SEMA3A-mediated crosstalk between prostate cancer cells and tumor-associated macrophages promotes androgen deprivation therapy resistance.
Ontology highlight
ABSTRACT:
SUBMITTER: Liu F
PROVIDER: S-EPMC8027038 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
Publications
SEMA3A-mediated crosstalk between prostate cancer cells and tumor-associated macrophages promotes androgen deprivation therapy resistance.
Liu Fei F Wang Chao C Huang Hai H Yang Yue Y Dai Lihe L Han Sujun S Xing Nianzeng N Ren Shancheng S
Cellular & molecular immunology 20210208 3
Similar Datasets
Project description:Increasing evidence reveals that the interaction between tumor cells and tumor-associated macrophages (TAMs) facilitates the progression of prostate cancer, but the related mechanisms remained unclear. This study determined how gankyrin, a component of the 19S regulatory complex of the 26S proteasome, regulates the progression and androgen deprivation therapy (ADT) resistance of prostate cancer through tumor cell-TAM interactions. In vitro functional experiments and in vivo subcutaneous tumor models were used to explore the biological role and molecular mechanisms of gankyrin in prostate cancer cell-TAM interactions. 234 prostate cancer patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin through immunohistochemistry (IHC) and statistical analyses, and high gankyrin expression was correlated with poor prognosis. In addition, gankyrin facilitated the progression and ADT resistance of prostate cancer. Mechanistically, gankyrin recruited and upregulated non-POU-domain-containing octamer-binding protein (NONO) expression, resulting in increased androgen receptor (AR) expression. AR then bound to the high-mobility group box 1 (HMGB1) promoter to trigger HMGB1 transcription, expression, and secretion. Moreover, HMGB1 was found to promote the recruitment and activation of TAMs, which secrete IL-6 to reciprocally promote prostate cancer progression, ADT resistance and gankyrin expression via STAT3, resulting in formation of a gankyrin/NONO/AR/HMGB1/IL-6/STAT3 positive feedback loop. Furthermore, targeting the interaction between tumor cells and TAMs by blocking this loop inhibited ADT resistance in a tumor xenograft model. Taken together, the data show that gankyrin serves as a reliable prognostic indicator and therapeutic target for prostate cancer patients.
| S-EPMC9908295 | biostudies-literature
Project description:Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.
| S-EPMC6886683 | biostudies-literature
Project description:Metastatic and castration-resistant disease is a fatal manifestation of prostate cancer (PCa). The mechanism through which resistance to androgen deprivation in PCa is developed remains largely unknown. Our understanding of the tumor microenvironment (TME) and key signaling pathways between tumors and their TME is currently changing in light of the generation of new knowledge with regard to cancer progression. A disintegrin and metalloproteinase domain-containing protein 9 (ADAM9) is a membranous bridge forming cell-cell and cell-matrix connections that regulate tumor aggressiveness and metastasis. However, it is not known whether ADAM9 expressed in the TME contributes to the CRPC phenotype. In this study, we aimed to investigate the expression patterns of ADAM9 in prostate cancer-associated fibroblasts (CAFs). We also intended to elucidate the effects of both stromal cell- and cancer cell-derived ADAM9 on the progression of CRPC and the implicated molecular pathways. By using both clinical specimens and cell lines, we herein showed that unlike the membrane anchored ADAM9 overexpressed by both PCa cells and prostate CAFs, the secreted isoform of ADAM9 (sADAM9) was strongly detected in CAFs, but rarely in tumor cells, and that could be a serum marker for PCa patients. We demonstrated that functionally sADAM9 are characterized as chemoattractant for the directed movement of androgen-independent PCa cells through integrin downstream FAK/AKT pathway, supporting that elevated sADAM9 by prostate CAFs could be responsible for the promotion of CRPC metastasis. Moreover, by stimulating PCa cells with sADAM9, we found that ubinuclein-2 (UBN2) expression was increased. A positive correlation of ADAM9 and UBN2 expression was observed in androgen receptor-expressing PCa cell lines and further confirmed in clinical PCa specimens. Using a genetic modification approach, we identified UBN2 as a downstream target gene of ADAM9 that is critical for the survival of androgen-dependent PCa cells in response to androgen deprivation, through the induction and effect of the aldo-keto reductase family 1 member C3 (AKR1C3). Collectively, our results reveal a novel action of ADAM9 on the transition of androgen-dependent PCa cells into an androgen-independent manner through the UBN2/AKR1C3 axis; the aforementioned action could contribute to the clinically-observed acquired androgen-deprivation therapy resistance.
| S-EPMC8822277 | biostudies-literature
Project description:Cancer cell molecular mimicry of stem cells (SC) imbues neoplastic cells with enhanced proliferative and renewal capacities. In support, numerous mediators of SC self-renewal have been evinced to show oncogenic potential. We have recently reported that short-hairpin RNA-mediated knockdown of the embryonic stem cell (ESC) self-renewal gene NANOG significantly reduced the clonogenic and tumorigenic capabilities of various cancer cells. In this study, we sought to test the potential pro-tumorigenic functions of NANOG, particularly, in prostate cancer (PCa). Using qRT-PCR, we first confirmed that PCa cells expressed NANOG mRNA primarily from the NANOGP8 locus on chromosome 15q14. We then constructed a lentiviral promoter reporter in which the -3.8-kb NANOGP8 genomic fragment was used to drive the expression of green fluorescence protein (GFP). We observed that NANOGP8-GFP(+) PCa cells showed cancer stem cell (CSC) characteristics such as enhanced clonal growth and tumor regenerative capacity. To further investigate the functions and mechanisms of NANOG in tumorigenesis, we established tetracycline-inducible NANOG-overexpressing cancer cell lines, including both PCa (Du145 and LNCaP) and breast (MCF-7) cancer cells. NANOG induction promoted drug resistance in MCF-7 cells, tumor regeneration in Du145 cells and, most importantly, castration-resistant tumor development in LNCaP cells. These pro-tumorigenic effects of NANOG were associated with key molecular changes, including an upregulation of molecules such as CXCR4, IGFBP5, CD133 and ALDH1. The present gain-of-function studies, coupled with our recent loss-of-function work, establish the integral role for NANOG in neoplastic processes and shed light on its mechanisms of action.
| S-EPMC3140601 | biostudies-literature
Project description:Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.
| S-EPMC3695935 | biostudies-literature
Project description:Inhibition of androgen-receptor (AR)signaling is the foundation of therapeutic regimens for advanced prostate cancers. However, nearly all patientsdevelop resistance and some never respond. To identify genes that mediate resistance to androgen ablation therapy, we performed an open reading frame (ORF) expression screen of17,255 ORFs and found that the transcription factorCREB5robustly conferred resistance to androgen deprivation and AR inhibition by enzalutamide. CREB5 overexpressionincreased enzalutamide-resistance 45-fold, enhanced resistance of tumor xenografts. CREB5 expression was also essential for enzalutamide-resistance patient-derived organoids. In clinical mCRPC, CREB5is frequently amplified and itsoverexpression positively correlated with castration resistance gene signatures including those of MYC and cell cycle. Mechanistically, CREB5 directly interacted at AR binding sites andenhanced site-specific AR bindingin enzalutamide. This dysregulated expression of 393 AR target genes including MYC and CDK1.These observations identifyCREB5asadriver of enzalutamide-resistance in a subset of advancedprostate cancer.
2019-09-21 | GSE137775 | GEO
Project description:BackgroundAndrogen ablation is the first-line therapy for patients with metastatic prostate cancer (CaP). However, castration resistance will eventually emerge. In the present study, we have investigated the role of bone morphogenetic protein-6 (BMP-6) in the development of castration-resistant prostate cancer (CRPC) in the context of bone metastases.MethodsWe initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model.ResultsIn the 158 patients, we found that the median time to prostate-specific antigen progression was significantly shorter when bone metastases were present (14 months (95% CI, 10.2-17.8 months) vs 57 months (95% CI, 19.4-94.6 months)). These results suggest that bone-tumour interactions may accelerate castration resistance. Consistent with this hypothesis, in vitro co-cultures demonstrated that CaP cells proliferated under an androgen-depleted condition when incubated with bone stromal cells. Mechanistically, gene expression analysis using quantitative polymerase chain reaction arrays showed a dramatic induction of BMP-6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP-6 by CaP cells; BMP-6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and β-catenin. Intracellularly, WNT5A increased BMP-6 expression via protein kinase C/NF-κB pathway in CaP cell lines.ConclusionsThese observations suggest that bone-CaP interaction leads to castration resistance via WNT5A/BMP-6 loop.
| S-EPMC3960605 | biostudies-literature
Project description:BackgroundAndrogen deprivation therapy (ADT), or chemical castration, is the first-line therapy for prostate cancer; however, resistance leaves few treatment options. Prostatic tumor-associated macrophages (TAMs) have been shown to promote prostate cancer growth and are abundant in castration-resistant prostate cancer (CRPC), suggesting a role in promoting CRPC. We recently showed a tumor cell-intrinsic mechanism by which RON promotes CRPC. Given previous reports that RON alters prostate cancer cell chemokine production and RON-overexpressing tumors alter macrophage function, we hypothesized that a macrophage-dependent mechanism regulated by tumor cell intrinsic RON also promotes CRPC.MethodsUsing RON-modulated genetically engineered mouse models (GEMMs) and GEMM-derived cell lines and co-cultures with bone marrow-derived macrophages, we show functional and molecular characteristics of signaling pathways in supporting CRPC. Further, we used an unbiased phosphokinase array to identify pathway interactions regulated by RON. Finally, using human prostate cancer cell lines and prostate cancer patient data sets, we show the relevance of our findings to human prostate cancer.ResultsStudies herein show that macrophages recruited into the prostate tumor microenvironment (TME) serve as a source for Gas6 secretion which serves to further enhance RON and Axl receptor activation in prostate tumor cells thereby driving CRPC. Further, we show targeting RON and macrophages in a murine model promotes CRPC sensitization to ADT.ConclusionsWe discovered a novel role for the RON receptor in prostate cancer cells in promoting CRPC through the recruitment of macrophages into the prostate TME. Macrophage-targeting agents in combination with RON/Axl inhibition are likely to provide clinical benefits for patients with CRPC.
| S-EPMC9492645 | biostudies-literature
Project description:Androgen deprivation therapy (ADT) is used to treat prostate cancer (PCa). However, ADT may increase the expression of androgen receptor (AR) through the amplification of chromosome X. The gene oligophrenin 1 (OPHN1) is located in the same region as the AR gene, which could be amplified by ADT. Thus, the role of OPHN1 in PCa pathology was investigated. The expression status of OPHN1 in PCa was searched in The Cancer Genome Atlas (TCGA) database. Androgen‑sensitive cells LNCaP and 22RV1 were cultured under ADT conditions, and then the expression of OPHN1 was evaluated by northern blotting. The expression of OPHN1 was enhanced or knocked down in LNCaP and 22RV1 cells by transfection. Subsequently, the LNCaP and 22RV1 cells were cultured under ADT, and the viability rate, apoptosis, and migration of cells were assessed by MTT, flow cytometry, and Transwell assay respectively. The expression of OPHN1 was also enhanced or knocked down in androgen‑insensitive PC3 cells, and then the effects of OPHN1 on the viability, apoptosis, and migration of PC3 cells were assessed. A mouse xenograft model was created by injecting LNCaP cells with OPHN1 overexpression subcutaneously, and the tumor growth rates were monitored. In TCGA database, amplification of the OPHN1 gene was observed in the PCa tumors. ADT increased the expression of OPHN1 in LNCaP and 22RV1 cells (P<0.05). OPHN1 could promote resistance of LNCaP and 22RV1 cells to ADT by promoting cell survival and preventing their apoptosis (P<0.05). In addition, OPHN1 contributed to cell viability (P<0.05) and enhanced the migration ability in LNCaP, 22RV1 and PC3 cells (P<0.05). In the mouse model, the PCa xenograft with OPHN1 overexpression had a higher growth rate and was more resistant to the ADT condition (P<0.05). In summary, ADT induced the overexpression of OPHN1 in PCa, which facilitated PCa cell survival and promoted PCa progression.
| S-EPMC8600397 | biostudies-literature
Project description:Intratumoral synthesis of dihydrotestosterone (DHT) from precursors cannot completely explain the castration resistance of prostate cancer. We showed that DHT was intratumorally synthesized from the inactive androgen metabolites 5α-androstane-3α/β,17β-diol (3α/β-diol) in prostate cancer cells via different pathways in a concentration-dependent manner. Additionally, long-term culture in androgen-deprived media increased transcriptomic expression of 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), a key enzyme of oxidative 3α-HSD that catalyzes the conversion of 3α-diol to DHT in prostate cancer cells. Correspondingly, the score for HSD17B6 in tissues of 42 prostate cancer patients undergoing androgen deprivation therapy (ADT) was about 2-fold higher than that in tissues of 100 untreated individuals. In men receiving ADT, patients showing biochemical progression had a higher HSD17B6 score than those without progression. These results suggested that 3α/β-diol also represent potential precursors of DHT, and the back conversion of DHT from androgen derivatives can be a promising target for combination hormone therapy.
| S-EPMC3607121 | biostudies-other