The Prognostic Value of Plasma YKL-40 in Patients With Chemotherapy-Resistant Ovarian Cancer Treated With Bevacizumab

Boisen, Mogens K.; Madsen, Christine Vestergård; Dehlendorff, Christian; Jakobsen, Anders; Johansen, Julia S.; Steffensen, Karina Dahl

doi:10.1097/igc.0000000000000798

Cited by 19 publications

(21 citation statements)

References 31 publications

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“…In addition, we found that this mesenchymal change had an associated biomarker in the form of elevated serum YKL-40 in BRG patients. Similarly, serum YKL-40 elevation during bevacizumab treatment of ovarian cancer patients has been described as a predictor of shorter PFS (27) and a low baseline YKL-40 was associated with improved outcomes both in this ovarian cancer study (27) as well as among newly diagnosed glioblastoma patients receiving bevacizumab in a randomized trial (28).…”

Section: Discussionmentioning

confidence: 57%

“…Similarly, serum YKL-40 elevation during bevacizumab treatment of ovarian cancer patients has been described as a predictor of shorter PFS with low baseline YKL-40 associated with improved outcomes. 2 Besides providing insight into potential biomarkers of bevacizumab resistance, our xenograft model could also offer insight into the optimal upstream regulators of bevacizumab resistance to target in order to prevent the evolution of this resistance before it becomes entrenched. Because bevacizumab resistance has been challenging to pharmacologically target, 24 these insights and the ability to screen inhibitors of bevacizumab resistance in our model could provide meaningful benefit to glioblastoma patients.…”

Section: Discussionmentioning

confidence: 99%

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A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

Jahangiri

Chen

Chandra

et al. 2018

Preprint

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Bevacizumab treatment of glioblastoma is limited by transient responses and acquired resistance. Because of the lengthy duration of treatment that can precede resistance in patients, in order to study changes underlying the evolution of bevacizumab resistance, we created a novel multigenerational xenograft model of acquired bevacizumab resistance. Glioblastoma xenografts were treated with bevacizumab or IgG, and the fastest growing tumor reimplanted into new mice, generating paired isogeneic responsive or resistant multigenerational xenografts. Microarray analysis revealed significant overexpression across generations of the mesenchymal subtype gene signature, paralleling results from patient bevacizumab-resistant gliobalstomas (BRGs) that exhibited increasing mesenchymal gene expression correlating with increased bevacizumab treatment duration. Key mesenchymal markers, including YKL-40, CD44, SERPINE1, and TIMP1 were upregulated across generations, with altered morphology, increased invasiveness, and increased neurosphere formation confirmed in later xenograft generations. Interestingly, YKL-40 levels were elevated in serum of patients with bevacizumab-resistant vs. bevacizumab-naïve glioblastomas (52.4 vs. 24.2 ng/mL; P<0.05). Finally, despite upregulation of VEGF-independent pro-angiogenic genes across xenograft generations, immunostaining revealed increased hypoxia and decreased vessel density with increasing generation of treatment, mirroring our findings in patient BRGs and suggesting tumor growth despite effective devascularization caused by VEGF blockade. Besides identifying novel targets for preventing the evolution of resistance and offering a xenograft model for testing resistance inhibitors, our work suggests YKL-40 as a blood biomarker of bevacizumab resistance worthy of further evaluation.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

Jahangiri

Chen

Chandra

et al. 2018

Preprint

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“…The YKL-40 gene may increase the sensitivity of cisplatin-based chemotherapy, while undertaking a mechanism of EC chemoresistance. Research into ovarian cancer has demonstrated that YKL-40 may act as an evaluation index to aid the prognosis of cancer chemotherapy (27). Cell migration assays revealed that si-YKL-40 inhibited the HEC-1A cell migration abilities, as well as chemoresistance in gliomas (28).…”

Section: Discussionmentioning

confidence: 99%

Influence of YKL‑40 gene RNA interference on the biological behaviors of endometrial cancer HEC‑1A cells

Fan

et al. 2018

Oncol Lett

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The present study aimed to investigate the effects of chitinase-3-like protein 1 (YKL-40) gene RNA interference on the biological behaviors and enhanced chemosensitivity of endometrial cancer (EC) HEC-1A cells. YKL-40 small interfering (si)RNA was transduced into EC HEC-1A cells using a lentivirus. The experiment was divided into three groups: The experimental group was transfected with YKL-40 siRNA (si-YKL-40); the mock-treatment group was transfected with transfection reagent only; and the blank control group was left untreated. A reverse transcription-quantitative polymerase chain reaction was performed to investigate the mRNA expression levels of YKL-40. The biological behaviors, including cell proliferation, migration, invasion and apoptosis, were detected by MTT and Transwell assays, and flow cytometry (FCM) analysis, respectively. The results of the present study demonstrated that the mRNA expression levels of YKL-40 were downregulated within HEC-1A cells upon transfection with si-YKL-40 (P<0.05). The proliferative, migratory and invasive abilities of HEC-1A cells were inhibited by si-YKL-40 (P<0.05). The mRNA expression levels of YKL-40 were upregulated within HEC-1A cells following treatment with cisplatin (P<0.05). FCM analysis revealed that the average cellular apoptosis rate increased following the inhibition of YKL-40 gene expression via siRNA (P<0.05). Therefore, the YKL-40 gene may be associated with the proliferative, migratory, invasive and anti-apoptotic ability of HEC-1A cells. YKL-40 downregulation may enhance the sensitivity of human EC HEC-1A cells to chemotherapy.

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“…Since then, it has been of special interest because it is associated with degradation of extracellular matrix and promotes angiogenesis in a vascular endothelial growth factor (VEGF)-independent manner ( 6 , 7 ) . During the last decade, YKL-40 has been increasingly studied in several tumor types ( 6 , 8 , 9 , 10 ) . In vitro , YKL-40 upregulates VEGF and is associated with tumor angiogenesis ( 9 ) .…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies showed that neutrophils and tumour cells expressed and released YKL-40 into the blood ( 9 , 14 ) . Increased serum levels of YKL-40 were shown in some cancer types such as breast cancer, lung cancer, colorectal cancer, melanoma, and endometrial cancer ( 6 , 7 , 10 , 15 , 16 ) . YKL-40 was suggested to have the potential to be a better marker than cancer antigen-125 (CA-125) for early diagnosis of EOC ( 17 , 18 ) .…”

Section: Introductionmentioning

confidence: 99%

YKL-40 in the diagnosis, prediction of prognosis, and platinum sensitivity in serous epithelial ovarian cancer

Kahramanoğlu¹,

Tokgözoğlu²,

Turan³

et al. 2018

tjod

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Objective:To evaluate the use of YKL-40 in the discrimination between benign and malignant adnexal mass and to determine its prognostic value in assessing residual tumor after primary cytoreduction and platinum sensitivity in serous epithelial ovarian carcinoma (EOC). Materials and Methods:During the three years from January 2015 to December 2017, a nonconsecutive series of 100 patient (60 malignant, 40 benign) who underwent surgery for an adnexal mass were enrolled in the study. Preoperatively, serum samples were collected for YKL-40 level analysis.Results:YKL-40 [receiver operator characteristics (ROC)-area under curve (AUC)=0.83] was a significantly better predictor of EOC than cancer antigen-125 (ROC-AUC=0.75). Using a cut-off for YKL-40 of 47.7 ng/mL had a sensitivity of 80% and a specificity of 70%. Higher serum YKL-40 levels were associated with advanced stage, higher grade, residual tumor after primary cytoreduction and recurrence. Platinum-sensitive patients had significantly elevated levels of YKL-40 compared with platinum-resistant or refractory patients.Conclusion:The results obtained from our study support the use of serum YKL-40 for the discrimination between malignant and benign ovarian tumors. YKL-40 levels in patients with serous EOC may also predict disease residual disease after primary cytoreduction and recurrence. Further studies are needed to understand the relationship between YKL-40 and platinum sensitivity.

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The Prognostic Value of Plasma YKL-40 in Patients With Chemotherapy-Resistant Ovarian Cancer Treated With Bevacizumab

Abstract: Low plasma YKL-40 at baseline and during treatment is associated with improved outcomes in patients with chemotherapy-refractory advanced ovarian cancer treated with single-agent bevacizumab.

Cited by 19 publications

References 31 publications

A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

Influence of YKL‑40 gene RNA interference on the biological behaviors of endometrial cancer HEC‑1A cells

YKL-40 in the diagnosis, prediction of prognosis, and platinum sensitivity in serous epithelial ovarian cancer

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