Tumor microenvironment mechanisms and bone metastatic disease progression of prostate cancer.

During disease progression from primary towards metastatic prostate cancer (PCa), and in particular bone metastases, the tumor microenvironment (TME) evolves in parallel with the cancer clones, altering extracellular matrix composition (ECM), vasculature architecture, and recruiting specialized tumor-supporting cells that favor tumor spread and colonization at distant sites. We introduce the clinical profile of advanced metastatic PCa in terms of common genetic alterations. Findings from recently developed models of PCa metastatic spread are discussed, focusing mainly on the role of the TME (mainly matrix and fibroblast cell types), at distinct stages: premetastatic niche orchestrated by the primary tumor towards the metastatic site and bone metastasis. We report evidence of premetastatic niche formation, such as the mechanisms of distant site conditioning by extracellular vesicles, chemokines and other tumor-derived mechanisms, including altered cancer cell-ECM interactions. Furthermore, evidence supporting the similarities of stroma alterations among the primary PCa and bone metastasis, and contribution of TME to androgen deprivation therapy resistance are also discussed. We summarize the available bone metastasis transgenic mouse models of PCa from a perspective of pro-metastatic TME alterations during disease progression and give an update on the current diagnostic and therapeutic radiological strategies for bone metastasis clinical management.

West Oakland's Experience in Building Community Power to Confront Environmental Injustice Through California's Assembly Bill 617.

We explored how air quality management processes associated with Assembly Bill 617 (AB 617) in West Oakland, California, represent a shift in power relationships between government agencies and communities toward the goal of addressing legacies of environmental injustice. We drew from a statewide assessment of community engagement in AB 617's first year, and an analysis of the West Oakland AB 617 process. The first comprised 2 statewide surveys (n = 102 and n = 106), 70 key informant interviews, observation of all AB 617 first-year sites, and analysis of related planning documents. The second comprised 2 rounds of interviews (n = 22 and n = 23, with a total of 19 individuals) and extensive participant observation. Several factors are necessary for pursuing environmental justice: (1) invest in community partnerships and collaborations, (2) honor community knowledge and data, (3) ensure that community constituents share power in environmental governance, and (4) adopt explicit racial justice frameworks. Although still a work in progress, AB 617 offers important lessons for community and policy organizations nationwide engaged in environmental justice. (Am J Public Health. 2022;112(2):262-270. https://doi.org/10.2105/AJPH.2021.306592).

Recurrent Home Flooding in Detroit, MI 2012-2020: Results of a Household Survey.

Household flooding has wide ranging social, economic and public health impacts particularly for people in resource poor communities. The determinants and public health outcomes of recurrent home flooding in urban contexts, however, are not well understood. A household survey was used to assess neighborhood and household level determinants of recurrent home flooding in Detroit, MI. Survey activities were conducted from 2012 to 2020. Researchers collected information on past flooding, housing conditions and public health outcomes. Using the locations of homes, a "hot spot" analysis of flooding was performed to find areas of high and low risk. Survey data were linked to environmental and neighborhood data and associations were tested using regression methods. 4803 households participated in the survey. Flooding information was available for 3842 homes. Among these, 2085 (54.26%) reported experiencing pluvial flooding. Rental occupied units were more likely to report flooding than owner occupied homes (Odd ratio (OR) 1.72 [95% Confidence interval (CI) 1.49, 1.98]). Housing conditions such as poor roof quality and cracks in basement walls influenced home flooding risk. Homes located in census tracts with increased percentages of owner occupied units (vs. rentals) had a lower odds of flooding (OR 0.92 [95% (CI) 0.86, 0.98]). Household factors were found the be more predictive of flooding than neighborhood factors in both univariate and multivariate analyses. Flooding and housing conditions associated with home flooding were associated with asthma cases. Recurrent home flooding is far more prevalent than previously thought. Programs that support recovery and which focus on home improvement to prevent flooding, particularly by landlords, might benefit the public health. These results draw awareness and urgency to problems of urban flooding and public health in other areas of the country confronting the compounding challenges of aging infrastructure, disinvestment and climate change.

MYC-Mediated Ribosomal Gene Expression Sensitizes Enzalutamide-resistant Prostate Cancer Cells to EP300/CREBBP Inhibitors.

Patients with advanced prostate cancer are frequently treated with the antiandrogen enzalutamide. However, resistance eventually develops in virtually all patients, and various mechanisms have been associated with this process. The histone acetyltransferases EP300 and CREBBP are involved in regulation of cellular events in advanced prostate cancer. This study investigated the role of EP300/CREBBP inhibitors in enzalutamide-resistant prostate cancer. EP300/CREBBP inhibitors led to the same inhibition of androgen receptor activity in enzalutamide-resistant and -sensitive cells. However, enzalutamide-resistant cells were more sensitive to these inhibitors in viability assays. As indicated by the RNA-sequencing-based pathway analysis, genes related to the ribosome and MYC activity were significantly altered upon EP300/CREBBP inhibitor treatment. EP300/CREBBP inhibitors led to the down-regulation of ribosomal proteins RPL36 and RPL29. High-level ribosomal proteins amplifications and MYC amplifications were observed in castration-resistant prostate cancer samples of the publicly available Stand Up to Cancer data set. An inhibitor of RNA polymerase I-mediated transcription was used to evaluate the functional implications of these findings. The enzalutamide-resistant cell lines were more sensitive to this treatment. In addition, the migration rate of enzalutamide-resistant cells was strongly inhibited by this treatment. Taken together, the current data show that EP300/CREBBP inhibitors affect the MYC/ribosomal protein axis in enzalutamide-resistant cells and may have promising therapeutic implications.

Building Youth Capacity to Address Environmental Health and Justice Concerns in Dearborn, Michigan.

BACKGROUND: Environmental Health Research-to-Action (EHRA) is a community-academic partnership focused on building skills and intergenerational knowledge in environmental health, community science, and policy advocacy to address cumulative exposures in Dearborn, Michigan and nearby communities, primarily through a youth academy. OBJECTIVES: This article outlines our EHRA Youth Academy curriculum with sample recruitment materials, and we describe its beginnings, steering committee (SC), learning objectives, design, implementation, and recommendations from ongoing program evaluation and reflections of the SC. METHODS: In 2018 and 2019, we piloted the EHRA Academy with a total of forty-five fellows (16-18 years old), primarily Arab youth living in or near frontline communities. Fellows participated in a 2-week academy of interactive sessions, including a tour of local industry, participatory mapping, practice using handheld monitors to measure air pollution, and a policy advocacy 101 training. Applying lessons in accessing secondary data and environmental health literacy, fellows then created scientifically-informed materials including infographics and oral presentations for varied audiences. They completed a pre-survey, brief daily surveys, and a post-survey, and reported increased likelihood of advocacy behaviors and knowledge related to all content areas. CONCLUSIONS: In Southeast Dearborn, Michigan, threats to environmental health are constant, and intergenerational community mobilization remains necessary to reduce their adverse effects. Grounded in the principles of community-based participatory research (CBPR) and using high-impact active learning strategies, the EHRA Academy may provide one effective model for centering youth to build community capacity towards environmental justice (EJ).

Independent and joint contributions of economic, social and physical environmental characteristics to mortality in the Detroit Metropolitan Area: A study of cumulative effects and pathways.

OBJECTIVE: Previous studies have demonstrated associations between race-based residential segregation, neighborhood socioeconomic and physical environmental characteristics, and mortality. Relatively few studies have examined independent and joint effects of these multiple neighborhood characteristics and mortality, including potential mediating pathways. In this study we examine the extent to which associations between race-based residential segregation and all-cause mortality may be explained by multiple socioeconomic indicators and exposure to air pollutants. METHODS: Drawing on data from multiple sources, we assessed bivariate associations between race-based residential segregation (operationalized as percent non-Hispanic Black), education (percent with graduate equivalency degree), poverty (percent below poverty), income inequality (GINI coefficient) and air pollution (ambient PM2.5) and age adjusted all-cause, all race mortality (henceforth all cause mortality) at the census tract level in the Detroit Metropolitan Area. We used inequality curves to assess the (in)equitable distribution of economic and environmental characteristics by census tract racial composition. Finally, we used generalized estimating equations (GEE) to examine independent and joint associations among percent NHB, education, income inequality, and air pollution to all-cause mortality, and test for mediating effects. RESULTS: Bivariate associations between racial composition, education, poverty, income inequality, PM2.5 and all-cause mortality were statistically significant. Census tracts with higher concentrations of NHB residents had significantly lower educational attainment, higher poverty, and greater exposure to PM2.5. In multivariate models, education, income inequality and PM2.5 fully attenuated associations between racial composition and all-cause mortality. CONCLUSIONS: Results are consistent with the hypothesis that race-based residential segregation is associated with heightened all-cause mortality, and that those effects are mediated by education, income inequality, and exposure to air pollution at the census tract level. Public health and cross-sector interventions to eliminate race-based residential segregation or to eliminate the maldistribution of educational and economic resources, and environmental exposures, across census tracts could substantially reduce regional inequities in all-cause mortality.

Mobilizing for Community Benefits to Assess Health and Promote Environmental Justice near the Gordie Howe International Bridge.

Transportation infrastructure decisions contribute to social, economic, and health inequities in the U.S. Health Impact Assessments (HIAs) may improve understanding of potential strategies to mitigate adverse effects on quality of life from planned developments. We use the Gordie Howe International Bridge (GHIB), currently under construction in southwest Detroit, MI, as a case study to examine 15 years of community mobilization, which resulted in community benefits that included an HIA. We describe community engagement processes, household survey methods, and select findings of the baseline HIA, with a focus on their application to inform recommendations to promote quality of life. Baseline HIA results indicated significantly higher self-reported asthma rates among children living within 500 feet of trucking routes. Residents reported substantial economic (e.g., decreased home values), health (e.g., adverse outcomes, lack of health care access), and environmental (e.g., air pollution) concerns related to the GHIB. We discuss specific recommendations, based on HIA results, to reduce adverse impacts of the GHIB. These recommendations will inform ongoing community benefits negotiations. This case study provides lessons for community, academic, and government partners conducting HIAs, especially during building and operation of major infrastructure, and discusses their potential role in improving community engagement opportunities towards environmental justice.

p300 is upregulated by docetaxel and is a target in chemoresistant prostate cancer.

Administration of the microtubule inhibitor docetaxel is a common treatment for metastatic castration-resistant prostate cancer (mCRPC) and results in prolonged patient overall survival. Usually, after a short period of time chemotherapy resistance emerges and there is urgent need to find new therapeutic targets to overcome therapy resistance. The lysine-acetyltransferase p300 has been correlated to prostate cancer (PCa) progression. Here, we aimed to clarify a possible function of p300 in chemotherapy resistance and verify p300 as a target in chemoresistant PCa. Immunohistochemistry staining of tissue samples revealed significantly higher p300 protein expression in patients who received docetaxel as a neoadjuvant therapy compared to control patients. Elevated p300 expression was confirmed by analysis of publicly available patient data, where significantly higher p300 mRNA expression was found in tissue of mCRPC tumors of docetaxel-treated patients. Consistently, docetaxel-resistant PCa cells showed increased p300 protein expression compared to docetaxel-sensitive counterparts. Docetaxel treatment of PCa cells for 72 h resulted in elevated p300 expression. shRNA-mediated p300 knockdown did not alter colony formation efficiency in docetaxel-sensitive cells, but significantly reduced clonogenic potential of docetaxel-resistant cells. Downregulation of p300 in docetaxel-resistant cells also impaired cell migration and invasion. Taken together, we showed that p300 is upregulated by docetaxel, and our findings suggest that p300 is a possible co-target in treatment of chemoresistant PCa.

MI-Environment: Geospatial patterns and inequality of relative heat stress vulnerability in Michigan.

Heat stress causes morbidity and mortality and is increasing with climate change. Heat stress can pose particular challenges in northern regions not well adapted to heat. To assist decision makers, we identified the relative vulnerability of census tracts within Michigan to factors that increase exposure to heat stress or reflect susceptibilities in the population based on a California heat vulnerability index. In the MI-Environment assessment, we used a Geographic Information System (GIS) to combine future ensemble climate model projections to create a total of 9 geospatial and demographic variables. As part of a broader planned cumulative environmental exposure assessment, the statewide heat vulnerability index (HVI) maps display the location and relative magnitude of exposure on three metrics: built environment (Place), future expected long-term temperature averages (Temperature), and population susceptibility (People). We observed varied and distinct patterns for each of the three component indices. We assessed how equitably those exposures are distributed by racial and socioeconomic factors. This analysis showed that each of the component indices and the aggregate HVI are disproportionately distributed along racial and socioeconomic lines in Michigan. Census tracts with higher percentages of people of color had larger exposure to HVI factors with a deviation from equity of -0.115 [95% CI -0.108, -0.122]. Similarly, for census tracts with higher percentage of people experiencing poverty, the deviation from equity was -0.101 [95% CI -0.094, -0.107]. The MI-Environment visualization tool can help communities prepare for climate change and resolve inequities by identifying census tracts with the most vulnerable residents and highest potential exposures.

Pathophysiology of Benign Prostatic Hyperplasia and Benign Prostatic Enlargement: A Mini-Review.

Benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS) belong to the most frequent diseases in ageing men. Beyond the 6th decade of life, more than 30% of men suffer from moderate to severe LUTS requiring intervention. The pathophysiology of BPH/BPE is still incompletely understood. The dominant role of the androgen system and the androgen receptor is well defined. Androgen receptors are expressed in BPH tissue in which they are activated by the potent androgen dihydrotestosterone. Synthesis of dihydrotestosterone is under control of the 5α-reductase enzyme, activity of which is antagonized by finasteride and dutasteride. More recently, the impact of prostatic inflammation and metabolic parameters particularly for the development of BPE and LUTS has increasingly been recognized. A better understanding of the pathophysiology is a prerequisite for the development of novel, more effective medical treatment options.

NADPH oxidase 4 expression in the normal endometrium and in endometrial cancer.

The aim of this study was to explore the role of NOX4 in the biology of the normal endometrium and endometrial cancer. NOX4 plays a key role in other adenocarcinomas and has been implicated in the pathogenesis of diabetes and obesity, which are important risk factors for endometrial cancer. NOX4 expression was assessed in 239 endometrial cancer and 25 normal endometrium samples by quantitative real-time polymerase chain reaction, in situ hybridization, and immunohistochemistry. DNA methylation of the NOX4 promoter was determined by means of MethyLight PCR. Data were correlated with clinicopathological parameters and analyzed in the context of diabetes and body mass index. In the normal endometrium, NOX4 microRNA expression was significantly higher in the secretory transformed compared with proliferative endometrium ( p = 0.008). In endometrial cancer specimens, NOX4 expression did not differ between diabetic and non-diabetic patients, but was the highest in patients with a body mass index ≤ 26 ( p = 0.037). The lowest NOX4 expression was found in carcinosarcomas ( p = 0.007). High NOX4 expression predicted poorer clinical outcome with regard to overall survival, especially in non-diabetic patients and those with a body mass index > 20. Independent prognostic significance of NOX4 transcripts was retained in type I endometrial cancer and was the most meaningful in patients with a body mass index > 20. No prognostic impact was shown for NOX4 promoter methylation in endometrial cancer. For the first time, we demonstrate that NOX4 plays a considerable role in the cycle-dependent changes in the normal endometrium and in the biology of endometrial cancer.

"We're Just Sitting Ducks": Recurrent Household Flooding as An Underreported Environmental Health Threat in Detroit's Changing Climate.

Recurrent inland urban flooding is an understudied phenomenon that warrants greater attention, particularly in post-industrial cities where aging infrastructure, disinvestment, and climate change threaten public health. We conducted semi-structured interviews in 2017⁻2018 with 18 Detroit residents experiencing recurrent household flooding. We used standard qualitative coding analysis to generate 30 theoretically- and in vivo- derived themes related to flood experience, socioeconomic and health factors, and household, community, and policy interventions for reducing environmental exposures before, during, and after flood events. Snowball sampling yielded interviewees across both high- and low-risk areas for flood events, indicating vulnerability may be widespread and undocumented in formal ways. Residents described exposure to diverse risk factors for chronic and infectious diseases, particularly for seniors and young children, and emphasized stressors associated with repeated economic loss and uncertainty. Opinions varied on the adequacy, responsibility, and equity of local and federal relief funding and programs. We expand knowledge of flood-related vulnerability, offer innovative suggestions for risk communication based on residents' experiences, and recommend additional research for documenting patterns of recurrent flooding and response, even for precipitation events that are not characterized as extreme or disaster-level in the media or by agencies. These findings should guide local public health, emergency preparedness, sustainability, water and sewage, and community leaders in post-industrial cities.

Examining Joint Effects of Air Pollution Exposure and Social Determinants of Health in Defining "At-Risk" Populations Under the Clean Air Act: Susceptibility of Pregnant Women to Hypertensive Disorders of Pregnancy.

Pregnant women are uniquely susceptible to adverse effects of air pollution exposure due to vulnerabilities and health consequences during pregnancy (e.g., hypertensive disorders of pregnancy [HDP]) compared to the general population. Because the Clean Air Act (CAA) creates a duty to protect at-risk groups, the regulatory assessment of at-risk populations has both policy and scientific foundations. Previously, pregnant women have not been specially protected in establishing the margin of safety for the ozone and particulate matter (PM) standards. Due to physiological changes, pregnant women can be at greater risk of adverse effects of air pollution and should be considered an at-risk population. Women with preexisting conditions, women experiencing poverty, and groups that suffer systematic discrimination may be particularly susceptible to cardiac effects of air pollutants during pregnancy. We rigorously reviewed 11 studies of over 1.3 million pregnant women in the United States to characterize the relationship between ozone or PM exposure and HDP. Findings were generally mixed, with a few studies reporting a joint association between ozone or PM and social determinants or pre-existing chronic health conditions related to HDP. Adequate evidence associates exposure to PM with an adverse effect of HDP among pregnant women not evident among non-gravid populations.

Succinate Accumulation Is Associated with a Shift of Mitochondrial Respiratory Control and HIF-1α Upregulation in PTEN Negative Prostate Cancer Cells.

The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells. Moreover, PCa cells showed a substantial shift towards succinate-supported mitochondrial respiration compared to benign cells, indicating a re-programming of respiratory control. This study aimed to investigate the role of succinate and its main plasma membrane transporter NaDC3 (sodium-dependent dicarboxylate transporter member 3) in PCa cells and to determine whether targeting succinate metabolism can be potentially used to inhibit PCa cell growth. Using high-resolution respirometry analysis, we observed that ROUTINE respiration in viable cells and succinate-supported respiration in permeabilized cells was higher in cells lacking the tumor suppressor phosphatase and tensin-homolog deleted on chromosome 10 (PTEN), which is frequently lost in PCa. In addition, loss of PTEN was associated with increased intracellular succinate accumulation and higher expression of NaDC3. However, siRNA-mediated knockdown of NaDC3 only moderately influenced succinate metabolism and did not affect PCa cell growth. By contrast, mersalyl acid-a broad acting inhibitor of dicarboxylic acid carriers-strongly interfered with intracellular succinate levels and resulted in reduced numbers of PCa cells. These findings suggest that blocking NaDC3 alone is insufficient to intervene with altered succinate metabolism associated with PCa. In conclusion, our data provide evidence that loss of PTEN is associated with increased succinate accumulation and enhanced succinate-supported respiration, which cannot be overcome by inhibiting the succinate transporter NaDC3 alone.

Independent and Joint Contributions of Fine Particulate Matter Exposure and Population Vulnerability to Mortality in the Detroit Metropolitan Area.

Fine particulate matter is associated with adverse health outcomes. Exposure to fine particulate matter may disproportionately affect urban communities with larger numbers of vulnerable residents. We used multilevel logistic regression models to estimate the joint effects of fine particulate matter (PM2.5) and population vulnerabilities on cardiopulmonary mortality (CPM). We estimated the health benefits of reductions in PM2.5 across census tracts in the Detroit metropolitan area with varying levels of population vulnerability, using cluster-specific odds ratios scaled to reflect PM2.5-attributable cardiopulmonary risk. PM2.5 and population vulnerability were independently associated with odds of CPM. Odds of CPM and the number of deaths attributable to PM2.5 were greatest in census tracts with both high PM2.5 exposures and population vulnerability. Reducing PM2.5 in census tracts with high PM2.5 would lead to an estimated 18% annual reduction in PM2.5-attributable CPM. Between 78⁻79% of those reductions in CPM would occur within census tracts with high population vulnerabilities. These health benefits of reductions in PM2.5 occurred at levels below current U.S. reference concentrations. Focusing efforts to reduce PM2.5 in the Detroit metropolitan area in census tracts with currently high levels would also lead to greater benefits for residents of census tracts with high population vulnerabilities.

Inhibition of Nox4-dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal-mediated protumorigenic interactions.

Carcinoma-associated fibroblasts (CAFs) play a key onco-supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)-producing enzyme NADPH oxidase 4 (Nox4) is essential for TGFß1-mediated activation of primary prostate human fibroblasts to a CAF-like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine-mediated PCa-relevant processes. RNA in situ hybridization revealed significantly elevated Nox4 mRNA levels predominantly in the peri-tumoral stroma of clinical PCa with intense stromal Nox4 staining adjacent to tumor foci expressing abundant TGFß protein levels. At pharmacologically relevant concentrations, the Nox1/Nox4 inhibitor GKT137831 attenuated ROS production, CAF-associated marker expression and migration of TGFß1-activated but not nonactivated primary human prostate fibroblasts. Similar effects were obtained upon shRNA-mediated silencing of Nox4 but not Nox1 indicating that GKT137831 primarily abrogates TGFß1-driven fibroblast activation via Nox4 inhibition. Moreover, inhibiting stromal Nox4 abrogated the enhanced proliferation and migration of PCa cell lines induced by TGFß1-activated prostate fibroblast conditioned media. These effects were not restricted to recombinant TGFß1 as conditioned media from PCa cell lines endogenously secreting high TGFß1 levels induced fibroblast activation in a stromal Nox4- and TGFß receptor-dependent manner. Importantly, GKT137831 also attenuated PCa cell-driven fibroblast activation. Collectively, these findings suggest the TGFß-Nox4 signaling axis is a key interface to dysregulated reciprocal stromal-epithelial interactions in PCa pathophysiology and provide a strong rationale for further investigating the applicability of Nox4 inhibition as a stromal-targeted approach to complement current PCa treatment modalities.

Landscape care of urban vacant properties and implications for health and safety: Lessons from photovoice.

Care of vacant properties in urban environments is of particular interest to planners and residents alike. We report on a photovoice project completed by community leaders, researchers, and residents in two Detroit neighborhoods experiencing longtime systemic disinvestment. Participants photographed and discussed examples of care in a series of three focus groups in each neighborhood. Analyses highlight how acts of landscape care and visible cues to care contribute to changes in physical and social environments, and explore various links to health. We suggest theoretical and practical applications of residents' perspectives on landscape care and identify implications for well-being and neighborhood stability.

A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling.

The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca2+ signaling leading to a parallel increase in the cytosolic Ca2+ pools that activate the Ca2+-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca2+ uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca2+ dynamics and redox transients in neuronal cytotoxicity.

Cancer-Associated Fibroblasts Modify the Response of Prostate Cancer Cells to Androgen and Anti-Androgens in Three-Dimensional Spheroid Culture.

Androgen receptor (AR) targeting remains the gold standard treatment for advanced prostate cancer (PCa); however, treatment resistance remains a major clinical problem. To study the therapeutic effects of clinically used anti-androgens we characterized herein a tissue-mimetic three-dimensional (3D) in vitro model whereby PCa cells were cultured alone or with PCa-associated fibroblasts (CAFs). Notably, the ratio of PCa cells to CAFs significantly increased in time in favor of the tumor cells within the spheroids strongly mimicking PCa in vivo. Despite this loss of CAFs, the stromal cells, which were not sensitive to androgen and even stimulated by the anti-androgens, significantly influenced the sensitivity of PCa cells to androgen and to the anti-androgens bicalutamide and enzalutamide. In particular, DuCaP cells lost sensitivity to enzalutamide when co-cultured with CAFs. In LAPC4/CAF and LNCaP/CAF co-culture spheroids the impact of the CAFs was less pronounced. In addition, 3D spheroids exhibited a significant increase in E-cadherin and substantial expression of vimentin in co-culture spheroids, whereas AR levels remained unchanged or even decreased. In LNCaP/CAF spheroids we further found increased Akt signaling that could be inhibited by the phosphatidyl-inositol 3 kinase (PI3K) inhibitor LY294002, thereby overcoming the anti-androgen resistance of the spheroids. Our data show that CAFs influence drug response of PCa cells with varying impact and further suggest this spheroid model is a valuable in vitro drug testing tool.

Multidirectional Translation of Environmental Health Science in Community Settings: The Case of Oxidative Stress Pathways.

BACKGROUND: Translation of environmental health science in vulnerable communities is particularly important to promote public health and reduce health inequities. METHODS: We describe a structured, multidirectional process used to develop a suite of health promotion tools (e.g., fact sheets, video, maps) documenting patterning of local air pollution sources and availability of antioxidant-rich foods in Detroit, Michigan as factors that jointly affect oxidative stress (OS). OS underlies many pathological processes associated with air pollution, including asthma, metabolic syndrome, cancer, diabetes, and obesity. This translational effort involved a 2-year dialogue among representatives from community-based and environmental organizations, health service providers, and academic researchers. RESULTS: This dialogue led to development of tools, as well as new opportunities to inform related policies and research. CONCLUSIONS: Through this example, we highlight how collaborative partnerships can enhance multidirectional dialogue to inform translation of environmental health science by promoting consideration of multilevel risk factors, local priorities and context, and diverse audiences.