Loss of androgen receptor signaling in prostate cancer‐associated fibroblasts (CAFs) promotes CCL2‐ and CXCL8‐mediated cancer cell migration

Cioni, Bianca; Nevedomskaya, Ekaterina; Melis, Monique; Burgsteden, Johan van; Stelloo, Suzan; Hodel, Emma; Spinozzi, Daniele; Jong, Jeroen de; Poel, Henk van der; Boer, Jan Paul de; Wessels, Lodewyk; Zwart, Wilbert; Bergman, Andries M.

doi:10.1002/1878-0261.12327

Cited by 88 publications

(80 citation statements)

References 48 publications

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“…Among the several chemokines, CXCL8 plays an important role in PC proliferation, promoting phosphorylation and signaling through Src-kinases, focal adhesion kinase (FAK), PI3K/AKT/mTOR/cyclin D1, and MAPK in cancer cells, thereby promoting CRPC progression and proliferation in PC3 cells. 55 CXCL8 also leads to an up-regulation of the AR. While the CXCL8:CXCR1 axis leads to proliferation, the CXCL8:CXCR2 axis leads to angiogenesis.…”

Section: Pc Stem Cells Play An Important Role In Proliferation; Andmentioning

confidence: 98%

“…On stimulation of CAFs with testosterone, the AR binds at CCL2 and CXCL8 loci, thereby down-regulating the CCL2 and CXCL8 genes and regulating PC migration and invasion. 55 ECM is the noncellular matrix component of the tissue that provides structural and metabolic support to the cellular components. The ECM serves as a functionally active compartment composed of and supporting the production of collagen, elastin, laminin, and proteoglycans.…”

Section: Mesenchymal Stem Cellsmentioning

confidence: 99%

“…55 Binding of the AR to androgen response element sites on the CCL2 gene on stimulation with testosterone led to a down-regulation of CCL2 expression, and blocking CCL2 with a specific CCL2 antibody led to an annulment of migratory and invasive properties of the PC cells. 55 The CCL5:CCR5 axis plays an important role in PC, and both the components are expressed in PC. CCL5 promotes invasion and is inhibited by the CCR5 antagonist TAK-779, which blocks signaling through the CCL5/CCR5 axis.…”

Section: Cancer Cell Migration and Invasionmentioning

confidence: 99%

“…80 CXCL8 plays a pivotal role in CAF-based migration and invasion of PC cells, as studied using a genomewide assay. 55 Binding of the AR to androgen response elements on the CXCL8 genome on stimulation with testosterone led to a down-regulation of CCL2 and CXCL2 expression, and blocking CXCL8 with a specific CXCL8 antibody led to an annulment of migratory and invasive properties of the PC cells. 55 The CCL18/PITPNM3 complex enhances EMT and invasion through enhanced NF-kB activity and regulating the PI3K/AKT/GSK3b-SNAIL pathway.…”

Section: Chemotactic Inflammation In Pcmentioning

confidence: 99%

“…55 Binding of the AR to androgen response elements on the CXCL8 genome on stimulation with testosterone led to a down-regulation of CCL2 and CXCL2 expression, and blocking CXCL8 with a specific CXCL8 antibody led to an annulment of migratory and invasive properties of the PC cells. 55 The CCL18/PITPNM3 complex enhances EMT and invasion through enhanced NF-kB activity and regulating the PI3K/AKT/GSK3b-SNAIL pathway. 1 The CXCL13:CXCR5 axis plays an important role in PC progression through the control of the migratory and invasive potential of PC cells.…”

Section: Chemotactic Inflammation In Pcmentioning

confidence: 99%

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Prostate Cancer

Rani

Dasgupta

Murphy

2019

The American Journal of Pathology

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Prostate cancer (PC) is a leading cause of death in men. Inflammation is one of the initiating processes whereby cells are trafficked into the tumor microenvironment by specific cytokines termed chemokines. This recruitment is complex and involves diverse leukocyte subsets with procancer and anticancer functions. Chemokines promote/abrogate proliferation of cancerous cells, block/aid apoptosis, and are instrumental/ detrimental in cancer cell migration required for metastasis. Chemokines guide the release/transport of immune cells that serve as chaperones at sites of inflammation, and after subsequent activation, they lead to an immune response. The variety of immune cells recruited at the site of tumor initiation possess unique functions, and the plethora of chemokines released by each cell derived from a progenitor cell activated under a defined set of conditions dictates its specific role in cancer progression/regression. Geographic consequences that govern the climate and endemic diseases, along with the associated evolutionary effects that at times protect populations from one disease, could lead to genetic variations that determine a role for ethnicity and race in PC risk and susceptibility. Dysregulated expression or an imbalance in the homeostatic mechanisms associated with chemokines is implicated in PC. This review discusses the role of inflammation and chemokines in PC.

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Section: Pc Stem Cells Play An Important Role In Proliferation; Andmentioning

confidence: 98%

Section: Mesenchymal Stem Cellsmentioning

confidence: 99%

Section: Cancer Cell Migration and Invasionmentioning

confidence: 99%

Section: Chemotactic Inflammation In Pcmentioning

confidence: 99%

Section: Chemotactic Inflammation In Pcmentioning

confidence: 99%

See 3 more Smart Citations

Prostate Cancer

Rani

Dasgupta

Murphy

2019

The American Journal of Pathology

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Integrative characterisation of secreted factors involved in intercellular communication between prostate epithelial or cancer cells and fibroblasts

Clark

Niranjan

et al. 2023

Molecular Oncology

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Reciprocal interactions between prostate cancer cells and carcinomaassociated fibroblasts (CAFs) mediate cancer development and progression; however, our understanding of the signalling pathways mediating these cellular interactions remains incomplete. To address this, we defined secretome changes upon co-culture of prostate epithelial or cancer cells with fibroblasts that mimic bi-directional communication in tumours. Using antibody arrays, we profiled conditioned media from mono-and cocultures of prostate fibroblasts, epithelial and cancer cells, identifying secreted proteins that are upregulated in co-culture compared to monoculture. Six of these (CXCL10, CXCL16, CXCL6, FST, PDGFAA, IL-17B) were functionally screened by siRNA knockdown in prostate cancer cell/fibroblast co-cultures, revealing a key role for follistatin (FST), a secreted glycoprotein that binds and bioneutralises specific members of the TGF-b superfamily, including activin A. Expression of FST by both cell types was required for the fibroblasts to enhance prostate cancer cell proliferation and migration, whereas FST knockdown in co-culture grafts decreased tumour growth in mouse xenografts. This study highlights the complexity of prostate cancer cell-fibroblast communication, demonstrates that co-culture secretomes cannot be predicted from individual cultures, and identifies FST as a tumour-microenvironment-derived secreted factor that represents a candidate therapeutic target.

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Cell‐by‐cell quantification of the androgen receptor in benign and malignant prostate leads to a better understanding of changes linked to cancer initiation and progression

Derderian

Benidir

Scarlata

et al. 2023

The Journal of Pathology CR

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The androgen receptor (AR) plays a crucial role in the development and homeostasis of the prostate and is a key therapeutic target in prostate cancer (PCa). The gold standard therapy for advanced PCa is androgen deprivation therapy (ADT), which targets androgen production and AR signaling. However, resistance to ADT develops via AR‐dependent and AR‐independent mechanisms. As reports on AR expression patterns in PCa have been conflicting, we performed cell‐by‐cell AR quantification by immunohistochemistry in the benign and malignant prostate to monitor changes with disease development, progression, and hormonal treatment. Prostates from radical prostatectomy (RP) cases, both hormone‐naïve and hormone‐treated, prostate tissues from patients on palliative ADT, and bone metastases were included. In the normal prostate, AR is expressed in >99% of luminal cells, 51% of basal cells, and 61% of fibroblasts. An increase in the percentage of AR negative (%AR−) cancer cells along with a gradual loss of fibroblastic AR were observed with increasing Gleason grade and hormonal treatment. This was accompanied by a parallel increase in staining intensity of AR positive (AR+) cells under ADT. Staining AR with N‐ and C‐terminal antibodies yielded similar results. The combination of %AR− cancer cells, %AR− fibroblasts, and AR intensity score led to the definition of an AR index, which was predictive of biochemical recurrence in the RP cohort and further stratified patients of intermediate risk. Lastly, androgen receptor variant 7 (ARV7)+ cells and AR− cells expressing neuroendocrine and stem markers were interspersed among a majority of AR+ cells in ADT cases. Altogether, the comprehensive quantification of AR expression in the prostate reveals concomitant changes in tumor cell subtypes and fibroblasts, emphasizing the significance of AR− cells with disease progression and palliative ADT.

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Loss of androgen receptor signaling in prostate cancer‐associated fibroblasts (CAFs) promotes CCL2‐ and CXCL8‐mediated cancer cell migration

Cited by 88 publications

References 48 publications

Prostate Cancer

Prostate Cancer

Integrative characterisation of secreted factors involved in intercellular communication between prostate epithelial or cancer cells and fibroblasts

Cell‐by‐cell quantification of the androgen receptor in benign and malignant prostate leads to a better understanding of changes linked to cancer initiation and progression

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