Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner

Kato, Manabu; Placencio-Hickok, Veronica; Madhav, Anisha; Haldar, Subhash; Tripathi, Manisha; Billet, Sandrine; Mishra, Rajeev; Smith, Bethany N.; Rohena-Rivera, Krizia; Agarwal, Priyanka; Duong, Frank; Angara, Bryan; Hickok, David F.; Liu, Zhenqiu; Bhowmick, Neil A.

doi:10.1038/s41388-018-0461-3

Cited by 77 publications

(106 citation statements)

References 45 publications

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“…Androgen deprivation therapy is the gold standard of care for advanced prostate cancer, but the development to castration-resistant prostate cancer is inevitable, ultimately leads to treatment failure and death. Importantly, recent studies have demonstrated that CAFs, as key components of the tumour microenvironment, contributes to PCa progression and resistance to ADT [7][8][9]. Furthermore, mounting studies provided new evidence to the role of CAF-derived exosomes in cancer progression [28,29].…”

Section: Discussionmentioning

confidence: 99%

Loss of Exosomal miR-146a-5p from Cancer-Associated Fibroblasts After Androgen Deprivation Therapy Contributes to Prostate Cancer Metastasis

Zhao

Ding

et al. 2020

Preprint

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Background: Androgen deprivation therapy (ADT) is the backbone of therapy for advanced prostate cancer (PCa). Despite the good initial response, castration resistance and metastatic progression will inevitably occur. Cancer-associated fibroblasts (CAFs) may be implicated in promoting metastasis of PCa after ADT. Our aim is to investigate the role and mechanism of CAF-derived exosomes involving in metastasis of PCa after ADT. Methods: PCa cells were co-cultured with exosomes derived from 10 nM dihydrotestosterone (DHT)-treated (simulating the high androgen level of prostate cancer microenvironment） or ethanol (ETOH) -treated (simulating the castration level of prostate cancer microenvironment after ADT) CAFs, and their migration and invasion differences under castration condition were examined both in vitro and in vivo. The miRNA profiles of exosomes derived from DHT-treated CAFs and matched ETOH-treated CAFs were analysed via next generation sequencing. The transfer of exosomal miR-146a-5p from CAFs to PCa cells was identified by fluorescent microscopy. The function and direct target gene of exosomal miR-146a-5p in PCa cells were confirmed through Transwell assays, luciferase reporter, and western blot.Results: Compared with DHT-treated CAFs, exosomes derived from ETOH-treated CAFs dramatically increase migration and invasion of PCa cells under castration condition. MiR-146a-5p level in exosomes from ETOH-treated CAFs was significantly reduced. The loss of miR-146a-5p may strengthen the epithelial-mesenchymal transition (EMT) to accelerate cancer cells metastasis by modulating epidermal growth factor receptor (EGFR)/ERK pathway. Conclusions: CAFs-derived exosomal miR-146a-5p confers metastasis in PCa cells under ADT through the EGFR/ERK pathway and it may present a new treatment for PCa

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Section: Discussionmentioning

confidence: 99%

Loss of Exosomal miR-146a-5p from Cancer-Associated Fibroblasts After Androgen Deprivation Therapy Contributes to Prostate Cancer Metastasis

Zhao

Ding

et al. 2020

Preprint

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“…Cultured LNCaP, TRAMPC2, and PC3 (all from ATCC) were grown in Roswell Park Memorial Institute (RPMI) media supplemented with 5% fetal bovine serum and treated with docetaxel (Sano-fiAventis) or SB290157 (1 μM, Calbiochem) for 48 h. Conditioned medium was treated with DNase1 (0.1 mg/mL, Sigma-Aldrich) in 37°C for 1 h followed by heat inactivation. Cultured primary NAF and CAF derived in our laboratory (4) were treated with LNCaP-CM, CpG-ODN (5 μM, InvivoGen), and N-acetylcysteine (10 mM [Sigma-Aldrich]).…”

Section: Methodsmentioning

confidence: 99%

“…Incidentally, higher doses of docetaxel were used for PC3 cells compared to the other two lines due to its inherent resistance. The influence of stromal-epithelial cross talk in the development of docetaxel resistance was tested in coculture studies within a three-dimensional (3D) matrix of collagen I and Matrigel (4,18). The coculture of PC3 and CAF resulted in a doubling of EpCAM + /Ki67 + proliferative epithelia compared to that when PC3 cells were grown alone (Fig.…”

Section: Synergistic Effect Of Docetaxel and C3ar Antagonism Inhibitmentioning

confidence: 99%

“…prostate cancer | docetaxel | mtDNA | carcinoma-associated fibroblast P rostate cancer (PCa) is the second leading cause of cancerrelated death of men in the United States (1). Stromalepithelial interactions define tumor initiation, progression, and therapeutic resistance (2)(3)(4)(5)(6). In the prostate tumor microenvironment, stromal fibroblasts coevolve with the cancer epithelia in a reciprocal relationship (7).…”

mentioning

confidence: 99%

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Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance

Haldar

Mishra

Billet

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity.

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“…It was later found that higher preoperative plasma levels of CD105 were associated with poor clinical outcomes of PC such as higher PSA values, higher Gleason scores, and biochemical recurrence after radical prostatectomy (5). The expression of CD105 on cancer associated fibroblasts has been demonstrated to be elevated with and contribute to PC resistance to androgen targeted therapy (6). A study has measured endoglin in urine and serum samples of men at high risk of PC (7).…”

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confidence: 99%

Soluble Endoglin (sCD105) as a Novel Biomarker for Detecting Aggressive Prostate Cancer

et al. 2020

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Background/Aim: We have previously found elevated levels of endoglin (CD105) in the prostate cancer (PC) tissue of men with poor prognosis, compared to men with indolent disease. Herein, we examined whether plasma levels of the soluble form of CD105 (sCD105) differ according to the PC grade at diagnosis. Patients and Methods: We measured sCD105 in 73 subjects with biopsy-confirmed PC at the Durham, North Carolina, Veteran Affairs Health System. The association between sCD105 and intermediate/high-grade PC risk [Gleason Group (GG) 2-5 vs. 1] was examined using regression models. Results: Of 73 men, 27 had low-grade PC and 46 high-grade PC. Higher GG was linked to lower sCD105 (GG1: 6938 pg/ml, GG2-3: 6150 pg/ml, GG4-5: 5554 pg/ml; p=0.012). On multivariable analysis, lower sCD105 was associated with increased high-grade PC risk (OR per 1000 units =1.33, p=0.028). Conclusion: Lower sCD105 levels were associated with intermediate and high-risk PC. Further investigation is warranted in a larger PC cohort.

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Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner

Cited by 77 publications

References 45 publications

Loss of Exosomal miR-146a-5p from Cancer-Associated Fibroblasts After Androgen Deprivation Therapy Contributes to Prostate Cancer Metastasis

Loss of Exosomal miR-146a-5p from Cancer-Associated Fibroblasts After Androgen Deprivation Therapy Contributes to Prostate Cancer Metastasis

Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance

Soluble Endoglin (sCD105) as a Novel Biomarker for Detecting Aggressive Prostate Cancer

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