Cancer Stem Cells: Current Status and Therapeutic Implications in Cancer Therapy- a New Paradigm

Current Stem Cell Research & Therapy ◽

10.2174/1574888x16666210203105800 ◽

2021 ◽

Vol 16 ◽

Author(s):

Suman Kumar Ray ◽

Sukhes Mukherjee

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Therapy Resistance ◽

Current Status ◽

Environmental Niche ◽

Malignant Growth ◽

New Paradigm ◽

Promising Technique ◽

Therapeutic Implications ◽

Traditional Therapies

Recent evidence confirms that not each tumor cell is proficient in instigating a tumor. Merely a small part of the cancer cells, so-called cancer stem cells (CSCs), can produce cancer indistinguishable from the first one. CSC model has been recognized as a cellular component that adds to phenotypic and functional heterogeneity in different cancers. Latest explanations have featured numerous complexities and difficulties like CSC phenotype that can differ extensively between patients. Tumors may harbor various phenotypically or genetically specific CSCs, and consequently, metastatic CSCs can develop from vital CSCs and tumor cells. Scientists have discovered a few markers for CSCs. The recent finding reveals that CSCs are resistant to radiotherapy and chemotherapy and may clarify the disease's reappearance. Minimal amounts of CSCs can repopulate a tumor. Subsequently, it is essential to understand the attributes and mechanisms by which CSCs show their resistance to therapeutic agents. These aptitudes contribute to new bits of knowledge that gives better therapeutic motivations to discover novel anticancer therapeutics. Accordingly, remedial procedures that emphasize focusing on CSCs and their micro environmental niche are insufficient for conventional malignant growth treatments to eradicate the CSCs that, in any case, bring about therapy resistance. Mutual utilization of traditional therapies with CSC- specific agents may offer a promising technique for enduring cancer treatment as well as remedy.

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PIK3C3 Inhibition Promotes Sensitivity to Colon Cancer Therapy by Inhibiting Cancer Stem Cells

Cancers ◽

10.3390/cancers13092168 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2168

Author(s):

Balawant Kumar ◽

Rizwan Ahmad ◽

Swagat Sharma ◽

Saiprasad Gowrikumar ◽

Mark Primeaux ◽

...

Keyword(s):

Stem Cells ◽

Colon Cancer ◽

Cancer Therapy ◽

Cancer Stem Cells ◽

Side Population ◽

Therapy Resistance ◽

Fluorescent Reporter ◽

Combination Treatments ◽

Gsk 3Β ◽

Resistance To Chemotherapy

Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, such strategies are limited. Autophagy promotes resistance to cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3β/Wnt/β-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3β/Wnt/β-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy.

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Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications

Neurotherapeutics ◽

10.1007/s13311-017-0524-0 ◽

2017 ◽

Vol 14 (2) ◽

pp. 372-384 ◽

Cited By ~ 32

Author(s):

Tamara J. Abou-Antoun ◽

James S. Hale ◽

Justin D. Lathia ◽

Stephen M. Dombrowski

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Brain Cancer ◽

Cell Biology ◽

Therapeutic Implications ◽

Adults And Children

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Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells

Science Advances ◽

10.1126/sciadv.abe3445 ◽

2021 ◽

Vol 7 (5) ◽

pp. eabe3445

Author(s):

Yicun Wang ◽

Jinhui Wu ◽

Hui Chen ◽

Yang Yang ◽

Chengwu Xiao ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Negative Feedback ◽

Direct Interaction ◽

Therapy Resistance ◽

Negative Regulator ◽

Chemotherapy Response ◽

Genome Wide

Cancer stem cells (CSCs) are involved in tumorigenesis, recurrence, and therapy resistance. To identify critical regulators of sarcoma CSCs, we performed a reporter-based genome-wide CRISPR-Cas9 screen and uncovered Kruppel-like factor 11 (KLF11) as top candidate. In vitro and in vivo functional annotation defined a negative role of KLF11 in CSCs. Mechanistically, KLF11 and YAP/TEAD bound to adjacent DNA sites along with direct interaction. KLF11 recruited SIN3A/HDAC to suppress the transcriptional output of YAP/TEAD, which, in turn, promoted KLF11 transcription, forming a negative feedback loop. However, in CSCs, this negative feedback was lost because of epigenetic silence of KLF11, causing sustained YAP activation. Low KLF11 was associated with poor prognosis and chemotherapy response in patients with sarcoma. Pharmacological activation of KLF11 by thiazolidinedione effectively restored chemotherapy response. Collectively, our study identifies KLF11 as a negative regulator in sarcoma CSCs and potential therapeutic target.

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Therapeutic potency of oncolytic virotherapy–induced cancer stem cells targeting in brain tumors, current status, and perspectives

Journal of Cellular Biochemistry ◽

10.1002/jcb.27661 ◽

2018 ◽

Vol 120 (3) ◽

pp. 2766-2773 ◽

Cited By ~ 2

Author(s):

Amirhossein Bahreyni ◽

Elnaz Ghorbani ◽

Hamid Fuji ◽

Mikhail Ryzhikov ◽

Majid Khazaei ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Brain Tumors ◽

Current Status ◽

Oncolytic Virotherapy

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Therapeutic implications of cancer stem cells

Current Opinion in Genetics & Development ◽

10.1016/j.gde.2003.11.007 ◽

2004 ◽

Vol 14 (1) ◽

pp. 43-47 ◽

Cited By ~ 379

Author(s):

Muhammad Al-Hajj ◽

Michael W Becker ◽

Max Wicha ◽

Irving Weissman ◽

Michael F Clarke

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Therapeutic Implications

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Therapeutic Targeting of Cancer Stem Cells in Lung, Head and Neck, and Bladder Cancers

Cancers ◽

10.3390/cancers13205098 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5098

Author(s):

Sarah E. Mudra ◽

Pritam Sadhukhan ◽

M. Talha Ugurlu ◽

Shorna Alam ◽

Mohammad O. Hoque

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Acquired Resistance ◽

Therapy Resistance ◽

Stem Cell Population ◽

Molecular Characteristics ◽

Targeted Agents ◽

Regulatory Pathways ◽

Lineage Differentiation ◽

Solid Malignancies

Resistance to cancer therapy remains a significant obstacle in treating patients with various solid malignancies. Exposure to current chemotherapeutics and targeted agents invariably leads to therapy resistance, heralding the need for novel agents. Cancer stem cells (CSCs)—a subpopulation of tumor cells with capacities for self-renewal and multi-lineage differentiation—represent a pool of therapeutically resistant cells. CSCs often share physical and molecular characteristics with the stem cell population of the human body. It remains challenging to selectively target CSCs in therapeutically resistant tumors. The generation of CSCs and induction of therapeutic resistance can be attributed to several deregulated critical growth regulatory signaling pathways such as WNT/β-catenin, Notch, Hippo, and Hedgehog. Beyond growth regulatory pathways, CSCs also change the tumor microenvironment and resist endogenous immune attack. Thus, CSCs can interfere with each stage of carcinogenesis from malignant transformation to the onset of metastasis to tumor recurrence. A thorough review of novel targeted agents to act against CSCs is fundamental for advancing cancer treatment in the setting of both intrinsic and acquired resistance.

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Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

Cancers ◽

10.3390/cancers13184550 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4550

Author(s):

Laura Gramantieri ◽

Catia Giovannini ◽

Fabrizia Suzzi ◽

Ilaria Leoni ◽

Francesca Fornari

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Anticancer Agents ◽

Tumor Heterogeneity ◽

Molecular Mechanisms ◽

Driving Forces ◽

Predictive Biomarkers ◽

Molecular Classification ◽

Circulating Biomarkers ◽

Therapeutic Implications

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. HCC is associated with multiple risk factors and is characterized by a marked tumor heterogeneity that makes its molecular classification difficult to apply in the clinics. The lack of circulating biomarkers for the diagnosis, prognosis, and prediction of response to treatments further undermines the possibility of developing personalized therapies. Accumulating evidence affirms the involvement of cancer stem cells (CSCs) in tumor heterogeneity, recurrence, and drug resistance. Owing to the contribution of CSCs to treatment failure, there is an urgent need to develop novel therapeutic strategies targeting, not only the tumor bulk, but also the CSC subpopulation. Clarification of the molecular mechanisms influencing CSC properties, and the identification of their functional roles in tumor progression, may facilitate the discovery of novel CSC-based therapeutic targets to be used alone, or in combination with current anticancer agents, for the treatment of HCC. Here, we review the driving forces behind the regulation of liver CSCs and their therapeutic implications. Additionally, we provide data on their possible exploitation as prognostic and predictive biomarkers in patients with HCC.

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