Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion

Wang, Yugang; Singhal, Udit; Qiao, Yuanyuan; Kasputis, Tadas; Chung, Jaewoo; Zhao, Haiming; Chammaa, Farah; Belardo, Jacob A.; Roth, Therese M.; Zhang, Hao; Zaslavsky, Alexander; Palapattu, Ganesh S.; Pienta, Kenneth J.; Chinnaiyan, Arul M.; Taichman, Russell S.; Cackowski, Frank C.; Morgan, Todd M.

doi:10.1016/j.tranon.2020.100747

Cited by 41 publications

(29 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As PCa progresses, APC and CTNNB1 become mutated in 22% of castration resistant PCa to drive Wnt pathway activation (Murillo-Garzon and Kypta, 2017). In PCa cell lines, disruption of e-cadherin enhanced Wnt signaling and increased tumor growth (Davies et al, 2000) and WNT5A has been shown to promote cancer cell invasion (Wang et al, 2020). Our results indicate that vitamin D sufficiency could provide negative pressure on the Wnt pathway to complement other therapies and improve PCa patient outcome.…”

Section: 25d Regulates Dkk3 In Lineage-committed Cellsmentioning

confidence: 70%

Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids

McCray

Pacheco

Baumann

et al. 2020

Preprint

View full text Add to dashboard Cite

Vitamin D is an essential steroid hormone that regulates systemic calcium homeostasis and cell fate decisions, including differentiation in many cell types. The prostate gland is hormonally regulated, requiring steroids for proliferation and terminal differentiation of secretory luminal cells. Vitamin D deficiency is associated with higher risk of lethal prostate cancer with an aggressive dedifferentiated pathology, linking vitamin D sufficiency to epithelial differentiation homeostasis. To determine regulation of prostate epithelial differentiation by vitamin D status, patient-derived benign prostate epithelial organoids were maintained in vitamin D deficient (vehicle) or sufficient (10 nM 1,25-dihydroxyvitamin D) conditions and assessed by phenotype and single cell RNA sequencing. Mechanistic validation demonstrated that vitamin D sufficiency promoted organoid growth and accelerated differentiation of lineage-committed cells by inhibiting canonical Wnt activity and Wnt family member DKK3. Wnt dysregulation is a known contributor to aggressive prostate cancer, thus these findings further link vitamin D deficiency to lethal disease.

show abstract

Section: 25d Regulates Dkk3 In Lineage-committed Cellsmentioning

confidence: 70%

Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids

McCray

Pacheco

Baumann

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Mounting evidences showed that FZD8 was involved in various malignant tumors including prostate cancer [31][32][33], lung cancer [34], breast cancer [35], and gastric cancer [36]. Yin et al [37] suggested that FZD8 had an important role in resistance to treatment with cisplatin plus TRAIL in patients triple-negative breast cancer, thus making it a potential target for chemosensitization.…”

Section: Discussionmentioning

confidence: 99%

Expression and Prognostic Impact of FZDs in Pancreatic Adenocarcinoma

Liu

Zhang

2020

Preprint

View full text Add to dashboard Cite

Background: Despite the high number of researches on pancreatic adenocarcinoma (PAAD) over past decades, little progress had been made due to lack of effective treatment regimens. we aimed to investigate the expression level, mutation, and clinical significance of the Frizzled (FZD) family in PAAD so as to establish a sufficient scientific evidence for clinical decisions and risk management.Methods: PAAD samples were extracted from The Cancer Genome Atlas (TCGA). Oncomine, Gene expression profiling interactive analysis (GEPIA), Human Protein Atlas (HPA), Kaplan-Meier Plotter, cBioPortal, LinkedOmics, DAVID database, and R software (x64 3.6.2) were used to comprehensively analyze the roles of FZDs. p-value below to 0.05 was considered as significant difference.Results: In total, 179 PAAD tissues and 171 paracancerous tissues were included. The expression levels of FZD1, 2, 6, 7, and 8 were higher in PAAD tissues than those in normal pancreatic tissue. The higher the expression levels of FZD2 and FZD7, the higher the clinical stage. PAAD patients with high expression of FZD6 had shorter overall survival (OS) than those with low expression, indicating that FZD6 could be a potential prognostic and predictive marker in PAAD. PAAD patients with high expression of FZD8 had shorter recurrence free survival (RFS) than those with low expression, indicating that FZD8 could be a potential therapeutic target in PAAD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that FZDs played a critical role in the Wnt signaling pathway, which was further confirmation that FZDs were transmembrane receptors of Wnt signaling pathway. Conclusions: Our results strongly indicated a crucial role of the FZD family in PAAD. FZD3, 4, 5, 6, and 9 could be potential prognostic and predictive markers, and FZD4 and 8 might function as potential therapeutic targets in PAAD.

show abstract

“…Therefore, more potent strategies to abrogate the ADT-induced redox signaling network amplifications will be necessary to decrease CRPC selection and metastasis. Indeed, a crucial issue that is often overlooked is the role of sudden hormonal changes in facilitating the metastasis of CRPC cells, primarily to the bone marrow and brain [167,168] . Since androgen signaling plays an important role in normal physiology and cellular functions [169][170][171][172] , whole body hormone deprivation may result in systemic oxidative stress, especially in the bone marrow and brain, where the CRPC cells with an acquired redox-signaling network can find new sanctuaries and form metastatic foci, resulting in increased mortality associated with mCRPCs.…”

Section: Is There a Therapeutic Benefit Of Antioxidants In Crpc Progrmentioning

confidence: 99%

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

Mondal¹,

Narwani²,

Notta³

et al. 2020

CDR

View full text Add to dashboard Cite

Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.

show abstract

Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion

Cited by 41 publications

References 47 publications

Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids

Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids

Expression and Prognostic Impact of FZDs in Pancreatic Adenocarcinoma

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

Contact Info

Product

Resources

About