Combination therapy with androgen deprivation for hormone sensitive prostate cancer: A new frontier

Etheridge, Tyler; Damodaran, Shivashankar; Schultz, Adam; Richards, Kyle A.; Gawdzik, Joseph; Yang, Bing; Cryns, Vincent L.; Jarrard, David F.

doi:10.1016/j.ajur.2018.09.001

Cited by 16 publications

(17 citation statements)

References 65 publications

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“…We performed an experiment using the SMO inhibitor, vismodegib, to verify that the increased SEMA3C‐induced steroidogenic activities observed in PrSCs is mediated by Shh. Vismodegib is a potent SMO antagonist that inhibits the expression of Hh pathway target genes, such as Gli1 1‐6 . We plated LNCaP Vector and LNCaP SEMA3C cells ( n = 5 each) and PrSCs ( n = 10) in their respective full growth media overnight, then we serum‐starved PrSCs and cultured LNCaP cells in 5% steroid‐depleted CSS containing RPMI media for 72 h. Then, we treated PrSCs with CM‐LN SEMA3C or CM‐LN Vector supplemented with DMSO or vesmodegib (3 nM), in the presence of 1.7 uM DHEA for 72 h. Subsequently, steroid analysis of the conditioned media from treated PrSCs by LCMS showed that vismodegib attenuated the effect of CM‐LN SEMA3C on androgen synthesis in PrSCs.…”

Section: Resultsmentioning

confidence: 99%

“…Vismodegib is a potent SMO antagonist that inhibits the expression of Hh pathway target genes, such as Gli1. [1][2][3][4][5][6] We plated LNCaP Vector Figure 4A). To validate the activity of vismodegib in blocking Shh signaling pathway in PrSCs, we quantified Gli1 mRNA expression in PrSCs by qPCR ( Figure 4B).…”

Section: Smo Inhibitor Suppressed the Effect Of Sema3c Overexpressimentioning

confidence: 99%

“…This suggests that communication between these cells in a paracrine manner can influence malignant cells' survival and progression despite the gonadal androgen blockade. 3,4 Here, we present results of a study on possible effects of semaphorin 3C (SEMA3C) directly on stromal cells, or through paracrine interaction between epithelial and stromal cell types.…”

Section: Introductionmentioning

confidence: 99%

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SEMA3C induces androgen synthesis in prostatic stromal cells through paracrine signaling

2021

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Background: Castration resistant prostate cancer progression is associated with an acquired intratumoral androgen synthesis. Signaling pathways that can upregulate androgen production in prostate tumor microenvironment are not entirely known. In this study, we investigate the potential effect of a secreted signaling protein named semaphorin 3C (SEMA3C) on steroidogenic activities of prostatic stromal cells. Methods: We treated human primary prostate stromal cells (PrSC) with 1uM recombinant SEMA3C protein and androgen precursor named dehydroepiandrosterone (DHEA) 1.7uM. Also, to test SEMA3C's effect on the conversion of DHEA to androgens, we exposed PrSCs to the conditioned media derived from LNCaP cells that were transduced with a lentiviral vector harboring full length SEMA3C gene or empty vector (CM-LN SEMA3C or CM-LN Vector). Then, liquid chromatography-mass spectrometry was performed on steroids isolated from PrSCs media. The messnger RNA expression of steroidogenic enzymes in PrSCs was quantified by quantitative polymerase chain reaction. Results: Recombinant SEMA3C had no effect on steroidogenic activities in PrSCs. However, key steroidogenic enzymes expression and androgen synthesis were upregulated in PrSCs treated with CM-LN SEMA3C , compared to those treated with CM-LN Vector. These results suggest that steroidogenic activities in PrSCs were upregulated in response to a signaling factor in CM-LN SEMA3C , other than SEMA3C. We hypothesized that SEMA3C overexpression in LNCaP cells affected androgen synthesis in PrSCs through sonic hedgehog (Shh) pathway activation in PrSCs. We verified this effect by blocking Shh signaling with smoothened antagonist. Conclusion: Based on known ability of Shh signaling pathway to activate steroidogenesis in stromal cells, we suggest that SEMA3C overexpression in LNCaP cells can upregulate Shh which in turn is able to stimulate steroidogenic activities in prostatic stromal cells.

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Section: Resultsmentioning

confidence: 99%

Section: Smo Inhibitor Suppressed the Effect Of Sema3c Overexpressimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SEMA3C induces androgen synthesis in prostatic stromal cells through paracrine signaling

2021

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“…Although ∼80% patients initially respond to ADT, incurable castration-resistant PCa develops almost invariably. 207,218,219 Importantly, androgen receptors continue to be critical for PCa growth and progression after ADT. It has been demonstrated that several putative consensus-binding sites for the oncogenic erythroblast transformation specific-related gene (ERG) transcription factor are present in the promoter region of CXCR4; thus, androgen-dependent regulation of ERG could induce CXCR4 expression in PCa cells.…”

Section: Cxcr4/cxcl12 Signaling and Prostate Cancermentioning

confidence: 99%

At the Bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer

Luker

Yang

Richmond

et al. 2020

Journal of Leukocyte Biology

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Signaling through chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) regulates essential processes in normal physiology, including embryogenesis, tissue repair, angiogenesis, and trafficking of immune cells. Tumors co-opt many of these fundamental processes to directly stimulate proliferation, invasion, and metastasis of cancer cells. CXCR4 signaling contributes to critical functions of stromal cells in cancer, including angiogenesis and multiple cell types in the tumor immune environment. Studies in animal models of several different types of cancers consistently demonstrate essential functions of CXCR4 in tumor initiation, local invasion, and metastasis to lymph nodes and distant organs. Data from animal models support clinical observations showing that integrated effects of CXCR4 on cancer and stromal cells correlate with metastasis and overall poor prognosis in >20 different human malignancies. Small molecules, Abs, and peptidic agents have shown anticancer efficacy in animal models, sparking ongoing efforts at clinical translation for cancer therapy. Investigators also are developing companion CXCR4-targeted imaging agents with potential to stratify patients for CXCR4-targeted therapy and monitor treatment efficacy. Here, pre-clinical studies demonstrating functions of CXCR4 in cancer are reviewed.

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“…Targeting other potent resistance mechanisms have showed promising results in experimental studies. Dr. David Jarrard and colleagues [7] examined the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target during ADT. Senescent tumor cells generate a catabolic state with increased glycolysis, protein turnover and other metabolic changes that represent targets for drugs, like metformin, to be applied in a synthetic lethal approach.…”

mentioning

confidence: 99%