A role for cancer stem cells in therapy resistance: Cellular and molecular mechanisms

In an increasing number of cancers, tumor populations called cancer stem cells (CSCs), or tumor-initiating cells, have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemotherapy and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/β-catenin and Notch signaling. Novel targeted therapies against the DNA damage checkpoint or stem-cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are antiangiogenic and vascular targeting agents, which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of antiangiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.

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Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL

Pharmaceutics ◽

10.3390/pharmaceutics13071062 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1062

Author(s):

Adriana G. Quiroz-Reyes ◽

Paulina Delgado-Gonzalez ◽

Jose Francisco Islas ◽

Juan Luis Delgado Gallegos ◽

Javier Humberto Martínez Martínez Garza ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Invasion Pathways ◽

Trail Resistance ◽

Novel Strategy ◽

Cancer Remission

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.

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Targeting Cancer Stem Cells in Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers11070965 ◽

2019 ◽

Vol 11 (7) ◽

pp. 965 ◽

Cited By ~ 30

Author(s):

Park ◽

Choi ◽

Nam

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Triple Negative Breast Cancer ◽

Molecular Mechanisms ◽

Triple Negative ◽

Therapy Resistance ◽

Therapeutic Effects ◽

Self Renewal ◽

The Future

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that lacks targeted therapy options, and patients diagnosed with TNBC have poorer outcomes than patients with other breast cancer subtypes. Emerging evidence suggests that breast cancer stem cells (BCSCs), which have tumor-initiating potential and possess self-renewal capacity, may be responsible for this poor outcome by promoting therapy resistance, metastasis, and recurrence. TNBC cells have been consistently reported to display cancer stem cell (CSC) signatures at functional, molecular, and transcriptional levels. In recent decades, CSC-targeting strategies have shown therapeutic effects on TNBC in multiple preclinical studies, and some of these strategies are currently being evaluated in clinical trials. Therefore, understanding CSC biology in TNBC has the potential to guide the discovery of novel therapeutic agents in the future. In this review, we focus on the self-renewal signaling pathways (SRSPs) that are aberrantly activated in TNBC cells and discuss the specific signaling components that are involved in the tumor-initiating potential of TNBC cells. Additionally, we describe the molecular mechanisms shared by both TNBC cells and CSCs, including metabolic plasticity, which enables TNBC cells to switch between metabolic pathways according to substrate availability to meet the energetic and biosynthetic demands for rapid growth and survival under harsh conditions. We highlight CSCs as potential key regulators driving the aggressiveness of TNBC. Thus, the manipulation of CSCs in TNBC can be a targeted therapeutic strategy for TNBC in the future.

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Cancer Stem Cells in Intrahepatic Cholangiocarcinoma; Their Molecular Basis, and Therapeutic Implications

Frontiers in Physiology ◽

10.3389/fphys.2021.824261 ◽

2022 ◽

Vol 12 ◽

Author(s):

Keiichi Tamai ◽

Haruna Fujimori ◽

Mai Mochizuki ◽

Kennichi Satoh

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Intrahepatic Cholangiocarcinoma ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Target Therapy ◽

Therapy Resistance ◽

Future Perspective ◽

Cancer Tissue ◽

Mesenchymal Transition

Cancer tissue consists of heterogenous cell types, and cancer stem cells (CSCs) are a subpopulation of the tissue which possess therapy resistance, tumor reconstruction capability, and are responsible for metastasis. Intrahepatic cholangiocarcinoma (iCCA) is one of the most common type of liver cancer that is highly aggressive with poor prognosis. Since no target therapy is efficient in improving patient outcomes, new therapeutic approaches need to be developed. CSC is thought to be a promising therapeutic target because of its resistance to therapy. Accumulating evidences suggests that there are many factors (surface marker, stemness-related genes, etc.) and mechanisms (epithelial-mesenchymal transition, mitochondria activity, etc.) which are linked to CSC-like phenotypes. Nevertheless, limited studies are reported about the application of therapy using these mechanisms, suggesting that more precise understandings are still needed. In this review, we overview the molecular mechanisms which modulate CSC-like phenotypes, and discuss the future perspective for targeting CSC in iCCA.

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Molecular Mechanisms Underlying the Functions of Cellular Markers Associated with the Phenotype of Cancer Stem Cells

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666180821154752 ◽

2019 ◽

Vol 14 (5) ◽

pp. 405-420 ◽

Cited By ~ 2

Author(s):

Eduardo Alvarado-Ortiz ◽

Miguel Á. Sarabia-Sánchez ◽

Alejandro García-Carrancá

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Molecular Mechanisms ◽

Tumor Biology ◽

Molecular Tools ◽

Recent Past ◽

Functional Roles ◽

Cellular Population ◽

Cellular Markers ◽

A Minor

Cancer Stem Cells (CSC) generally constitute a minor cellular population within tumors that exhibits some capacities of normal Stem Cells (SC). The existence of CSC, able to self-renew and differentiate, influences central aspects of tumor biology, in part because they can continue tumor growth, give rise to metastasis, and acquire drug and radioresistance, which open new avenues for therapeutics. It is well known that SC constantly interacts with their niche, which includes mesenchymal cells, extracellular ligands, and the Extra Cellular Matrix (ECM). These interactions regularly lead to homeostasis and maintenance of SC characteristics. However, the exact participation of each of these components for CSC maintenance is not clear, as they appear to be context- or cell-specific. In the recent past, surface cellular markers have been fundamental molecular tools for identifying CSC and distinguishing them from other tumor cells. Importantly, some of these cellular markers have been shown to possess functional roles that affect central aspects of CSC. Likewise, some of these markers can participate in regulating the interaction of CSC with their niche, particularly the ECM. We focused this review on the molecular mechanisms of surface cellular markers commonly employed to identify CSC, highlighting the signaling pathways and mechanisms involved in CSC-ECM interactions, through each of the cellular markers commonly used in the study of CSC, such as CD44, CD133, CD49f, CD24, CXCR4, and LGR5. Their presence does not necessarily implicate them in CSC biology.

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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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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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The molecular mechanisms of curcumin’s inhibitory effects on cancer stem cells

Journal of Cellular Biochemistry ◽

10.1002/jcb.27757 ◽

2018 ◽

Vol 120 (4) ◽

pp. 4739-4747 ◽

Cited By ~ 12

Author(s):

Elham Zendehdel ◽

Elham Abdollahi ◽

Amir Abbas Momtazi‐Borojeni ◽

Mitra Korani ◽

Seyedeh Hoda Alavizadeh ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Molecular Mechanisms ◽

Inhibitory Effects

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Current Strategies for Identification of Glioma Stem Cells: Adequate or Unsatisfactory?

Journal of Oncology ◽

10.1155/2012/376894 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 44

Author(s):

Paola Brescia ◽

Cristina Richichi ◽

Giuliana Pelicci

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Large Scale ◽

Molecular Mechanisms ◽

Cell Phenotype ◽

Multiple Tumor ◽

Early Results ◽

Tumorigenic Potential ◽

Tumor Types

Cancer stem cells (CSCs) were isolated in multiple tumor types, including human glioblastomas, and although the presence of surface markers selectively expressed on CSCs can be used to isolate them, no marker/pattern of markers are sufficiently robust to definitively identify stem cells in tumors. Several markers were evaluated for their prognostic value with promising early results, however none of them was proven to be clinically useful in large-scale studies, leading to outstanding efforts to identify new markers. Given the heterogeneity of human glioblastomas further investigations are necessary to identify both cancer stem cell-specific markers and the molecular mechanisms sustaining the tumorigenic potential of these cells to develop tailored treatments. Markers for glioblastoma stem cells such as CD133, CD15, integrin-α6, L1CAM might be informative to identify these cells but cannot be conclusively linked to a stem cell phenotype. Overlap of expression, functional state and morphology of different subpopulations lead to carefully consider the techniques employed so far to isolate these cells. Due to a dearth of methods and markers reliably identifying the candidate cancer stem cells, the isolation/enrichment of cancer stem cells to be therapeutically targeted remains a major challenge.

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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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