Cancer resistance to immunotherapy: What is the role of cancer stem cells?

Gupta, Gourab Sen; Merhej, George; Saravanan, Shakthika; Chen, Hexin

doi:10.20517/cdr.2022.19

Cited by 4 publications

(5 citation statements)

References 113 publications

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“…While using retinoids to treat other cancers has shown limited success [16,17], therapeutically inhibiting CYP26A1, as we have shown herein, to reduce RA metabolism may prove useful in designing approaches to promote the differentiation of CSCs with retinoids. Therefore, our findings are important because CRC development is driven by the overpopulation of CSCs, which are cell populations that show resistance to immunotherapy as well as conventional chemotherapy and radiation [47][48][49][50][51][52][53][54][55][56][57][58]. Thus, finding ways to promote retinoid-induced differentiation of CSCs in vivo may lead to new and more effective therapeutic strategies for CRC patients.…”

Section: Discussionmentioning

confidence: 85%

CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC

Facey,

Hunsu,

Zhang

et al. 2024

Cancers

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APC mutation is the main driving mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation. Hypotheses: A functional link exists between the WNT and RA pathways, and APC mutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we induce wt-APC expression in APC-mutant CRC cells, and we assess the ability of all-trans retinoic acid (ATRA) to induce differentiation. We found that ATRA increased expression of the WNT target gene, CYP26A1, and inducing wt-APC reduced this expression by 50%. Thus, the RA and WNT pathways crosstalk to modulate CYP26A1, which metabolizes retinoids. Moreover, inducing wt-APC augments ATRA-induced cell differentiation by: (i) decreasing cell proliferation; (ii) suppressing ALDH1A1 expression; (iii) decreasing ALDH+ SCs; and (iv) increasing neuroendocrine cell differentiation. A novel CYP26A1-based network that links WNT and RA signaling was also identified by NanoString profiling/bioinformatics analysis. Furthermore, CYP26A1 inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Notably, in wt-APC-CRCs, decreased CYP26A1 improved patient survival. These findings have strong potential for clinical translation.

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Section: Discussionmentioning

confidence: 85%

CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC

Facey,

Hunsu,

Zhang

et al. 2024

Cancers

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“…Personalized therapies, once a distant aspiration in the evolving landscape of cancer treatment, now loom as an impending reality. The heterogeneity of tumors, as suggested by our understanding of SLAM-related pathways, necessitates a patient-centric approach that tailors treatments based on individual tumors' unique molecular and genetic profiles [67].…”

Section: Discussionmentioning

confidence: 99%

“…Simultaneously, the distinctive properties of cancer stem cells (CSCs) have been mooted as pivotal contributors to this resistance. As Gupta et al elucidated, factors ranging from the unique surface marker profile of CSCs and the array of cytokines they release to the metabolites they produce all play roles in tailoring the immune landscape within the TME [67].…”

Section: Role Of Slam In Overcoming Immunotherapy Resistancementioning

confidence: 99%

SLAM Modification as an Immune-Modulatory Therapeutic Approach in Cancer

Tojjari,

Giles,

Vilbert

et al. 2023

Cancers

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In the field of oncology, the Signaling Lymphocyte Activation Molecule (SLAM) family is emerging as pivotal in modulating immune responses within tumor environments. The SLAM family comprises nine receptors, mainly found on immune cell surfaces. These receptors play complex roles in the interaction between cancer and the host immune system. Research suggests SLAM’s role in both enhancing and dampening tumor-immune responses, influencing the progression and treatment outcomes of various cancers. As immunotherapy advances, resistance remains an issue. The nuanced roles of the SLAM family might provide answers. With the rise in technologies like single-cell RNA sequencing and advanced imaging, there is potential for precise SLAM-targeted treatments. This review stresses patient safety, the importance of thorough clinical trials, and the potential of SLAM-focused therapies to transform cancer care. In summary, SLAM’s role in oncology signals a new direction for more tailored and adaptable cancer treatments.

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“…CSCs were first observed in 1937 by Furth and Kahn, who determined the number of cells necessary to transmit malignant leukemia tumors in mice 13 . It is believed that CSC populations are present in all cancers but in very low proportions 8,14 . In PCa, PCa stem cells (PCSCs) represent approximately 0.1% of the tumor cell population 15 .…”

Section: Prostate Cancer (Pca) Stem Cells: What Are They?mentioning

confidence: 99%

“…cells from apoptosis 19 . At least five mechanisms have been observed through which CSCs exhibit resistance to chemotherapy: maintaining an inactive proliferative state by exiting the cell cycle, activating drug efflux mechanisms, overexpressing DNA repair mechanisms, overexpressing anti-apoptotic genes, and releasing cytokines that make other cells in their tumor microenvironment resistant to therapy 14 .…”

Section: Se Enfatiza La Necesidad De Nuevas Terapias Dirigidas a Las ...mentioning

confidence: 99%

Understanding prostate cancer stem cells: implications for therapy and treatment resistance

Flores-Islas,

Rico-Fuentes,

Castro-Zazueta

et al. 2024

BCMU

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Prostate cancer (PCa) is a highly heterogeneous and rapidly progressing malignancy with a complex etiology. The presence of cancer stem cells (CSCs) within prostate tumors contributes to treatment resistance, relapses, and metastasis. Understanding the molecular mechanisms and signaling pathways involved in CSC regulation is crucial for developing effective therapies. This article highlights the role of CSCs, particularly PCa stem cells (PCSCs), in PCa initiation and progression. It discusses the cellular heterogeneity of prostate tumors, the theories of clonal evolution and CSCs, and the resistance mechanisms exhibited by CSCs. In addition, the involvement of signaling pathways such as Hedgehog, PI3K/AKT, and mitogen-activated protein kinase/extracellular regulated kinases in PCSC regulation is explored. The need for new therapies targeting CSCs is emphasized, and potential treatment approaches, including immunotherapy and genetic engineering, are discussed. Despite the challenges posed by advanced therapies, targeting PCSCs holds promise for improving patient outcomes in advanced PCa. Further research on PCSC biology is warranted to advance our understanding and develop more effective therapeutic strategies.

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Cancer resistance to immunotherapy: What is the role of cancer stem cells?

Cited by 4 publications

References 113 publications

CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC

CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC

SLAM Modification as an Immune-Modulatory Therapeutic Approach in Cancer

Understanding prostate cancer stem cells: implications for therapy and treatment resistance

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