scholarly journals TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3862
Author(s):  
Motasim Masood ◽  
Stefan Grimm ◽  
Mona El-Bahrawy ◽  
Ernesto Yagüe
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Transmembrane Protein ◽  
Intracellular Localization ◽  
Amyloid Β ◽  
Inverse Correlation ◽  
Response To Therapy ◽  
Endocrine Function ◽  
Type I ◽  
Amyloid Β Protein

Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) is a 374-residue long type-I transmembrane proteoglycan which is proteolytically shed from the cell surface. The protein is involved in a range of functions including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 is methylated in numerous cancers, and an inverse correlation with the stage, response to therapy and survival outcome has been observed. Moreover, TMEFF2 methylation increases with breast, colon and gastric cancer progression. TMEFF2 is methylated early during oncogenesis in breast and colorectal cancer, and the detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool. The TMEFF2 downregulation signature equals and sometimes outperforms the Gleason and pathological scores in prostate cancer. TMEFF2 is downregulated in glioma and cotricotropinomas, and it impairs the production of adrenocorticotropic hormone in glioma cells. Interestingly, through binding the amyloid β protein, its precursor and derivatives, TMEFF2 provides neuroprotection in Alzheimer’s disease. Despite undergoing extensive investigation over the last two decades, the primary literature regarding TMEFF2 is incoherent and offers conflicting information, in particular, the oncogenic vs. onco-suppressive role of TMEFF2 in prostate cancer. For the first time, we have compiled, contextualised and critically analysed the vast body of TMEFF2-related literature and answered the apparent discrepancies regarding its function, tissue expression, intracellular localization and oncogenic vs. onco-suppressive role.

scholarly journals Linking obesogenic dysregulation to prostate cancer progression

2015 ◽  
Vol 4 (4) ◽  
pp. R68-R80 ◽  
Author(s):  
Renea A Taylor ◽  
Jennifer Lo ◽  
Natasha Ascui ◽  
Matthew J Watt
Keyword(s):  
Prostate Cancer ◽  
Adipose Tissue ◽  
Cancer Progression ◽  
Prostate Gland ◽  
The Body ◽  
Endocrine Function ◽  
Low Grade ◽  
Prostate Cancer Progression ◽  
Cancer Aggressiveness ◽  
Increased Risk

The global epidemic of obesity is closely linked to the development of serious co-morbidities, including many forms of cancer. Epidemiological evidence consistently shows that obesity is associated with a similar or mildly increased incidence of prostate cancer but, more prominently, an increased risk for aggressive prostate cancer and prostate cancer-specific mortality. Studies in mice demonstrate that obesity induced by high-fat feeding increases prostate cancer progression; however, the mechanisms underpinning this relationship remain incompletely understood. Adipose tissue expansion in obesity leads to local tissue dysfunction and is associated with low-grade inflammation, alterations in endocrine function and changes in lipolysis that result in increased delivery of fatty acids to tissues of the body. The human prostate gland is covered anteriorly by the prominent peri-prostatic adipose tissue and laterally by smaller adipose tissue depots that lie directly adjacent to the prostatic surface. We discuss how the close association between dysfunctional adipose tissue and prostate epithelial cells might result in bi-directional communication to cause increased prostate cancer aggressiveness and progression. However, the literature indicates that several ‘mainstream’ hypotheses regarding obesity-related drivers of prostate cancer progression are not yet supported by a solid evidence base and, in particular, are not supported by experiments using human tissue. Understanding the links between obesity and prostate cancer will have major implications for the health policy for men with prostate cancer and the development of new therapeutic or preventative strategies.

scholarly journals PMEPA1 Gene Isoforms: A Potential Biomarker and Therapeutic Target in Prostate Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1221
Author(s):  
Shashwat Sharad ◽  
Albert Dobi ◽  
Shiv Srivastava ◽  
Alagarsamy Srinivasan ◽  
Hua Li
Keyword(s):  
Prostate Cancer ◽  
Solid Tumors ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Gene Networks ◽  
Transmembrane Protein ◽  
Regulatory Gene ◽  
Amino Acid Sequences ◽  
Binding Domains ◽  
Potential Biomarker

The identification of prostate transmembrane protein androgen induced 1 (PMEPA1), an androgen responsive gene, came initially from the studies of androgen regulatory gene networks in prostate cancer. It was soon followed by the documentation of the expression and functional analysis of transmembrane prostate androgen-induced protein (TMEPAI)/PMEPA1 in other solid tumors including renal, colon, breast, lung, and ovarian cancers. Further elucidation of PMEPA1 gene expression and sequence analysis revealed the presence of five isoforms with distinct extracellular domains (isoforms a, b, c, d, and e). Notably, the predicted amino acid sequences of PMEPA1 isoforms show differences at the N-termini, a conserved membrane spanning and cytoplasmic domains. PMEPA1 serves as an essential regulator of multiple signaling pathways including androgen and TGF-β signaling in solid tumors. Structure-function studies indicate that specific motifs present in the cytoplasmic domain (PY, SIM, SH3, and WW binding domains) are utilized to mediate isoform-specific functions through interactions with other proteins. The understanding of the “division of labor” paradigm exhibited by PMEPA1 isoforms further expands our knowledge of gene’s multiple functions in tumorigenesis. In this review, we aim to summarize the most recent advances in understanding of PMEPA1 isoform-specific functions and their associations with prostate cancer progression, highlighting the potentials as biomarker and therapeutic target in prostate cancer.

scholarly journals Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains

2016 ◽  
Vol 0 (0) ◽  
Author(s):  
Frederike Schmidt ◽  
Miryam Müller ◽  
Johannes Prox ◽  
Philipp Arnold ◽  
Caroline Schönherr ◽  
...  
Keyword(s):  
Cell Surface ◽  
Transmembrane Protein ◽  
Amyloid Β ◽  
Type I ◽  
Direct Binding ◽  
Small Intestinal ◽  
Split Ubiquitin ◽  
Biological Methods ◽  
Two Hybrid

AbstractMeprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It was shown that meprin β cleaves the amyloid precursor protein (APP), thereby releasing neurotoxic amyloid β peptides and implicating a role of meprin β in Alzheimer’s disease. In order to identify non-proteolytic regulators of meprin β, we performed a split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library. In this screen we identified tetraspanin 8 (TSPAN8) as interaction partner for meprin β. Since several members of the tetraspanin family were described to interact with metalloproteases thereby affecting their localization and/or activity, we hypothesized similar functions of TSPAN8 in the regulation of meprin β. We employed cell biological methods to confirm direct binding of TSPAN8 to meprin β. Surprisingly, we did not observe an effect of TSPAN8 on the catalytic activity of meprin β nor on the specific cleavage of its substrate APP. However, both proteins were identified being present in tetraspanin-enriched microdomains. Therefore we hypothesize that TSPAN8 might be important for the orchestration of meprin β at the cell surface with impact on certain proteolytic processes that have to be further identified.

Tracking clonal diversity in metastatic prostate cancer progression.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 193-193
Author(s):  
Christopher Hovens ◽  
Matthew Hong ◽  
Geoff Macintyre ◽  
David Wedge ◽  
Peter Van Loo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Large Scale ◽  
Metastatic Prostate Cancer ◽  
Genetic Relationships ◽  
Metastatic Potential ◽  
Response To Therapy ◽  
Tumor Evolution ◽  
End Stage ◽  
Lethal Prostate Cancer

193 Background: Genomic heterogeneity has been observed in a number of tumor types including prostate cancer. However, how subclonal tumor diversity changes during metastasis and progression to lethality remains unexplored. Large scale genomic analyses have reported the most prevalent somatic aberrations associated with the dominant clone of the tumor without permitting an analysis of subclonal complexity or how this complexity impinges on metastatic potential or resistance to treatment. Methods: To understand and track the evolution of lethal prostate cancer from initial therapy to end stage metastases, we performed longitudinal and multiregional sampling of tumors from 7 patients with lethal prostate cancer. We performed whole-genome sequencing, RNA sequencing, and SNP profiling. Computational approaches were used to reconstruct the genetic relationships and evolution of the tumors. These evolutionary tree reconstructions allowed us to observe the dynamics of chromoplexy and mutational processes along specific branches of tumor evolution. To refine the genetic landscape and spatial connections between subclones, we employed deep, targeted re-sequencing of variant loci in the original sequenced samples, in additional FFPE sites sampled from the organ confined tumors, and from blood. Results: We show that while all primary and metastatic prostate tumors share a single ancestral clone, metastases arise from subclones present at minor frequencies in the primary tumor. We reveal that individual metastases comprise mixtures of subclones indicative of intra-metastatic heterogeneity. We provide evidence for cross-metastatic site seeding and dynamic remolding of subclonal mixtures in response to therapy suggesting a distinct metastatic hierarchy. Ultra-deep sequencing of end-stage blood reveals the presence of diverse subclones with metastatic potential derived from various stages in the evolution of the tumor. Conclusions: Our results demonstrate unexpected complexity in the origins of both primary and metastatic prostate cancer, with distinct implications for treatment of advanced disease.

PACIFIC trial: A randomized phase II study of apatorsen and abiraterone in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC) who have had PSA progression while receiving abiraterone (ABI).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 146-146 ◽  
Author(s):  
Kim N. Chi ◽  
Mark T. Fleming ◽  
Katherine Sunderland ◽  
Costantine Albany ◽  
Joel Gingerich ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Cancer Progression ◽  
Type I Error ◽  
Clinical Activity ◽  
Type I ◽  
Castration Resistant Prostate Cancer ◽  
Free Psa ◽  
Predictors Of Response ◽  
Ecog Ps

146 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 chaperones androgen receptor (AR) and enhances transactivation of AR-regulated genes. Apatorsen is a 2nd generation antisense that inhibits Hsp27 expression with clinical activity demonstrated in pts with mCRPC. Methods: mCRPC patients with PSA-only progression on ABI + prednisone (P) 10-20 mg daily were randomized to continuing ABI + P (Control Arm) or ABI + P with Apatorsen 600 mg IV x 3 loading doses then 800 mg IV weekly (Study Arm). Control Arm pts could cross over to receive apatorsen at time of progression. Primary endpoint was the proportion of pts progression free (PSA, clinical and radiologic) at day 60. Assuming a 25% increase in proportion of pts progression free and a null hypothesis of 5%, the planned sample size was 74 patients (type I error 20%, type II error 10%). Results: 72 pts were randomized: 36 to Control Arm, 36 to Study Arm. Baseline characteristics were similar in both arms: median age was 72 years (53-89); ECOG PS 0/1 in 44/56% of pts; median PSA of 29.4 (2.5-470.0); metastases to bone/lymph nodes/liver or lung occurred in 63/27/10%; elevated LDH and alkaline phosphatase in 26% and 26% ; 47% had ≥ 5 CTC/7.5 mL. Adverse events (AEs) were mainly grade 1-2 infusion reactions. 18 pts had grade 3/4 adverse events considered apatorsen related including: dyspnea (14%), fatigue (14%), increased ALT (9%), increased AST (9%), and thrombocytopenia (9%). Primary and secondary outcomes are summarized in the Table. Conclusions: Apatorsen may have activity when added to abiraterone for mCRPC patients progressing on abiraterone. Establishing predictors of response should be a priority for future studies. Clinical trial information: NCT01681433. [Table: see text]

scholarly journals LncRNA UCA1 acts as a sponge of miR-204 to up-regulate CXCR4 expression and promote prostate cancer progression

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Chang He ◽  
Xuwei Lu ◽  
Fan Yang ◽  
Liang Qin ◽  
Zhuifeng Guo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Progression ◽  
Cell Function ◽  
Inverse Correlation ◽  
Positive Association ◽  
Cxcr4 Expression ◽  
Epithelial Cell Line ◽  
Normal Prostate ◽  
Expression Levels

AbstractProstate cancer (PCa) is a devastating malignant disease with a poor prognosis. The aim of current study is to investigate the role of lncRNA-urothelial carcinoma associated 1 (UCA1) in the progression of PCa. We evaluated the expression levels of UCA1 in a total of 16 benign prostatic hyperplasia tissues (BPH) and 40 PCa tissues, as well as PCa cells. The functional regulatory effects of UCA1 were investigated using a series of cell function approaches. Our data showed that UCA1 is frequently overexpressed in PCa tissues compared with BPH tissues (P<0.01). Moreover, the higher expression of UCA1 was observed in patients with Gleason score ≥8 (P<0.05). In consistent, we found the expression levels of UCA1 was higher in the PCa cell lines PC-3, LnCaP, and DU-145 than in the normal prostate epithelial cell line RWPE-1 (P<0.01). Functionally, we found knockdown of UCA1 in PC-3 significantly suppressed cell growth and invasion of PC-3, while overexpression of UCA1 in DU-145 cells promote cell growth and invasion. Mechanistically, UCA1 overexpression permitted activation of CXCR4 oncogenes through inhibition of miR-204 activity, as evidenced by the positive association of these two genes with UCA1 levels and inverse correlation with miR-204 expression in PCa tissues. Luciferase activity assay further confirmed the targetting relationship between UCA1 and miR-204, CXCR4, and miR-204. The up-regulation of UCA1 in PC-3 cells significantly impaired the inhibitory effect of miR-204 on CXCR4 expression. Taken together, our research revealed that UCA1 works as an oncogene by targetting miR-204. The UCA1-miR-204-CXCR4 regulatory network regulated the growth and metastasis of PCa, providing new insight in the management of patients with such malignancy.

scholarly journals Loss of SNAI2 in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy

2021 ◽  
pp. 1048-1059
Author(s):  
Marek Cmero ◽  
Natalie J. Kurganovs ◽  
Ryan Stuchbery ◽  
Patrick McCoy ◽  
Corrina Grima ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Response ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Resistance ◽  
Response To Therapy ◽  
Secondary Outcome ◽  
Short Term ◽  
Short Term Treatment ◽  
Mesenchymal Transition

PURPOSE Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.

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