Cancer Stem Cells as a Source of Drug Resistance in Bone Sarcomas

Bone sarcomas are commonly characterized by a high degree of intra-tumor heterogeneity, which in part is due to the presence of subpopulations of tumor cells presenting stem cell properties. Similar to normal stem cells, these cancer stem cells (CSCs) display a drug resistant phenotype and therefore are responsible for relapses and tumor dissemination. Drug resistance in bone sarcomas could be enhanced/modulated during tumor evolution though the acquisition of (epi)-genetic alterations and the adaptation to changing microenvironments, including drug treatments. Here we summarize findings supporting the involvement of pro-stemness signaling in the development of drug resistance in bone sarcomas. This include the activation of well-known pro-stemness pathways (Wnt/β-Cat, NOTCH or JAT/STAT pathways), changes in the metabolic and autophagic activities, the alteration of epigenetic pathways, the upregulation of specific non-coding RNAs and the crosstalk with different microenvironmental factors. This altered signaling is expected to be translated to the clinic in the form of biomarkers of response and new therapies able to overcome drug resistance.

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Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

Cells ◽

10.3390/cells9081896 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1896 ◽

Cited By ~ 3

Author(s):

Kevin Dzobo ◽

Dimakatso Alice Senthebane ◽

Chelene Ganz ◽

Nicholas Ekow Thomford ◽

Ambroise Wonkam ◽

...

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Treatment Strategies ◽

Cancer Recurrence ◽

Therapy Resistance ◽

Microenvironmental Factors ◽

Novel Treatment Strategies

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

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Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

10.20944/preprints202005.0315.v1 ◽

2020 ◽

Author(s):

Dimakatso Alice Senthebane ◽

Chelene Ganz ◽

Nicholas Ekow Thomford ◽

Kevin Dzobo

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Treatment Strategies ◽

Cancer Recurrence ◽

Therapy Resistance ◽

Repair Mechanisms ◽

Microenvironmental Factors ◽

Novel Treatment Strategies

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance, culminating in relapse and metastatic disease continue to be associated with fatal disease. Cancer stem cells (CSCs) are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterised in many cancers with data illustrating that CSCs display great abilities to self-renew, withstand therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ABC membrane transporters, activation of several survival signaling pathways and increased immune evasion DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we re-visit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

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Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells

Cells ◽

10.3390/cells10040918 ◽

2021 ◽

Vol 10 (4) ◽

pp. 918

Author(s):

Heejin Lee ◽

Oh-Bin Kwon ◽

Jae-Eon Lee ◽

Yong-Hyun Jeon ◽

Dong-Seok Lee ◽

...

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Ovarian Cancer Cells ◽

Therapeutic Drug ◽

G1 Arrest ◽

Dead Cell ◽

Trimebutine Maleate ◽

Simultaneous Inhibition

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV+/PI+ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/β-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/β-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance.

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The impact of fusion genes on cancer stem cells and drug resistance

Molecular and Cellular Biochemistry ◽

10.1007/s11010-021-04203-4 ◽

2021 ◽

Author(s):

Saurav Panicker ◽

Sivaramakrishnan Venkatabalasubramanian ◽

Surajit Pathak ◽

Satish Ramalingam

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Fusion Genes ◽

The Impact

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Natural products targeting cancer stem cells: a revisit

Current Medicinal Chemistry ◽

10.2174/0929867328666210405111913 ◽

2021 ◽

Vol 28 ◽

Author(s):

Jiahua Cui ◽

Jiajun Qian ◽

Larry Ming-Cheung Chow ◽

Jinping Jia

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Natural Products ◽

Cancer Stem Cells ◽

Therapeutic Potential ◽

Tumor Development ◽

Biologically Active ◽

Cellular Targets ◽

Drug Candidates ◽

Enhanced Expression

Background: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy. Introduction: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy. Results and Conclusion: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure-activity relationships. Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

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MicroRNA Targeted Therapy for Overcoming Drug Resistance, Reversal of EMT and Elimination of Cancer Stem Cells in Prostate and Pancreatic Cancer

MicroRNA Targeted Cancer Therapy ◽

10.1007/978-3-319-05134-5_12 ◽

2014 ◽

pp. 199-217 ◽

Cited By ~ 3

Author(s):

Yiwei Li ◽

Dejuan Kong ◽

Aamir Ahmad ◽

Bin Bao ◽

Fazlul H. Sarkar

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Targeted Therapy ◽

Cancer Stem Cells ◽

Resistance Reversal

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Long noncoding RNA LINC00261 upregulates ITIH5 to impair tumorigenic ability of pancreatic cancer stem cells

Cell Death Discovery ◽

10.1038/s41420-021-00575-0 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Lijuan Zou ◽

Hengpeng He ◽

Zhiguo Li ◽

Ou Chen ◽

Xiukun Jia ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cell Proliferation ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Noncoding Rna ◽

Cell Subset ◽

Luciferase Reporter ◽

Stem Cell Markers ◽

Self Renewal

AbstractLong noncoding RNAs (lncRNAs) are implicated tumor development in a range of different cancers, including pancreatic cancer (PC). Cancer stem cells (CSCs), a drug-resistant cancer cell subset, drive tumor progression in PC. In this work, we aimed to investigate the mechanism by which lncRNA LINC00261 affects the biological functions of CSCs during the progression of PC. Microarray analysis of differentially expressed genes and lncRNAs suggested that LINC00261 is downregulated in PC. Both LINC00261 and ITIH5 were confirmed to be downregulated in PC cells and PC stem cells. Gain-of-function and loss-of-function investigations were performed to analyze their effects on cell proliferation, drug resistance, cell cycle distribution, self-renewal, invasion, and ultimately overall tumorigenicity. These experiments revealed that the expression of stem cell markers was reduced, and cell proliferation, self-renewal ability, cell invasion, drug resistance, and tumorigenicity were all suppressed by upregulation of LINC00261 or ITIH5. The results of dual-luciferase reporter gene, ChIP, and RIP assays indicated that LINC00261 binds directly to GATA6, increasing its activity at the ITIH5 promoter. The presence of LINC00261 and GATA6 inhibited the self-renewal and tumorigenesis of PC stem cells, while silence of ITIH5 rescued those functions. Collectively, this study identifies the tumor suppressive activity of LINC00261 in PC, showing that this lncRNA limits the functions of PC stem through an ITIH5/GATA6 regulatory pathway.

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