCa were included. At final pathology, 143 (34.1%) patients had adverse features. In multivariate analysis, only unfavorable intermediate-risk/high-risk disease (defined on PSA or stage) was predictive of adverse features (OR 2.45, 95% CI 1.11-5.39, p = 0.02). A significant difference was observed in the 3-year biochemical recurrence-free survival between patients with and without adverse features (93.4 vs 87.8%, p = 0.026). In sensitivity analysis restricted low- and favorable intermediate-risk PCa, 122/383 patients (31.8%) had adverse features and no preoperative factors were statistically associated with this risk. CONCLUSION: In this European study, we showed that there is still a risk of underestimating GGG1 disease at biopsy despite the routine use of image-guided biopsies. Future studies are warranted to improve the detection of aggressive disease in GGG1-labeled patients by incorporating the latest tools such as genomic testing or radiomics.

Lipophagy and prostate cancer: association with disease aggressiveness and proximity to periprostatic adipose tissue.

The prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is believed to play a role in prostate cancer (PCa) progression. Cancer cells can take up lipids from the microenvironment and store them in lipid droplets (LDs). Fatty acids released from LDs are used by PCa cells as preferential metabolic fuels to provide energy and promote cancer progression. Recently, fatty acids have been associated with autophagy, a cellular recycling pathway. Lipophagy is a selective form of autophagy involved in LD degradation, the role of which in PCa progression remains unknown. Here, we explored markers of autophagy and lipophagy in human PCa tissues in correlation with factors of aggressiveness, and we evaluated the influence of PPAT adipocytes on autophagy and lipophagy. We analyzed markers of autophagy (p62, LC3), lipid droplets (PLIN and Oil Red O), androgen receptor (AR), proliferation (Ki67), and epithelial-mesenchymal transition (Zeb1) on 465 PCa samples. Co-cultures of PCa cell lines PC3 and 22RV1 with adipocytes isolated from patients' PPAT were used to analyze the influence of PPAT on autophagy and lipophagy in vitro. In human PCa tissues, we observed a correlation between markers of LD and those of autophagy, which are associated with clinical and biological factors of disease aggressiveness. In addition, PLIN staining was associated with AR expression. In locally advanced PCa, p62, LC3, and PLIN were increased in extraprostatic areas where cancer cells are in contact with PPAT. Co-culture of PCa cell lines with adipocytes decreased autophagy activity and increased LD flux in PC3 cells. These results suggest an active process of lipophagy in PCa, linked to disease aggressiveness, to the proximity of PPAT, and induced in vitro in co-culture with adipocytes. Lipophagy is therefore likely to be a crucial player in PCa progression. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Development of a High-Performance Thin-Layer Chromatography Method for the Quantification of Alkyl Glycerolipids and Alkenyl Glycerolipids from Shark and Chimera Oils and Tissues.

Ether lipids are composed of alkyl lipids with an ether bond at the sn-1 position of a glycerol backbone and alkenyl lipids, which possess a vinyl ether bond at the sn-1 position of the glycerol. These ether glycerolipids are present either as polar glycerophospholipids or neutral glycerolipids. Before studying the biological role of molecular species of ether glycerolipids, there is a need to separate and quantify total alkyl and alkenyl glycerolipids from biological samples in order to determine any variation depending on tissue or physiopathological conditions. Here, we detail the development of the first high-performance thin-layer chromatography method for the quantification of total alkyl and alkenyl glycerolipids thanks to the separation of their corresponding alkyl and alkenyl glycerols. This method starts with a reduction of all lipids after extraction, resulting in the reduction of neutral and polar ether glycerolipids into alkyl and alkenyl glycerols, followed by an appropriate purification and, finally, the linearly ascending development of alkyl and alkenyl glycerols on high-performance thin-layer chromatography plates, staining, carbonization and densitometric analysis. Calibration curves were obtained with commercial alkyl and alkenyl glycerol standards, enabling the quantification of alkyl and alkenyl glycerols in samples and thus directly obtaining the quantity of alkyl and alkenyl lipids present in the samples. Interestingly, we found a differential quantity of these lipids in shark liver oil compared to chimera. We quantified alkyl and alkenyl glycerolipids in periprostatic adipose tissues from human prostate cancer and showed the feasibility of this method in other biological matrices (muscle, tumor).

Interplay between Prostate Cancer and Adipose Microenvironment: A Complex and Flexible Scenario.

Adipose tissue is part of the prostate cancer (PCa) microenvironment not only in the periprostatic area, but also in the most frequent metastatic sites, such as bone marrow and pelvic lymph nodes. The involvement of periprostatic adipose tissue (PPAT) in the aggressiveness of PCa is strongly suggested by numerous studies. Many molecules play a role in the reciprocal interaction between adipocytes and PCa cells, including adipokines, hormones, lipids, and also lipophilic pollutants stored in adipocytes. The crosstalk has consequences not only on cancer cell growth and metastatic potential, but also on adipocytes. Although most of the molecules released by PPAT are likely to promote tumor growth and the migration of cancer cells, others, such as the adipokine adiponectin and the n-6 or n-3 polyunsaturated fatty acids (PUFAs), have been shown to have anti-tumor properties. The effects of PPAT on PCa cells might therefore depend on the balance between the pro- and anti-tumor components of PPAT. In addition, genetic and environmental factors involved in the risk and/or aggressiveness of PCa, including obesity and diet, are able to modulate the interactions between PPAT and cancer cells and their consequences on the growth and the metastatic potential of PCa.

Tissue cholesterol metabolism and prostate cancer aggressiveness: Ethno-geographic variations.

BACKGROUND: Prostate cancer (PCa) is more frequent and more aggressive in populations of African descent than in Caucasians. Since the fatty acid composition of peri-prostatic adipose tissue (PPAT) has been shown to differ according to the ethno-geographic origin and is involved in PCa aggressiveness, we aimed to analyze the cholesterol content of PPAT from Caucasian and African-Caribbean patients, in correlation with markers of disease aggressiveness and cholesterol metabolism in cancer tissues. METHODS: The quantification of cholesterol in PPAT was analyzed in 52 Caucasian and 52 African-Caribbean PCa patients, with in each group 26 indolent tumors (ISUP Group1 and pT2) and 26 potentially aggressive tumors (ISUP Group 3-5 and/or pT3). The expression of proteins involved in cholesterol metabolism was analyzed by immunohistochemistry on cancer tissue samples included in tissue microarrays. RESULTS: The amount of cholesterol esters was lower in PPAT from African-Caribbean patients compared with Caucasians, without any correlation with markers of disease aggressiveness. In cancer tissues from African-Caribbean patients, the expression of ABCA1 (involved in cholesterol efflux) was decreased, and that of SREBP-2 (involved in cholesterol uptake) was increased. In both groups of patients, SREBP-2 expression was strongly associated with that of Zeb1, a key player in the epithelial-to-mesenchymal transition (EMT) process. CONCLUSION: These results suggest that cholesterol metabolism differs according to the ethno-geographic origin, in both PPAT and cancer tissues. In African-Caribbeans, the orientation towards accumulation of cholesterol in cancer cells is associated with a more frequent state of EMT, which may promote PCa aggressiveness in this population.

The Chemokine Receptor CCR3 Is Potentially Involved in the Homing of Prostate Cancer Cells to Bone: Implication of Bone-Marrow Adipocytes.

Bone metastasis remains the most frequent and the deadliest complication of prostate cancer (PCa). Mechanisms leading to the homing of tumor cells to bone remain poorly characterized. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. Bone is an adipocyte-rich organ since 50 to 70% of the adult bone marrow (BM) volume comprise bone marrow adipocytes (BM-Ads), which are likely to produce chemokines within the bone microenvironment. Using in vitro migration assays, we demonstrated that soluble factors released by human primary BM-Ads are able to support the directed migration of PCa cells in a CCR3-dependent manner. In addition, we showed that CCL7, a chemokine previously involved in the CCR3-dependent migration of PCa cells outside of the prostate gland, is released by human BM-Ads. These effects are amplified by obesity and ageing, two clinical conditions known to promote aggressive and metastatic PCa. In human tumors, we found an enrichment of CCR3 in bone metastasis vs. primary tumors at mRNA levels using Oncomine microarray database. In addition, immunohistochemistry experiments demonstrated overexpression of CCR3 in bone versus visceral metastases. These results underline the potential importance of BM-Ads in the bone metastatic process and imply a CCR3/CCL7 axis whose pharmacological interest needs to be evaluated.

Roles of endogenous ether lipids and associated PUFAs in the regulation of ion channels and their relevance for disease.

Ether lipids (ELs) are lipids characterized by the presence of either an ether linkage (alkyl lipids) or a vinyl ether linkage [i.e., plasmalogens (Pls)] at the sn1 position of the glycerol backbone, and they are enriched in PUFAs at the sn2 position. In this review, we highlight that ELs have various biological functions, act as a reservoir for second messengers (such as PUFAs) and have roles in many diseases. Some of the biological effects of ELs may be associated with their ability to regulate ion channels that control excitation-contraction/secretion/mobility coupling and therefore cell physiology. These channels are embedded in lipid membranes, and lipids can regulate their activities directly or indirectly as second messengers or by incorporating into membranes. Interestingly, ELs and EL-derived PUFAs have been reported to play a key role in several pathologies, including neurological disorders, cardiovascular diseases, and cancers. Investigations leading to a better understanding of their mechanisms of action in pathologies have opened a new field in cancer research. In summary, newly identified lipid regulators of ion channels, such as ELs and PUFAs, may represent valuable targets to improve disease diagnosis and advance the development of new therapeutic strategies for managing a range of diseases and conditions.

Apolipoprotein-mediated regulation of lipid metabolism induces distinctive effects in different types of breast cancer cells.

BACKGROUND: The highest incidence of breast cancer is in the Western world. Several aspects of the Western lifestyle are known risk factors for breast cancer. In particular, previous studies have shown that cholesterol levels can play an important role in the regulation of tumor progression. METHODS: In the present study, we modulated cholesterol metabolism in the human breast cancer cell lines MCF-7 and MDA-MB-231 using a genetic approach. Apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE) were expressed in these cell lines to modulate cholesterol metabolism. The effects of these apolipoproteins on cancer cell properties were examined. RESULTS: Our results show that both apolipoproteins can regulate cholesterol metabolism and can control the epithelial-to-mesenchymal transition process. However, these effects were different depending on the cell type. We show that expressing apoA-I or apoE stimulates proliferation, migration, and tumor growth of MCF-7 cells. However, apoA-I or apoE reduces proliferation and migration of MDA-MB-231 cells. CONCLUSIONS: These data suggest that modulating sterol metabolism may be most effective at limiting tumor progression in models of triple-negative cancers.

Functional Organotypic Cultures of Prostate Tissues: A Relevant Preclinical Model that Preserves Hypoxia Sensitivity and Calcium Signaling.

In prostate cancer research, there is a lack of valuable preclinical models. Tumor cell heterogeneity and sensitivity to microenvironment signals, such as hypoxia or extracellular calcium concentration, are difficult to reproduce. Here, we developed and characterized an ex vivo tissue culture model preserving these properties. Prostate tissue slices from 26 patients were maintained ex vivo under optimized culture conditions. The expression of markers associated with proliferation, androgen-receptor signaling, and hypoxia was assessed by immunostaining. A macroscope was used to achieve real-time calcium fluorescence optical imaging. Tissue morphology was maintained successfully without necrosis for 5 days. Compared with native tumors and tissue cultured with androgens, androgen deprivation in the medium led to decreased expression of both androgen receptor and its target gene products, prostate specific antigen (PSA) and ETS-related gene (ERG). Ex vivo cultured slices also were sensitive to hypoxia because carbonic anhydrase IX and zinc finger E-box binding homeobox 1 (Zeb1) protein levels increased in 1% oxygen. Exposure of slices to supraphysiological extracellular Ca2+ concentration induced a robust and rapid Ca2+ entry, with a greater response in tumor compared with nontumor tissue. This ex vivo model reproduces the morphologic and functional characteristics of human prostate cancer, including sensitivity to androgen deprivation and induced response to hypoxia and extracellular Ca2+. It therefore could become an attractive tool for drug response prediction studies.