Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers

Ying, Jhih; Hsiao, Yu; Li, Chien‐Feng; Lo, Yu Chih; Lin, Zu Yau; Hong, Jhen Yi; Liu, Yang Ming; Han, Xiaochen; Wang, Shao Ming; Chen, Ben Kuen; Tsai, Kelvin K.; Wang, Ju Ming

doi:10.18632/oncotarget.4364

Cited by 52 publications

(69 citation statements)

References 50 publications

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“…1A). Our previous studies suggested that CEBPD is responsive to anticancer drugs (26,27). We further assessed whether CDDP affected CEBPD expression in UCUB cells.…”

Section: Significance Of Cebpd Immunoreactivity In Ucubmentioning

confidence: 98%

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Wang

Chu

et al. 2017

Clinical Cancer Research

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Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy.Experimental Design: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity.Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel.Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201.

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“…1A). Our previous studies suggested that CEBPD is responsive to anticancer drugs (26,27). We further assessed whether CDDP affected CEBPD expression in UCUB cells.…”

Section: Significance Of Cebpd Immunoreactivity In Ucubmentioning

confidence: 98%

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Wang

Chu

et al. 2017

Clinical Cancer Research

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“…Furthermore, as well as being a reflection of an inflammatory response, CRP has also been shown to inhibit expression of N-Cadherin and can activate human monocyte tumoricidal activity [38,39]. The pentraxin family includes CRP, and the soluble pattern recognition receptor long petraxin 3 can antagonize FGF and can inhibit FGF-dependent angiogenesis and tumor growth [40], and also can alter tumor matrix and microenvironment [41,42]. Furthermore, a new generation of IL-6 inhibitors has potential in cancer therapy, by disrupting the IL-6/CRP interactions [43-45].…”

Section: Discussionmentioning

confidence: 99%

The patient burden of opioidinduced bowel dysfunction

Akkız

Guerra

et al. 2018

clinical-practice

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C-reactive protein (CRP) is a blood marker for inflammation and is an independent prognostic factor for many human cancers. Combined with albumin levels, it forms the basis of the Glasgow Index for cancer prognosis. We reviewed the literature on CRP and HCC and also evaluated blood CRP levels and combination CRP plus albumin levels in a large HCC cohort. In order to understand the prognostic significance of CRP, we retrospectively examined a large HCC cohort and examined the relationship of CRP levels to tumor parameters. We report, that CRP alone and CRP plus albumin combined as well, significantly correlated with parameters of HCC aggressiveness, such as maximum tumor dimension (MTD), portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels, both as individual parameters and all parameters together (Aggressiveness Index). This extends current thinking, to suggest a possible explanation for the usefulness of blood CRP levels in HCC prognostication.

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“…Despite compelling analyses suggesting PTX3 promoter methylation in certain subtypes of cancer, we strongly believe that the role of PTX3 in regulating the tumor niche is complex and entirely context dependent. For example, Chi et al determined that PTX3 is a CCAAT/enhancer binding protein delta (CEBPD)-responsive gene and displays a pro-tumor phenotype(41), including acquired drug resistance, enhanced migration, and stem-like characteristics. Given these recent findings, we believe our results further support a pro-tumor role for PTX3 in a tissue niche with activated CAFs.…”

Section: Discussionmentioning

confidence: 99%

Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis

Zellmer

Schnepp

Fracci

et al. 2017

Molecular Cancer Research

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The tumor microenvironment (TME) is a dynamic tissue space in which the tumor exists, plays a significant role in tumor initiation, and is a key contributor in cancer progression; however, little is known about tumor-induced changes in the adjacent tissue stroma. Herein, tumor-induced changes in the TME were explored at the morphological and molecular level to further understand cancer progression. Tumor-adjacent mammary glands (TAGs) displayed altered branching morphology, expansion of myofibroblasts, and increased mammosphere formation, broadly suggesting a tumor-induced field effect. FACS analysis of TAGs demonstrated an increased number of Lin−CD24+/CD49+ enriched mammary gland stem cells (MaSCs), suggesting deregulated tissue homeostasis in TAGs. Comparative transcriptome analysis of TAGs and contralateral control glands coupled with meta-analysis on differentially expressed genes with two breast cancer stromal patient microarray datasets identified shared upregulation of STAT1. Knockdown of STAT1 in cancer-associated fibroblast (CAFs) co-cultured with human breast cancer cells altered cancer cell proliferation, indicating a role for STAT1 as a stromal contributor of tumorigenesis. Furthermore, depletion of STAT1 in CAFs significantly reduced periductal reactive fibrosis and delayed early breast cancer progression in vivo. Lastly, co-treatment with fludarabine, a FDA-approved STAT1 activation inhibitor and DNA synthesis inhibitor, in combination with doxorubicin, showed enhanced therapeutic efficacy in treating mouse mammary gland tumors. Taken together, these results demonstrate that stromal STAT1 expression promotes tumor progression and is a potential therapeutic target for breast cancer.

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Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers

Cited by 52 publications

References 50 publications

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

The patient burden of opioidinduced bowel dysfunction

Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis

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