Cancers

Research

14 pages, 2550 KiB

Open AccessArticle

Multiple Treatment Cycles of Neural Stem Cell Delivered Oncolytic Adenovirus for the Treatment of Glioblastoma

by Jennifer Batalla-Covello, Hoi Wa Ngai, Linda Flores, Marisa McDonald, Caitlyn Hyde, Joanna Gonzaga, Mohamed Hammad, Margarita Gutova, Jana Portnow, Tim Synold, David T. Curiel, Maciej S. Lesniak, Karen S. Aboody and Rachael Mooney

Cancers 2021, 13(24), 6320; https://doi.org/10.3390/cancers13246320 - 16 Dec 2021

Cited by 7 | Viewed by 3120

Abstract

Tumor tropic neural stem cells (NSCs) can improve the anti-tumor efficacy of oncovirotherapy agents by protecting them from rapid clearance by the immune system and delivering them to multiple distant tumor sites. We recently completed a first-in-human trial assessing the safety of a [...] Read more.

Tumor tropic neural stem cells (NSCs) can improve the anti-tumor efficacy of oncovirotherapy agents by protecting them from rapid clearance by the immune system and delivering them to multiple distant tumor sites. We recently completed a first-in-human trial assessing the safety of a single intracerebral dose of NSC-delivered CRAd-Survivin-pk7 (NSC.CRAd-S-pk7) combined with radiation and chemotherapy in newly diagnosed high-grade glioma patients. The maximum feasible dose was determined to be 150 million NSC.CRAd-Sp-k7 (1.875 × 10¹¹ viral particles). Higher doses were not assessed due to volume limitations for intracerebral administration and the inability to further concentrate the study agent. It is possible that therapeutic efficacy could be maximized by administering even higher doses. Here, we report IND-enabling studies in which an improvement in treatment efficacy is achieved in immunocompetent mice by administering multiple treatment cycles intracerebrally. The results imply that pre-existing immunity does not preclude therapeutic benefits attainable by administering multiple rounds of an oncolytic adenovirus directly into the brain. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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12 pages, 1024 KiB

Open AccessArticle

Transformed Lymphoma Is Associated with a Favorable Response to CAR-T-Cell Treatment in DLBCL Patients

by Anna Nydegger, Urban Novak, Marie-Noëlle Kronig, Myriam Legros, Sacha Zeerleder, Yara Banz, Ulrike Bacher and Thomas Pabst

Cancers 2021, 13(23), 6073; https://doi.org/10.3390/cancers13236073 - 2 Dec 2021

Cited by 19 | Viewed by 3132

Abstract

(1) Background: CAR-T-cell therapy is a novel therapeutic option for patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The parameters that predict a favorable outcome after CAR-T-cell treatment are a matter of ongoing exploration. (2) Methods: We analyzed 36 [...] Read more.

(1) Background: CAR-T-cell therapy is a novel therapeutic option for patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The parameters that predict a favorable outcome after CAR-T-cell treatment are a matter of ongoing exploration. (2) Methods: We analyzed 36 consecutive patients with r/r DLBCL receiving tisagenlecleucel or axicabtagene ciloleucel at a single academic institution. We hypothesized that lymphoma subtypes (transformed versus de novo DLBCL) are of prognostic importance. We also assessed age, previous treatment, bridging therapy, remission status at the time of CAR-T treatment and at six months, LDH, the occurrence of CRS or ICANS, and CAR-T-DNA ddPCR kinetics for their prognostic impact. (3) Results: CRS was observed in 24 (67%) patients, and ICANS was observed in 14 (39%) patients. CR was achieved in 20 (56%) patients. Achievement of CR within six months after CAR-T was associated with better PFS (p < 0.0001) and OS (p < 0.0001). Remarkably, transformed (=secondary) lymphoma was associated with a better outcome than de novo disease for PFS (p = 0.0093) and OS (p = 0.0209), and the CR rate was 78% versus 33% (p = 0.0176). Mortality in patients with transformed DLBCL was 23% compared with 56% in de novo patients (p = 0.0209). (4) Conclusion: The presence of transformed DLBCL seems to be associated with a more favorable course after CAR-T treatment than that observed in the de novo DLBCL patients. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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25 pages, 13001 KiB

Open AccessArticle

A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

by Qipeng Fan, Lihong Li, Tian-Li Wang, Robert E. Emerson and Yan Xu

Cancers 2021, 13(15), 3821; https://doi.org/10.3390/cancers13153821 - 29 Jul 2021

Cited by 13 | Viewed by 3268

Abstract

We have recently identified ZIP4 as a novel cancer stem cell (CSC) marker in high-grade serous ovarian cancer (HGSOC). While it converts drug-resistance to cisplatin (CDDP), we unexpectedly found that ZIP4 induced sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). Mechanistically, ZIP4 [...] Read more.

We have recently identified ZIP4 as a novel cancer stem cell (CSC) marker in high-grade serous ovarian cancer (HGSOC). While it converts drug-resistance to cisplatin (CDDP), we unexpectedly found that ZIP4 induced sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). Mechanistically, ZIP4 selectively upregulated HDAC IIa HDACs, with little or no effect on HDACs in other classes. HDAC4 knockdown (KD) and LMK-235 inhibited spheroid formation in vitro and tumorigenesis in vivo, with hypoxia inducible factor-1 alpha (HIF1α) and endothelial growth factor A (VEGFA) as functional downstream mediators of HDAC4. Moreover, we found that ZIP4, HDAC4, and HIF1α were involved in regulating secreted VEGFA in HGSOC cells. Furthermore, we tested our hypothesis that co-targeting CSC via the ZIP4-HDAC4 axis and non-CSC using CDDP is necessary and highly effective by comparing the effects of ZIP4-knockout/KD, HDAC4-KD, and HDACis, in the presence or absence of CDDP on tumorigenesis in mouse models. Our results showed that the co-targeting strategy was highly effective. Finally, data from human HGSOC tissues showed that ZIP4 and HDAC4 were upregulated in a subset of recurrent tumors, justifying the clinical relevance of the study. In summary, our study provides a new mechanistic-based targeting strategy for HGSOC. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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17 pages, 3968 KiB

Open AccessArticle

Preclinical Safety Evaluation of Intranasally Delivered Human Mesenchymal Stem Cells in Juvenile Mice

by Yolanda Aguilera, Nuria Mellado-Damas, Laura Olmedo-Moreno, Víctor López, Concepción Panadero-Morón, Marina Benito, Hugo Guerrero-Cázares, Catalina Márquez-Vega, Alejandro Martín-Montalvo and Vivian Capilla-González

Cancers 2021, 13(5), 1169; https://doi.org/10.3390/cancers13051169 - 9 Mar 2021

Cited by 13 | Viewed by 5064

Abstract

Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a [...] Read more.

Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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18 pages, 3938 KiB

Open AccessArticle

MSI1 Promotes the Expression of the GBM Stem Cell Marker CD44 by Impairing miRNA-Dependent Degradation

by Rebecca Pötschke, Jacob Haase, Markus Glaß, Sebastian Simmermacher, Claudia Misiak, Luiz O. F. Penalva, Caspar D. Kühnöl and Stefan Hüttelmaier

Cancers 2020, 12(12), 3654; https://doi.org/10.3390/cancers12123654 - 5 Dec 2020

Cited by 10 | Viewed by 4043

Abstract

The stem cell marker Musashi1 (MSI1) is highly expressed during neurogenesis and in glioblastoma (GBM). MSI1 promotes self-renewal and impairs differentiation in cancer and non-malignant progenitor cells. However, a comprehensive understanding of its role in promoting GBM-driving networks remains to be deciphered. We [...] Read more.

The stem cell marker Musashi1 (MSI1) is highly expressed during neurogenesis and in glioblastoma (GBM). MSI1 promotes self-renewal and impairs differentiation in cancer and non-malignant progenitor cells. However, a comprehensive understanding of its role in promoting GBM-driving networks remains to be deciphered. We demonstrate that MSI1 is highly expressed in GBM recurrences, an oncologist’s major defiance. For the first time, we provide evidence that MSI1 promotes the expression of stem cell markers like CD44, co-expressed with MSI1 within recurrence-promoting cells at the migrating front of primary GBM samples. With GBM cell models of pediatric and adult origin, including isolated primary tumorspheres, we show that MSI1 promotes stem cell-like characteristics. Importantly, it impairs CD44 downregulation in a 3′UTR- and miRNA-dependent manner by controlling mRNA turnover. This regulation is disturbed by the previously reported MSI1 inhibitor luteolin, providing further evidence for a therapeutic target potential of MSI1 in GBM treatment. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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Review

Jump to: Research, Other

18 pages, 1232 KiB

Open AccessReview

The Hematology of Tomorrow Is Here—Preclinical Models Are Not: Cell Therapy for Hematological Malignancies

by Lorena Arranz

Cancers 2022, 14(3), 580; https://doi.org/10.3390/cancers14030580 - 24 Jan 2022

Cited by 5 | Viewed by 5931

Abstract

The purpose of this review is to present the current knowledge on the clinical use of several forms of cell therapy in hematological malignancies and the preclinical models available for their study. In the context of allogeneic hematopoietic stem cell transplants, mesenchymal stromal [...] Read more.

The purpose of this review is to present the current knowledge on the clinical use of several forms of cell therapy in hematological malignancies and the preclinical models available for their study. In the context of allogeneic hematopoietic stem cell transplants, mesenchymal stromal cells are pursued to help stem cell engraftment and expansion, and control graft versus host disease. We further summarize the status of promising forms of cellular immunotherapy including CAR T cell and CAR NK cell therapy aimed at eradicating the cells of origin of leukemia, i.e., leukemia stem cells. Updates on other forms of cellular immunotherapy, such as NK cells, CIK cells and CAR CIK cells, show encouraging results in AML. The considerations in available in vivo models for disease modelling and treatment efficacy prediction are discussed, with a particular focus on their strengths and weaknesses for the study of healthy and diseased hematopoietic stem cell reconstitution, graft versus host disease and immunotherapy. Despite current limitations, cell therapy is a rapidly evolving field that holds the promise of improved cure rates, soon. As a result, we may be witnessing the birth of the hematology of tomorrow. To further support its development, improved preclinical models including humanized microenvironments in mice are urgently needed. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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32 pages, 1358 KiB

Open AccessReview

The Multifaceted Role of Aldehyde Dehydrogenases in Prostate Cancer Stem Cells

by Jakob Püschel, Anna Dubrovska and Ielizaveta Gorodetska

Cancers 2021, 13(18), 4703; https://doi.org/10.3390/cancers13184703 - 20 Sep 2021

Cited by 23 | Viewed by 5609

Abstract

Cancer stem cells (CSCs) are the only tumor cells possessing self-renewal and differentiation properties, making them an engine of tumor progression and a source of tumor regrowth after treatment. Conventional therapies eliminate most non-CSCs, while CSCs often remain radiation and drug resistant, leading [...] Read more.

Cancer stem cells (CSCs) are the only tumor cells possessing self-renewal and differentiation properties, making them an engine of tumor progression and a source of tumor regrowth after treatment. Conventional therapies eliminate most non-CSCs, while CSCs often remain radiation and drug resistant, leading to tumor relapse and metastases. Thus, targeting CSCs might be a powerful tool to overcome tumor resistance and increase the efficiency of current cancer treatment strategies. The identification and isolation of the CSC population based on its high aldehyde dehydrogenase activity (ALDH) is widely accepted for prostate cancer (PCa) and many other solid tumors. In PCa, several ALDH genes contribute to the ALDH activity, which can be measured in the enzymatic assay by converting 4, 4-difluoro-4-bora-3a, 4a-diaza-s-indacene (BODIPY) aminoacetaldehyde (BAAA) into the fluorescent product BODIPY-aminoacetate (BAA). Although each ALDH isoform plays an individual role in PCa biology, their mutual functional interplay also contributes to PCa progression. Thus, ALDH proteins are markers and functional regulators of CSC properties, representing an attractive target for cancer treatment. In this review, we discuss the current state of research regarding the role of individual ALDH isoforms in PCa development and progression, their possible therapeutic targeting, and provide an outlook for the future advances in this field. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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31 pages, 1200 KiB

Open AccessEditor’s ChoiceReview

The CXCL12 Crossroads in Cancer Stem Cells and Their Niche

by Juan Carlos López-Gil, Laura Martin-Hijano, Patrick C. Hermann and Bruno Sainz, Jr.

Cancers 2021, 13(3), 469; https://doi.org/10.3390/cancers13030469 - 26 Jan 2021

Cited by 36 | Viewed by 6713

Abstract

Cancer stem cells (CSCs) are defined as a subpopulation of “stem”-like cells within the tumor with unique characteristics that allow them to maintain tumor growth, escape standard anti-tumor therapies and drive subsequent repopulation of the tumor. This is the result of their intrinsic [...] Read more.

Cancer stem cells (CSCs) are defined as a subpopulation of “stem”-like cells within the tumor with unique characteristics that allow them to maintain tumor growth, escape standard anti-tumor therapies and drive subsequent repopulation of the tumor. This is the result of their intrinsic “stem”-like features and the strong driving influence of the CSC niche, a subcompartment within the tumor microenvironment that includes a diverse group of cells focused on maintaining and supporting the CSC. CXCL12 is a chemokine that plays a crucial role in hematopoietic stem cell support and has been extensively reported to be involved in several cancer-related processes. In this review, we will provide the latest evidence about the interactions between CSC niche-derived CXCL12 and its receptors—CXCR4 and CXCR7—present on CSC populations across different tumor entities. The interactions facilitated by CXCL12/CXCR4/CXCR7 axes seem to be strongly linked to CSC “stem”-like features, tumor progression, and metastasis promotion. Altogether, this suggests a role for CXCL12 and its receptors in the maintenance of CSCs and the components of their niche. Moreover, we will also provide an update of the therapeutic options being currently tested to disrupt the CXCL12 axes in order to target, directly or indirectly, the CSC subpopulation. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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Other

Jump to: Research, Review

9 pages, 489 KiB

Open AccessPerspective

Stem Cell Theory of Cancer: Rude Awakening or Bad Dream from Cancer Dormancy?

by Shi-Ming Tu, Marcos R. Estecio, Sue-Hwa Lin and Niki M. Zacharias

Cancers 2022, 14(3), 655; https://doi.org/10.3390/cancers14030655 - 27 Jan 2022

Cited by 8 | Viewed by 4028

Abstract

To be dormant or not depends on the origin and nature of both the cell and its niche. Similar to other cancer hallmarks, dormancy is ingrained with stemness, and stemness is embedded within dormancy. After all, cancer dormancy is dependent on multiple factors [...] Read more.

To be dormant or not depends on the origin and nature of both the cell and its niche. Similar to other cancer hallmarks, dormancy is ingrained with stemness, and stemness is embedded within dormancy. After all, cancer dormancy is dependent on multiple factors such as cell cycle arrest, metabolic inactivity, and the microenvironment. It is the net results and sum effects of a myriad of cellular interactions, interconnections, and interplays. When we unite all cancer networks and integrate all cancer hallmarks, we practice and preach a unified theory of cancer. From this perspective, we review cancer dormancy in the context of a stem cell theory of cancer. We revisit the seed and soil hypothesis of cancer. We reexamine its implications in both primary tumors and metastatic lesions. We reassess its roles in cell cycle arrest, metabolic inactivity, and stemness property. Cancer dormancy is particularly revealing when it informs us about the mysteries of late relapse, prolonged remission, and second malignancy. It is paradoxically rewarding when it delivers us the promises and power of cancer prevention and maintenance therapy in patient care. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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