scholarly journals A mouse model of neoadjuvant chemotherapy followed by interval cytoreductive surgery indicates impaired efficacy of perioperative cisplatin

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Mitchell Clark ◽  
Alexandra Kollara ◽  
Theodore J. Brown ◽  
Taymaa May
Keyword(s):  
Ovarian Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Mouse Model ◽  
Cytoreductive Surgery ◽  
Residual Disease ◽  
Accelerated Expansion ◽  
Ovarian Cancer Cells ◽  
Orthotopic Mouse Model ◽  
The Impact

Abstract Background Investigate the impact of interval cytoreductive surgery (ICS) on progression in an orthotopic mouse model of ovarian cancer and the impact of chemotherapy delivered at various timelines following surgery. Methods Luciferase-expressing ID8 murine ovarian cancer cells were implanted intra-bursally and IP to C57BL/7 mice. Once disease was established by bioluminescence, 2 cycles of neoadjuvant cisplatin were administered, and animals received either ICS (removal of the injected bursa/primary tumor) or anesthesia alone. Postsurgical chemotherapy was administered on the same day as the intervention (ICS/anesthesia), or on day 7 or day 28 following the intervention. Progression was quantified serially with in vivo bioluminescence imaging. Volume of ascitic fluid volume collected at necropsy was measured. Results Animals were matched for tumor burden at stratification. There was no accelerated growth of residual tumor after interval cytoreduction compared to controls. Animals who received chemotherapy on postoperative day (POD) 7 had better disease control compared to standard-of-care POD 28. Animals who underwent surgery had less ascites at necropsy compared to those who had anesthesia alone. Conclusions In this animal model, surgical wounding with suboptimal cytoreduction after neoadjuvant chemotherapy did not cause accelerated expansion of residual disease. Surgical wounding appears to impair cisplatin activity when given at time of surgery.

scholarly journals A mouse model of neoadjuvant chemotherapy followed by interval cytoreductive surgery indicates impaired efficacy of perioperative cisplatin

2021 ◽  
Author(s):  
Mitchell Clark ◽  
Alexandra Kollara ◽  
Theodore Brown ◽  
Taymaa May
Keyword(s):  
Ovarian Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Mouse Model ◽  
Cytoreductive Surgery ◽  
Residual Disease ◽  
Accelerated Expansion ◽  
Ovarian Cancer Cells ◽  
Orthotopic Mouse Model ◽  
The Impact

Abstract Background Investigate the impact of interval cytoreductive surgery (ICS) on progression in an orthotopic mouse model of ovarian cancer and the impact of chemotherapy delivered at various timelines following surgery. Methods Luciferase-expressing ID8 murine ovarian cancer cells were implanted intra-bursally and IP to C57BL/7 mice. Once disease was established by bioluminescence, 2 cycles of neoadjuvant cisplatin were administered, and animals received either ICS (removal of the injected bursa/primary tumor) or anesthesia alone. Postsurgical chemotherapy was administered on the same day as the intervention (ICS/anesthesia), or on day 7 or day 28 following the intervention. Progression was quantified serially with in vivo bioluminescence imaging. Volume of ascitic fluid volume collected at necropsy was measured. Results Animals were matched for tumor burden at stratification. There was no accelerated growth of residual tumor after interval cytoreduction compared to controls. Animals who received chemotherapy on postoperative day (POD) 7 had better disease control compared to standard-of-care POD 28. Animals who underwent surgery had less ascites at necropsy compared to those who had anesthesia alone. Conclusions In this animal model, surgical wounding with suboptimal cytoreduction after neoadjuvant chemotherapy did not cause accelerated expansion of residual disease. Surgical wounding appears to impair cisplatin activity when given at time of surgery.

scholarly journals Long non-coding RNA THOR promotes Ovarian Cancer cells progression via STAT3 pathway

2020 ◽  
Author(s):  
Jing Ge ◽  
Tao Han ◽  
Lili Shan ◽  
Jing Na ◽  
Ya Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Malignant Tumors ◽  
Ovarian Cancer Cells ◽  
Self Renewal ◽  
Stat3 Signaling ◽  
Non Coding Rna ◽  
The Impact ◽  
Long Non Coding Rna

Abstract Background Ovarian cancer (OC) is one of the most common malignant tumors in the world. The prognosis of OC remains poor due to the advanced stage and distant metastasis at the time of diagnosis. Recently, a novel lncRNA, THOR (testis-associated highly conserved oncogenic long non-coding RNA), was characterized in human cancers and shown to exhibit an oncogenic role. However, the role of THOR in OC was still unknown.Methods RT-PCR and western blot analysis were used to detect the expression of THOR and p-STAT3. The impact of THOR on OC proliferation, metastasis and self-renew was investigated in vitro and in vivo . The prognostic value of THOR was determined in OC patient cohorts.Results In this study, our results found that THOR was markedly upregulated in human OC tissues and predict the poor prognosis of OC patients. THOR knockdown resulted in significant inhibition of the growth, metastasis and self-renewal of OC cells. Mechanistically, THOR drives OC cell progression via the STAT3 signaling. Moreover, the specific STAT3 inhibitor S3I-201 diminished the discrepancy in the growth, metastatic and self-renewal capacity between THOR-silenced OC cells and control cells, which further confirmed that STAT3 was required in THOR-driven OC cells progression.Conclusion Our findings revealed that THOR could promote OC cells growth, metastasis and self-renew by activating STAT3 signaling and may be a good predictive factor and therapeutic target.

scholarly journals Long non-coding RNA THOR promotes Ovarian Cancer cells progression via IL-6/STAT3 pathway

2020 ◽  
Author(s):  
Jing Ge ◽  
Tao Han ◽  
Lili Shan ◽  
Jing Na ◽  
Ya Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Malignant Tumors ◽  
Ovarian Cancer Cells ◽  
Self Renewal ◽  
Stat3 Signaling ◽  
Non Coding Rna ◽  
The Impact ◽  
Long Non Coding Rna

Abstract Background: Ovarian cancer (OC) is one of the most common malignant tumors in the world. The prognosis of OC remains poor due to the advanced stage and distant metastasis at the time of diagnosis. Recently, a novel lncRNA, THOR (testis-associated highly conserved oncogenic long non-coding RNA), was characterized in human cancers and shown to exhibit an oncogenic role. However, the role of THOR in OC remains unclear. Methods: RT-PCR and western blot analysis were used to detect the expression of THOR, p-STAT3 and IL-6. The impact of THOR on OC proliferation, metastasis and self-renewal was investigated in vitro and in vivo. The prognostic value of THOR was determined in OC patient cohorts. Results: In this study, our results find that THOR is markedly upregulated in human OC tissues and predicts the poor prognosis of OC patients. Functional studies have revealed that knockdown of THOR inhibits the growth, metastasis and self-renewal of OC cells. Mechanistically, THOR drives OC cell progression via the IL-6/STAT3 signaling. Moreover, the specific STAT3 inhibitor S3I-201 or IL-6R inhibitor tocilizumab diminish the discrepancy in the growth, metastatic and self-renewal capacity between THOR-silenced OC cells and control cells, which further confirm that IL-6/STAT3 is required in THOR-driven OC cells progression. Conclusion: Our findings reveal that THOR could promote OC cells growth, metastasis and self-renewal by activating IL-6/STAT3 signaling and may be a good predictive factor and therapeutic target.

Primary Surgery or Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: The Debate Continues…

2016 ◽  
pp. 153-162 ◽  
Author(s):  
Renee Cowan ◽  
Dennis Chi ◽  
Sean Kehoe ◽  
Matthew Nankivell ◽  
Alexandra Leary
Keyword(s):  
Ovarian Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Residual Disease ◽  
Tumor Biology ◽  
Advanced Ovarian Cancer ◽  
Debulking Surgery ◽  
Primary Debulking Surgery ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
The Impact

Primary debulking surgery (PDS) followed by platinum-based chemotherapy has been the cornerstone of treatment for advanced ovarian cancer for decades. Primary debulking surgery has been repeatedly identified as one of the key factors in improving survival in patients with advanced ovarian cancer, especially when minimal or no residual disease is left behind. Achieving these results sometimes requires extensive abdominal and pelvic surgical procedures and consultation with other surgical teams. Some clinicians who propose a primary chemotherapy approach reported an increased likelihood of leaving no macroscopic disease after surgery and improved patient-reported outcomes and quality-of-life (QOL) measures. Given the ongoing debate regarding the relative benefit of PDS versus neoadjuvant chemotherapy (NACT), tumor biology may aid in patient selection for each approach. Neoadjuvant chemotherapy offers the opportunity for in vivo chemosensitivity testing. Studies are needed to determine the best way to evaluate the impact of NACT in each individual patient with advanced ovarian cancer. Indeed, the biggest utility of NACT may be in research, where this approach provides the opportunity for the investigation of predictive markers, mechanisms of resistance, and a forum to test novel therapies.

Targeting Dormant Ovarian Cancer Cells In Vitro and in an In Vivo Mouse Model of Platinum Resistance

2020 ◽  
Vol 20 (1) ◽  
pp. 85-95
Author(s):  
Zhiqing Huang ◽  
Eiji Kondoh ◽  
Zachary R. Visco ◽  
Tsukasa Baba ◽  
Noriomi Matsumura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance

scholarly journals Cisplatin Loaded Hyaluronic Acid Modified TiO2Nanoparticles for Neoadjuvant Chemotherapy of Ovarian Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Enling Liu ◽  
Yuxiu Zhou ◽  
Zheng Liu ◽  
Jun Li ◽  
Donghong Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Hyaluronic Acid ◽  
Neoadjuvant Chemotherapy ◽  
Tumor Targeting ◽  
Ovarian Cancer Cells ◽  
Release Property ◽  
Decreasing Ph ◽  
Targeting Ability

Novel tumor-targeting titanium dioxide (TiO2) nanoparticles modified with hyaluronic acid (HA) were developed to explore the feasibility of exploiting the pH-responsive drug release property ofTiO2and the tumor-targeting ability of HA to construct a tumor-targeting cisplatin (CDDP) delivery system (HA-TiO2) for potential neoadjuvant chemotherapy of ovarian cancer. The experimental results indicated that CDDP release from the HA-TiO2nanoparticles was significantly accelerated by decreasing pH from 7.4 to 5.0, which is of particular benefit to cancer therapy. CDDP-loaded HA-TiO2nanoparticles increased the accumulation of CDDP in A2780 ovarian cancer cells via HA-mediated endocytosis and exhibited superior anticancer activityin vitro.In vivoreal-time imaging assay revealed that HA-TiO2nanoparticles possessed preferable tumor-targeting ability which might potentially minimize the toxic side effects of CDDP in clinical application.

Influence of residual disease and extreme drug resistance assays on outcome in patients with epithelial ovarian cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5504-5504
Author(s):  
A. Karam ◽  
J. Wang Chiang ◽  
E. Fung ◽  
V. Nossov ◽  
B. Y. Karlan
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Epithelial Ovarian Cancer ◽  
Cytoreductive Surgery ◽  
Residual Disease ◽  
Cox Proportional Hazards ◽  
Risk Of Death ◽  
Extreme Drug Resistance ◽  
Increased Risk ◽  
The Impact

5504 Background: Extreme drug resistance (EDR) assays have been used as tools in identifying those agents that are least likely to be of clinical benefit in the treatment of epithelial ovarian cancer (EOC). We sought to examine the effect of obtaining EDR assays on the outcome of patients with EOC in the primary and recurrent setting. Methods: We conducted a retrospective review of demographic, pathologic, EDR assay and outcome data from 377 patients with EOC who had an assay sent at the time of their diagnosis or at recurrence. Univariate followed by multivariate analyses using Cox proportional hazards method were performed to identify and estimate the impact of independent prognostic factors on time to progression (TTP), overall survival (OS) and survival after recurrence (RS). Results: Increasing age was associated with a worse OS and RS (HR = 1.34; 95% CI, 1.14–1.58 and HR = 1.14; 95% CI, 1.00–1.31, for each decade increase in age respectively). Compared with patients with microscopic residual disease, patients who were left with 0.1 to 1.0 cm and >1.0 cm residual disease had an increased risk of recurrence (HR=1.94; 95% CI, 1.33 to 2.84 and HR=3.61; 95% CI; 2.07 to 6.39, respectively) and death (HR = 1.59; 95% CI, 1.03 to 2.45; and HR = 2.14; 95% CI, 1.09 to 4.20, respectively). For patients who recurred, those who did not undergo secondary cytoreductive surgery and patients who were left with >1.0 cm residual had an increased risk of death compared to patients with microscopic residual (HR = 2.13; 95% CI, 1.28 to 3.54; and HR = 2.84; 95% CI, 1.71 to 4.71, respectively). EDR assay results for single agents or combinations did not independently predict patient outcomes. Conclusions: The amount of residual disease continues to be an important prognostic factor, especially when all macroscopic disease is removed both in the primary and recurrent setting. Increasing age is also an independent predictor of OS and RS. EDR assay results do not independently predict or alter the outcomes of patients with EOC who are treated with the current standard of care including optimal cytoreductive surgery followed by platinum and taxane combination chemotherapy in either the primary or recurrent setting. No significant financial relationships to disclose.

scholarly journals Inhibition of SETMAR–H3K36me2–NHEJ repair axis in residual disease cells prevents glioblastoma recurrence

2020 ◽  
Vol 22 (12) ◽  
pp. 1785-1796
Author(s):  
Ekjot Kaur ◽  
Jyothi Nair ◽  
Atanu Ghorai ◽  
Saket V Mishra ◽  
Anagha Achareker ◽  
...  
Keyword(s):  
Mouse Model ◽  
Residual Disease ◽  
Fusion Gene ◽  
Molecular Signaling ◽  
End Joining ◽  
Orthotopic Mouse Model ◽  
Nhej Pathway ◽  
Nhej Repair

Abstract Background Residual disease of glioblastoma (GBM) causes recurrence. However, targeting residual cells has failed, due to their inaccessibility and our lack of understanding of their survival mechanisms to radiation therapy. Here we deciphered a residual cell–specific survival mechanism essential for GBM relapse. Methods Therapy resistant residual (RR) cells were captured from primary patient samples and cell line models mimicking clinical scenario of radiation resistance. Molecular signaling of resistance in RR cells was identified using RNA sequencing, genetic and pharmacological perturbations, overexpression systems, and molecular and biochemical assays. Findings were validated in patient samples and an orthotopic mouse model. Results RR cells form more aggressive tumors than the parental cells in an orthotopic mouse model. Upon radiation-induced damage, RR cells preferentially activated a nonhomologous end joining (NHEJ) repair pathway, upregulating Ku80 and Artemis while downregulating meiotic recombination 11 (Mre11) at protein but not RNA levels. Mechanistically, RR cells upregulate the Su(var)3-9/enhancer-of-zeste/trithorax (SET) domain and mariner transposase fusion gene (SETMAR), mediating high levels of H3K36me2 and global euchromatization. High H3K36me2 leads to efficiently recruiting NHEJ proteins. Conditional knockdown of SETMAR in RR cells induced irreversible senescence partly mediated by reduced H3K36me2. RR cells expressing mutant H3K36A could not retain Ku80 at double-strand breaks, thus compromising NHEJ repair, leading to apoptosis and abrogation of tumorigenicity in vitro and in vivo. Pharmacological inhibition of the NHEJ pathway phenocopied H3K36 mutation effect, confirming dependency of RR cells on the NHEJ pathway for their survival. Conclusions We demonstrate that the SETMAR-NHEJ regulatory axis is essential for the survival of clinically relevant radiation RR cells, abrogation of which prevents recurrence in GBM.

125 BISPHENOL A-INDUCED GROWTH OF OVARIAN CANCER CELLS WAS REVERSED BY A PHYTOESTROGEN, GENISTEIN, BY INHIBITION OF A CROSSTALK BETWEEN ESTROGEN RECEPTOR AND INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR IN IN VITRO AND XENOGRAFT MOUSE MODELS

2014 ◽  
Vol 26 (1) ◽  
pp. 176
Author(s):  
K.-A. Hwang ◽  
S.-H. Kim ◽  
K.-C. Choi
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Mouse Model ◽  
Tumour Growth ◽  
Corn Oil ◽  
Signaling Cascades ◽  
Ovarian Cancer Cells ◽  
In Vitro Experiments

It has been shown that oestrogen (E2) up-regulated the expression of components of insulin-like growth factor-1 (IGF-1) signaling pathway and induced the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). An interaction between oestrogen receptor (ER) and IGF-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to oestrogen-dependent cancers (i.e. breast and endometrial cancers). In the present study, we evaluated xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. The gene expressions in mRNA and protein levels were examined by semiquantitative RT-PCR and Western blot analysis, in which the primers for ERα, IGF-1R, and GAPDH and the antibodies against pIRS-1, pAkt, and GAPDH were used, respectively. Total RNA and protein samples were isolated from BG-1 cells treated with dimethyl sulfoxide (DMSO), estradiol (E2; 10–9 M), BPA (10–5 M), E2 (10–9 M) + GEN (10–4 M), and BPA (10–5 M) + GEN (10–4 M). The DMSO was used a vehicle of E2, BPA, and GEN in in vitro experiments. All in vitro experiments were done in triplicates. The effects on tumour growth and immunohistologic alterations were identified in in vivo mouse models. The mice were injected subcutaneously with corn oil (vehicle, n = 6), E2 (n = 6), BPA (n = 6), E2+GEN (n = 6), and BPA+GEN (n = 6) for 8 weeks. The BPA treatment resulted in up-regulation of ERα and IGF-1R mRNA, and induced phosphorylation of IRS-1 and Akt proteins compared with a control (DMSO) in BG-1 ovarian cancer cells as E2 did in triplicates. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumour burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumour mass compared with the vehicle (corn oil), indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model with triplicates. The GEN also significantly decreased tumour growth and in vivo expressions of ERα, pIRS-1, and pAkt in a xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ER and IGF-1R signaling pathways up-regulated by BPA or E2. This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ009599), Rural Development Administration, Republic of Korea.

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