Salinomycin reduces the viability of circulating epithelial tumor cells (CETCs) and tumorspheres cultured from circulating cancer stem cells (cCSC) and may potentially prevent progression in patients with solid cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23143-e23143
Author(s):  
Monika Pizon ◽  
Dorothea Schott ◽  
Katharina Pachmann ◽  
Ulrich Pachamnn ◽  
Norbert Szalus
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Cytotoxic Effect ◽  
Solid Cancer ◽  
Dependent Manner ◽  
Epithelial Tumor ◽  
Short Time

e23143 Background: Recently the hypothesis has been proposed that a more aggressive subpopulation of circulating tumor cells, circulating cancer stem cells are the source of metastatic spread from the primary tumor. These cells are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. The antibiotic Salinomycin has been shown to reduce the expression of markers for stemness and spheroid-forming ability. In this study, we evaluated the cytotoxic effect of salinomycin on CETCs and tumorspheres cultured from cCSC. Methods: 20 patients with solid tumors in different stages of disease were included. The determination of CETCs and cCSC was performed using maintrac method and tumorsphere forming assay, respectively. To evaluate the cytotoxic effect of salinomycin on CETCs and spheroids they were exposed to different concentrations of salinomycin in short time culture for different periods of time. Results: 80% of patients had detectable CETCs but sphere formation was observed in 95% of solid cancer patients. Growth of spheroids was detected also in patients without CETCs. The number of tumorspheres increased significantly with tumor progression. Treatment with salinomycin showed an 80% reduction in spheroid formation compared with control. Salinomycin reduced the viability of spheroids in a dose–dependent manner. Salinomycin had stronger cytotoxic effect on CETCs in non-metastatic as compared to metastatic patients (median of dead CETCs 85% vs. 34%, p < 0.001). Patients without chemotherapy responded better to salinomycin treatment than patients after several lines of chemotherapy (median of dead CETCs 87%vs.35%, p < 0.001) Conclusions: Using a method for cultivation of tumorspheres from blood of cancer patients and an effective in vitro platform for screening anti-cancer stem cells drugs was developed. Thus it could be shown that salinomycin targets not only more differentiated circulating cancer cells but also cancer stem cells from peripheral blood. It may evolve as a novel and promising therapeutic strategy for future cancer treatment

scholarly journals Cancer Stem Cells and Somatic Stem Cells as Potential New Drug Targets, Prognosis Markers, and Therapy Efficacy Predictors in Breast Cancer Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1223
Author(s):  
Olga Pershina ◽  
Natalia Ermakova ◽  
Angelina Pakhomova ◽  
Darius Widera ◽  
Edgar Pan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Drug Targets ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Epithelial Tumor

New drug targets, markers of disease prognosis, and more efficient treatment options are an unmet clinical need in breast cancer (BC). We have conducted a pilot study including patients with luminal B stage breast cancer IIA–IIIB. The presence and frequency of various populations of cancer stem cells (CSC) and somatic stem cells were assessed in the blood, breast tumor tissue, and normal breast tissue. Our results suggest that patients with BC can be divided into two distinct groups based on the frequency of aldehyde dehydrogenase positive cells (ALDH1+ cells) in the blood (ALDH1hi and ALDH1low). In the ALDH1hi cells group, the tumor is dominated by epithelial tumor cells CD44+CD24low, CD326+CD44+CD24−, and CD326−CD49f+, while in the ALDH1low cells group, CSCs of mesenchymal origin and epithelial tumor cells (CD227+CD44+CD24− and CD44+CD24−CD49f+) are predominant. In vitro CSCs of the ALDH1low cells group expressing CD326 showed high resistance to cytostatics, CD227+ CSCs of the ALDH1hi cells group are sensitive to cytostatics. Epithelial precursors of a healthy mammary gland were revealed in normal breast tissue of patients with BC from both groups. The cells were associated with a positive effect of chemotherapy and remission in BC patients. Thus, dynamic control of their presence in blood and assessment of the sensitivity of CSCs to cytostatics in vitro can improve the effectiveness of chemotherapy in BC.

scholarly journals Modeling the Treatment of Glioblastoma Multiforme and Cancer Stem Cells with Ordinary Differential Equations

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Kristen Abernathy ◽  
Jeremy Burke
Keyword(s):  
Stem Cells ◽  
Glioblastoma Multiforme ◽  
Cancer Therapy ◽  
Cancer Stem Cells ◽  
Differential Equations ◽  
Ordinary Differential Equations ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Tumor Recurrence ◽  
Common Event

Despite improvements in cancer therapy and treatments, tumor recurrence is a common event in cancer patients. One explanation of recurrence is that cancer therapy focuses on treatment of tumor cells and does not eradicate cancer stem cells (CSCs). CSCs are postulated to behave similar to normal stem cells in that their role is to maintain homeostasis. That is, when the population of tumor cells is reduced or depleted by treatment, CSCs will repopulate the tumor, causing recurrence. In this paper, we study the application of the CSC Hypothesis to the treatment of glioblastoma multiforme by immunotherapy. We extend the work of Kogan et al. (2008) to incorporate the dynamics of CSCs, prove the existence of a recurrence state, and provide an analysis of possible cancerous states and their dependence on treatment levels.

Differences in Repair of DNA Cross-links between Lymphocytes and Epithelial Tumor Cells from Colon Cancer Patients Measured In vitro with the Comet Assay

2009 ◽  
Vol 15 (17) ◽  
pp. 5466-5472 ◽  
Author(s):  
Mercedes Herrera ◽  
Gemma Dominguez ◽  
Jose M. Garcia ◽  
Cristina Peña ◽  
Carmen Jimenez ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Comet Assay ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Epithelial Tumor ◽  
Cross Links ◽  
Epithelial Tumor Cells

scholarly journals O-Acetyl-GD2 as a Therapeutic Target for Breast Cancer Stem Cells

2022 ◽  
Vol 12 ◽  
Author(s):  
Jing-Yan Cheng ◽  
Jung-Tung Hung ◽  
Juway Lin ◽  
Fei-Yun Lo ◽  
Jing-Rong Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Growth ◽  
Dependent Manner ◽  
Breast Cancer Stem Cells ◽  
Lipid Molecule ◽  
Mammosphere Formation

SynopsisA sugar-lipid molecule called OAcGD2 is a novel marker for breast cancer stem cells. Treatment with anti-OAcGD2 mAb8B6 may have superior anticancer efficacy by targeting cancer stem cells, thereby reducing metastasis and recurrence of cancer.BackgroundCancer stem cells (CSCs) that drive tumor progression and disease recurrence are rare subsets of tumor cells. CSCs are relatively resistant to conventional chemotherapy and radiotherapy. Eradication of CSCs is thus essential to achieve durable responses. GD2 was reported to be a CSC marker in human triple-negative breast cancer, and anti-GD2 immunotherapy showed reduced tumor growth in cell lines. Using a specific anti-OAcGD2 antibody, mAb8D6, we set out to determine whether OAcGD2+ cells exhibit stem cell properties and mAb8D6 can inhibit tumor growth by targeting OAcGD2+CSCs.MethodOAcGD2 expression in patient-derived xenografts (PDXs) of breast cancer was determined by flow cytometric analyses using mAb8D6. The stemness of OAcGD2+ cells isolated by sorting and the effects of mAb8B6 were assessed by CSC growth and mammosphere formation in vitro and tumor growth in vivo using PDX models.ResultWe found that the OAcGD2 expression levels in six PDXs of various molecular subtypes of breast cancer highly correlated with their previously defined CSC markers in these PDXs. The sorted OAcGD2+ cells displayed a greater capacity for mammosphere formation in vitro and tumor initiation in vivo than OAcGD2− cells. In addition, the majority of OAcGD2+ cells were aldehyde dehydrogenase (ALDH+) or CD44hiCD24lo, the known CSC markers in breast cancer. Treatment of PDXs-bearing mice with mAb8B6, but not doxorubicin, suppressed the tumor growth, along with reduced CSCs as assessed by CSC markers and in vivo tumorigenicity. In vitro, mAb8B6 suppressed proliferation and mammosphere formation and induced apoptosis of OAcGD2+ breast cancer cells harvested from PDXs, in a dose-dependent manner. Finally, administration of mAb8B6 in vivo dramatically suppressed tumor growth of OAcGD2+ breast CSCs (BCSCs) with complete tumor abrogation in 3/6 mice.ConclusionOAcGD2 is a novel marker for CSC in various subtypes of breast cancer. Anti-OAcGD2 mAb8B6 directly eradicated OAcGD2+ cells and reduced tumor growth in PDX model. Our data demonstrate the potential of mAb8B6 as a promising immunotherapeutic agent to target BCSCs.

Pharmacodynamic properties of the anti-IGF-IR monoclonal antibody CP-751,871 in cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3587-3587 ◽  
Author(s):  
M. N. Pollak ◽  
M. Q. Lacy ◽  
A. Lipton ◽  
L. Demers ◽  
K. Leitzel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Human Monoclonal Antibody ◽  
Dose Range ◽  
Dependent Manner ◽  
Igf I ◽  
Dose Dependent ◽  
Igfbp 3

3587 Background: The Insulin like Growth Factor I receptor (IGF-IR), a tyrosine kinase, is widely expressed in human tissues. IGF- IR and its ligands (IGF-I and IGF-II) are expressed by many human cancers (e.g., breast, prostate, colorectal and non-small cell lung). Binding of the ligands to the IGF-IR activates key cellular signaling pathways important for stimulating cellular proliferation and inhibiting apoptosis. IGF- I and IGF-II are present in the circulation, but also locally expressed in neoplastic tissue. Bioavailability of these ligands is regulated by a family of IGF binding proteins (IGFBPs1–6). CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of IGF-IR activation. In vitro experiments show that binding of CP 751,871 to IGF-IR induces receptor internalization and degradation. This antibody has been shown to have antineoplastic activity using both in vivo and in vitro pre-clinical models. Methods: Blood samples were collected for characterization of the pharmacokinetic and pharmacodynamic properties of CP-751,871 in phase 1 trials of this agent given to cancer patients either alone or in combination with chemotherapy. The endpoints assessed included among others: CP-751,871 plasma concentrations, total and free IGF-I, IGFBP-3, soluble IGF-IR and IGF-IR expression on granulocytes and tumor cells. Results: CP 751,871 exposure increased with dose over the 800-fold dose range investigated. Pharmacokinetic profiles were consistent with target-mediated disposition. A dose-dependent downregulation of soluble IGF-IR serum concentration and IGF-IR expression was observed, with sustained inhibition for the entire dosing period (3–4 week cycles) observed at doses ≥ 1.5 mg/kg. As predicted for an agent that interferes with IGF-I action, IGF-I and IGFBP-3 serum levels were up-regulated in a similar dose-dependent manner. Conclusions: The pharmacodynamic endpoints of clinical trials provide evidence that CP-751,871 targets IGF-IR in granulocytes, tumor cells and tissues involved in regulation of the growth hormone -IGF-I axis. These data provide proof of principle for the use of CP-751,871 as a first-in-class therapeutic approach to inhibit the IGF-IR pathway in cancer patients. No significant financial relationships to disclose.

The expression of pluripotency genes regulates properties of cancer stem cells in MCF-7 breast cancer model.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23018-e23018
Author(s):  
Regina R. Miftakhova ◽  
Aigul R Rakhmatullina ◽  
Rimma N. Mingaleeva ◽  
Ekaterina E Garanina ◽  
Svetlana F Khaiboullina ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Chemotherapy Resistance ◽  
Competitive Growth ◽  
Russian Government ◽  
Drug Induced ◽  
Mcf 7

e23018 Background: More than 1.6 million cases of breast cancer (BC) are diagnosed annually worldwide. Despite advances in diagnoses and treatment, BC remains the third leading cause of death in women. Metastases and chemotherapy resistance are the main factors contributing to BC mortality. The ability of tumor cells to overcome the drug-induced growth inhibition is now linked to a unique population of cancer initiating tumor cells, often referred as cancer stem cells (CSC). CSC represent a small fraction of tumor cells, therefore, currently used isolation protocols have a low yield and are poorly reproducible, hampering research on the role of these cells in cancer chemoresistance. We propose a novel approach to generate large quantities of CSC-like cells by genetic reprogramming of non-stem cancer cells. Methods: We postulate that CSC-enriched cell line can be developed in vitro by upregulating of proteins controlling cancer cell pluripotency including Oct4, Sox2, NANOG, KLF4 and c-Myc. Increased transcriptional and translational activity of these genes in MCF-7 cells was demonstrated by real time-PCR and Western blot. Proliferation and migration of cells overexpressing Oct4, Sox2, NANOG, KLF4 and c-Myc were analyzed as well. Also, changes in CSC population counts and their sensitivity to chemotherapy were investigated using sphere formation assay. Results: We found that cell proliferation rate was correlated with the expression level of c-Myc and Oct4. Increased CSC counts were found in cells with overexpressed Oct4 (62.7%), KLF4 (97%) and NANOG (121.3%) proteins as compared to the parental cells. Overexpression of SOX2, NANOG and KLF4 significantly increased CSC resistance to docetaxel (83,3±6,8; 93,3±4,5 and 80,3±5,0 spheres respectively) when compared to the original cells (48,3±3,0 spheres). Conclusions: We conclude that overexpression of pluripotency proteins Oct4, Sox2, NANOG, KLF4 and c-Myc changes the CSC counts and proliferation capacity of BC cells. Acknowledgements: The study was funded by RFBR, according to the research project No. 16-34-60210 mol_а_dk, and by Russian Government Program of Competitive Growth of Kazan Federal University.

Detection of circulating cancer stem cells (cCSCs) as a predictive biomarker for breast cancer relapse or metastasis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14559-e14559
Author(s):  
Monika Pizon ◽  
Ulrich A. Pachmann ◽  
Katharina Pachmann ◽  
Dorothea Schott
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Surface Marker ◽  
Breast Cancer Patients ◽  
Stage Of Disease ◽  
Surface Marker Expression ◽  
Sphere Formation

e14559 Background: Breast cancer is one of the most common types of cancer in women worldwide. It has been demonstrated that even localized tumors without clinically apparent metastases give rise to circulating epithelial tumor cells (CETCs). Recent studies have provided strong support for the cCSC hypothesis, which suggests that a more aggressive subpopulation of circulating tumor cells is the source of metastatic spread from the primary tumor. Measuring CETCs in blood of patients has emerged as a non-invasive diagnostic procedure for screening patients who may be at high risk for developing metastatic cancers. However, accurate detection of CETCs may provide erroneous results, since CETCs undergoing EMT during metastasis are down-regulated for the expression of epithelial cell markers. Methods: 26 breast cancer patients were included into the study. The determination of CETCs and cCSC was performed using maintrac method and tumorsphere forming assay, respectively. Cell viability, surface marker expression and ALDH 1 activity of the cells in the spheres were evaluated by fluorescence scanning microscope. Results: Sphere formation was observed in 80 % of patients. We found that the number of tumorspheres depended on stage of disease. The number of tumorspheres increased significantly with tumor progression, especially with the presence of metastases. Tumorsphere formation was observed in all metastatic patients (median of 30 tumorspheres/100µl of blood), although only 27% of them had detectable CETCs. Analysis of surface marker expression profile showed that the cells in the spheres had typical phenotype of cancer stem cells. Sphere formation was not observed in healthy subjects (n = 20). Conclusions: There is a high correlation between the numbers of tumorspheres cultured from peripheral blood with clinical stage of disease. Identifying cCSC in blood sample can help clinicians to monitor breast cancer patients and to detect metastasis in early stages.

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