Integrin β3 links therapy resistance and cancer stem cell properties

In ovarian cancer, therapy resistance mechanisms complicate cancer cell eradication. Targeting Musashi RNA-binding proteins (MSI) may increase therapeutic efficacy. Database analyses were performed to identify gene expression associations between MSI proteins and key therapy resistance and cancer stem cell (CSC) genes. Then, ovarian cancer cells were subjected to siRNA-based dual knockdown of MSI-1 and MSI-2. CSC and cell cycle gene expression was investigated using quantitative polymerase chain reaction (qPCR), western blots, and flow cytometry. Metabolic activity and chemoresistance were assessed by MTT assay. Clonogenic assays were used to quantify cell survival post-irradiation. Database analyses demonstrated positive associations between MSI proteins and putative CSC markers NOTCH, MYC, and ALDH4A1 and negative associations with NOTCH inhibitor NUMB. MSI-2 expression was negatively associated with the apoptosis regulator p21. MSI-1 and MSI-2 were positively correlated, informing subsequent dual knockdown experiments. After MSI silencing, CSC genes were downregulated, while cell cycle progression was reduced. Metabolic activity was decreased in some cancer cells. Both chemo- and radioresistance were reduced after dual knockdown, suggesting therapeutic potential. Dual knockdown of MSI proteins is a promising venue to impede tumor growth and sensitize ovarian cancer cells to irradiation and chemotherapy.

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STEM-21. CLINICAL RELEVANCE OF CANCER STEM CELL CYTOTOXICITY ASSAY IN GUIDING TREATMENT FOR GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.838 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii200-ii200

Author(s):

Claudio Pier Paolo ◽

Tulika Ranjan ◽

Candace Howard ◽

Alexander Yu ◽

Linda Xu ◽

...

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Clinical Investigation ◽

Therapy Resistance ◽

Chemotherapeutic Agents ◽

Cytotoxicity Assay ◽

Recurrence Time ◽

Cell Cytotoxicity ◽

Treatment Protocols ◽

Time To Recurrence

Abstract BACKGROUND. The prognosis of glioblastoma (GBM) treated with standard-of-care regimens remains very poor with a median time to recurrence of 7-9 months, and a median survival of 15-18 months. GBMs contain a small, but resilient population of cancer stem cells (CSCs) that contribute to tumor initiation, maintenance, and therapy resistance. For these reasons, its is extremely important to determine the sensitivity of CSCs to chemotherapeutic agents, with the intent of identifying more effective treatment protocols which would then translate into improved clinical survival. METHODS. We have used a novel CLIA and CAP-accredited Cancer Stem Cell Cytotoxicity Assay (ChemoID) to guide treatment for 55 Grade III and Grade IV glioma patients with the most efficacious chemotherapy treatments from a panel of FDA approved drugs or their combinations. Patients were evaluated by MRI scans and response was assessed according to RANO criteria. RESULTS: We report here a prospective clinical investigation using the ChemoID assay to measure the sensitivity and resistance of CSCs and bulk of tumor cells cultured from 55 GBM clinical specimens challenged with several chemotherapy agents, which were also correlated to the clinical response of the treated patients, independently of other biomarkers. The median recurrence time was 15 months for patients with a sensitive (>40% cell kill) CSCs test versus only 6 months for patients with a resistant CSCs test. CONCLUSIONS. The data suggests that GBM patients treated with CSC Cytotoxicity Assay-guided responsive drugs have delayed time to recurrence and the assay has the potential to help tailor chemotherapy choices to improve clinical outcomes.

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Abstract 1123: The role of proto-oncogene PELP1 in breast cancer stem cell maintenance and therapy resistance

10.1158/1538-7445.am2016-1123 ◽

2016 ◽

Author(s):

Suryavathi Viswanadhapalli ◽

Monica Mann ◽

Gangadhara Reddy Sareddy ◽

Xaionan Lix ◽

Hariprasad Vankayalapati ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Therapy Resistance ◽

Breast Cancer Stem Cell ◽

Stem Cell Maintenance ◽

Cell Maintenance

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Plasticity of Cancer Stem Cell: Origin and Role in Disease Progression and Therapy Resistance

Stem Cell Reviews and Reports ◽

10.1007/s12015-019-09942-y ◽

2020 ◽

Vol 16 (2) ◽

pp. 397-412 ◽

Cited By ~ 6

Author(s):

Plabon Kumar Das ◽

Suja Pillai ◽

Md. Abdur Rakib ◽

Jahan Ara Khanam ◽

Vinod Gopalan ◽

...

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Disease Progression ◽

Therapy Resistance

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Emerging candidates in breast cancer stem cell maintenance, therapy resistance and relapse

Journal of Carcinogenesis ◽

10.4103/1477-3163.91119 ◽

2011 ◽

Vol 10 (1) ◽

pp. 36 ◽

Cited By ~ 5

Author(s):

RakeshK Singh ◽

Bhawna Sharma

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Maintenance Therapy ◽

Therapy Resistance ◽

Breast Cancer Stem Cell ◽

Stem Cell Maintenance ◽

Cell Maintenance

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Cancer Stem Cell as Target of CAR-T Cell Therapy

E3S Web of Conferences ◽

10.1051/e3sconf/202021803043 ◽

2020 ◽

Vol 218 ◽

pp. 03043

Author(s):

Xinran Li

Keyword(s):

Stem Cell ◽

T Cell ◽

Cell Therapy ◽

Cancer Stem Cell ◽

Therapy Resistance ◽

Surface Markers ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Chimeric antigen receptor-T cell (CAR-T) therapy has been studied intensively these years and is considered a promising cancer treatment. So far, Food and Drug Administration has approved 2 CAR-T cell therapy for patients with refractory leukemia and the result is positive. However, CAR-T cell therapy is still facing several challenges, including antigen escape, which will diminish the efficacy of treatment and lead to relapse. This review investigates the potential of cancer stem cell (CSC), a small group of cancer cells that contribute to tumorigenesis, metastasis, therapy resistance and relapse, as the target of CAR-T cell therapy, focusing on representative CSC surface markers: CD123, CD133 and CD44. Evidence indicates that CAR-T cell therapy directed by CSC surface markers is effective and feasible. Therefore, CSC targeted CAR-T cell therapy is a prospective treatment for cancer.

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Exosomes Derived from Radioresistant Breast Cancer Cells Promote Therapeutic Resistance in Naïve Recipient Cells

Journal of Personalized Medicine ◽

10.3390/jpm11121310 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1310

Author(s):

Chantell Payton ◽

Lisa Y. Pang ◽

Mark Gray ◽

David J. Argyle

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Cells ◽

Cell Line ◽

Radiation Resistance ◽

Human Breast Cancer ◽

Therapy Resistance ◽

Biologically Active ◽

Human Breast

Radiation resistance is a significant challenge in the treatment of breast cancer in humans. Human breast cancer is commonly treated with surgery and adjuvant chemotherapy/radiotherapy, but recurrence and metastasis upon the development of therapy resistance results in treatment failure. Exosomes are extracellular vesicles secreted by most cell types and contain biologically active cargo that, when transferred to recipient cells, can influence the cells’ genome and proteome. We propose that exosomes secreted by radioresistant (RR) cells may be able to disseminate the RR phenotype throughout the tumour. Here, we isolated exosomes from the human breast cancer cell line, MDA-MB-231, and the canine mammary carcinoma cell line, REM134, and their RR counterparts to investigate the effects of exosomes derived from RR cells on non-RR recipient cells. Canine mammary cancer cells lines have previously been shown to be excellent translational models of human breast cancer. This is consistent with our current data showing that exosomes derived from RR cells can increase cell viability and colony formation in naïve recipient cells and increase chemotherapy and radiotherapy resistance, in both species. These results are consistent in cancer stem cell and non-cancer stem cell populations. Significantly, exosomes derived from RR cells increased the tumoursphere-forming ability of recipient cells compared to exosomes derived from non-RR cells. Our results show that exosomes are potential mediators of radiation resistance that could be therapeutically targeted.

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