International Journal of Molecular Sciences

Research

35 pages, 14402 KiB

Open AccessArticle

Molecular Characterization and Inhibition of a Novel Stress-Induced Mitochondrial Protecting Role for Misfolded TrkAIII in Human SH-SY5Y Neuroblastoma Cells

by Lucia Cappabianca, Marianna Ruggieri, Michela Sebastiano, Maddalena Sbaffone, Ilaria Martelli, Pierdomenico Ruggeri, Monica Di Padova, Antonietta Rosella Farina and Andrew Reay Mackay

Int. J. Mol. Sci. 2024, 25(10), 5475; https://doi.org/10.3390/ijms25105475 - 17 May 2024

Viewed by 1656

Abstract

Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumors that originate from cells of neural crest origin committed to the sympathoadrenal progenitor cell lineage. Stress- and drug-resistance mechanisms drive post-therapeutic relapse and metastatic progression, the characterization and inhibition of which are major goals [...] Read more.

Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumors that originate from cells of neural crest origin committed to the sympathoadrenal progenitor cell lineage. Stress- and drug-resistance mechanisms drive post-therapeutic relapse and metastatic progression, the characterization and inhibition of which are major goals in improving therapeutic responses. Stress- and drug-resistance mechanisms in NBs include alternative TrkAIII splicing of the neurotrophin receptor tropomyosin-related kinase A (NTRK1/TrkA), which correlates with post-therapeutic relapse and advanced-stage metastatic disease. The TrkAIII receptor variant exerts oncogenic activity in NB models by mechanisms that include stress-induced mitochondrial importation and activation. In this study, we characterize novel targetable and non-targetable participants in this pro-survival mechanism in TrkAIII-expressing SH-SY5Y NB cells, using dithiothreitol (DTT) as an activator and a variety of inhibitors by regular and immunoprecipitation Western blotting of purified mitochondria and IncuCyte cytotoxicity assays. We report that stress-induced TrkAIII misfolding initiates this mechanism, resulting in Grp78, Ca²⁺-calmodulin, adenosine ribosylating factor (Arf) and Hsp90-regulated mitochondrial importation. TrkAIII imported into inner mitochondrial membranes is cleaved by Omi/high temperature requirement protein A2 (HtrA2) then activated by a mechanism dependent upon calmodulin kinase II (CaMKII), alpha serine/threonine kinase (Akt), mitochondrial Ca²⁺ uniporter and reactive oxygen species (ROS), involving inhibitory mitochondrial protein tyrosine phosphatase (PTPase) oxidation, resulting in phosphoinositide 3 kinase (PI3K) activation of mitochondrial Akt, which enhances stress resistance. This novel pro-survival function for misfolded TrkAIII mitigates the cytotoxicity of mitochondrial Ca²⁺ homeostasis disrupted during integrated stress responses, and is prevented by clinically approved Trk and Akt inhibitors and also by inhibitors of 78kDa glucose regulated protein (Grp78), heat shock protein 90 (Hsp90), Ca²⁺-calmodulin and PI3K. This identifies Grp78, Ca²⁺-calmodulin, Hsp90, PI3K and Akt as novel targetable participants in this mechanism, in addition to TrkAIII, the inhibition of which has the potential to enhance the stress-induced elimination of TrkAIII-expressing NB cells, with the potential to improve therapeutic outcomes in NBs that exhibit TrkAIII expression and activation. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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17 pages, 3728 KiB

Open AccessArticle

Inhibition of PRMT1 Suppresses the Growth of U87MG-Derived Glioblastoma Stem Cells by Blocking the STAT3 Signaling Pathway

by Nayeong Yuk and Hye Jin Jung

Int. J. Mol. Sci. 2024, 25(5), 2950; https://doi.org/10.3390/ijms25052950 - 3 Mar 2024

Cited by 2 | Viewed by 1981

Abstract

Glioblastoma stem cells (GSCs) play a pivotal role in the initiation, progression, resistance to treatment, and relapse of glioblastoma multiforme (GBM). Thus, identifying potential therapeutic targets and drugs that interfere with the growth of GSCs may contribute to improved treatment outcomes for GBM. [...] Read more.

Glioblastoma stem cells (GSCs) play a pivotal role in the initiation, progression, resistance to treatment, and relapse of glioblastoma multiforme (GBM). Thus, identifying potential therapeutic targets and drugs that interfere with the growth of GSCs may contribute to improved treatment outcomes for GBM. In this study, we first demonstrated the functional role of protein arginine methyltransferase 1 (PRMT1) in GSC growth. Furamidine, a PRMT1 inhibitor, effectively inhibited the proliferation and tumorsphere formation of U87MG-derived GSCs by inducing cell cycle arrest at the G0/G1 phase and promoting the intrinsic apoptotic pathway. Moreover, furamidine potently suppressed the in vivo tumor growth of U87MG GSCs in a chick embryo chorioallantoic membrane model. In particular, the inhibitory effect of furamidine on U87MG GSC growth was associated with the downregulation of signal transducer and activator of transcription 3 (STAT3) and key GSC markers, including CD133, Sox2, Oct4, Nanog, aldehyde dehydrogenase 1, and integrin α6. Our results also showed that the knockdown of PRMT1 by small interfering RNA significantly inhibited the proliferation of U87MG GSCs in vitro and in vivo through a molecular mechanism similar to furamidine. In addition, combined treatment with furamidine and berbamine, a calcium/calmodulin-dependent protein kinase II gamma (CaMKIIγ) inhibitor, inhibited the growth of U87MG GSCs more strongly than single-compound treatment. The increased antiproliferative effect of combining the two compounds resulted from a stronger downregulation of STAT3-mediated downstream GBM stemness regulators through dual PRMT1 and CaMKIIγ function blockade. In conclusion, these findings suggest that PRMT1 and its inhibitor, furamidine, are potential novel therapeutic targets and drug candidates for effectively suppressing GSC growth. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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16 pages, 3524 KiB

Open AccessArticle

BAP31 Promotes Angiogenesis via Galectin-3 Upregulation in Neuroblastoma

by Mwichie Namusamba, Yufei Wu, Jiaying Yang, Qi Zhang, Changli Wang, Tianyi Wang and Bing Wang

Int. J. Mol. Sci. 2024, 25(5), 2946; https://doi.org/10.3390/ijms25052946 - 3 Mar 2024

Viewed by 1480

Abstract

Neuroblastoma (NB) is one of the highly vascularized childhood solid tumors, and understanding the molecular mechanisms underlying angiogenesis in NB is crucial for developing effective therapeutic strategies. B-cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression, but its role in angiogenesis [...] Read more.

Neuroblastoma (NB) is one of the highly vascularized childhood solid tumors, and understanding the molecular mechanisms underlying angiogenesis in NB is crucial for developing effective therapeutic strategies. B-cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression, but its role in angiogenesis remains unexplored. This study investigated BAP31 modulation of pro-angiogenic factors in SH-SY5Y NB cells. Through protein overexpression, knockdown, antibody blocking, and quantification experiments, we demonstrated that overexpression of BAP31 led to increased levels of vascular endothelial growth factor A (VEGFA) and Galectin-3 (GAL-3), which are known to promote angiogenesis. Conditioned medium derived from BAP31-overexpressing neuroblastoma cells stimulated migration and tube formation in endothelial cells, indicating its pro-angiogenic properties. Also, we demonstrated that BAP31 enhances capillary tube formation by regulating hypoxia-inducible factor 1 alpha (HIF-1α) and its downstream target, GAL-3. Furthermore, GAL-3 downstream proteins, Jagged 1 and VEGF receptor 2 (VEGFR2), were up-regulated, and blocking GAL-3 partially inhibited the BAP31-induced tube formation. These findings suggest that BAP31 promotes angiogenesis in NB by modulating GAL-3 and VEGF signaling, thereby shaping the tumor microenvironment. This study provides novel insights into the pro-angiogenic role of BAP31 in NB. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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18 pages, 3163 KiB

Open AccessArticle

The Link between Autosomal Dominant Polycystic Kidney Disease and Chromosomal Instability: Exploring the Relationship

by Phang-Lang Chen, Chi-Fen Chen, Hugo Y.-H. Lin, Daniel J. Riley and Yumay Chen

Int. J. Mol. Sci. 2024, 25(5), 2936; https://doi.org/10.3390/ijms25052936 - 2 Mar 2024

Cited by 1 | Viewed by 1750

Abstract

In autosomal dominant polycystic kidney disease (ADPKD) with germline mutations in a PKD1 or PKD2 gene, innumerable cysts develop from tubules, and renal function deteriorates. Second-hit somatic mutations and renal tubular epithelial (RTE) cell death are crucial features of cyst initiation and disease [...] Read more.

In autosomal dominant polycystic kidney disease (ADPKD) with germline mutations in a PKD1 or PKD2 gene, innumerable cysts develop from tubules, and renal function deteriorates. Second-hit somatic mutations and renal tubular epithelial (RTE) cell death are crucial features of cyst initiation and disease progression. Here, we use established RTE lines and primary ADPKD cells with disease-associated PKD1 mutations to investigate genomic instability and DNA damage responses. We found that ADPKD cells suffer severe chromosome breakage, aneuploidy, heightened susceptibility to DNA damage, and delayed checkpoint activation. Immunohistochemical analyses of human kidneys corroborated observations in cultured cells. DNA damage sensors (ATM/ATR) were activated but did not localize at nuclear sites of damaged DNA and did not properly activate downstream transducers (CHK1/CHK2). ADPKD cells also had the ability to transform, as they achieved high saturation density and formed colonies in soft agar. Our studies indicate that defective DNA damage repair pathways and the somatic mutagenesis they cause contribute fundamentally to the pathogenesis of ADPKD. Acquired mutations may alternatively confer proliferative advantages to the clonally expanded cell populations or lead to apoptosis. Further understanding of the molecular details of aberrant DNA damage responses in ADPKD is ongoing and holds promise for targeted therapies. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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16 pages, 2352 KiB

Open AccessArticle

The Prognostic Significance of Selected HLA Alleles on Prostate Cancer Outcome

by Savvas Stokidis, Constantin N. Baxevanis and Sotirios P. Fortis

Int. J. Mol. Sci. 2023, 24(19), 14454; https://doi.org/10.3390/ijms241914454 - 22 Sep 2023

Viewed by 1136

Abstract

Recently, we have shown that HLA-A*02:01 and HLA-A*24:02 in de novo metastatic prostate cancer (MPCa) have an important role in disease progression. Since de novo MPCa represents a small group among patients diagnosed with prostate cancer (PCa), it was obvious to try to [...] Read more.

Recently, we have shown that HLA-A*02:01 and HLA-A*24:02 in de novo metastatic prostate cancer (MPCa) have an important role in disease progression. Since de novo MPCa represents a small group among patients diagnosed with prostate cancer (PCa), it was obvious to try to extend the validity of our results to larger cohorts of PCa patients. Herein, we analyzed patients irrespective of their disease status at diagnosis to include, besides patients with MPCa, those with localized PCa (LPCa). Our goal was to specify the prognostic value of HLA-A*02:01 and HLA-A*24:02 for overall survival (OS) prospectively and for early biochemical recurrence (BCR) and castrate resistance (CR) as additional clinical endpoints in a prospective/retrospective manner, to improve clinical decisions for patients covering all stages of PCa. On univariate analysis, HLA-A alleles were significantly associated as prognostic biomarkers with early BCR (p = 0.028; HR = 1.822), OS (p = 0.013; HR = 1.547) and showed a trend for CR (p = 0.150; HR = 1.239). On multivariate analysis, HLA-A alleles proved to be independent prognosticators for early BCR (p = 0.017; HR = 2.008), CR (p = 0.005; HR = 1.615), and OS (p = 0.002; HR = 2.063). Kaplan–Meier analyses revealed that patients belonging to the HLA-A*02:01⁺HLA-A*24:02⁻ group progressed much faster to BCR and CR and had also shorter OS compared to HLA-A*24:02⁺ patients. Patients being HLA-A*02:01⁻HLA-A*24:02⁻ exhibited varying clinical outcomes, pointing to the presence of additional HLA-A alleles with potential prognostic value. Our data underline the HLA-A alleles as valuable prognostic biomarkers for PCa that may assist with the appropriate treatment and follow-up schedule based on the risk for disease progression to avoid over-diagnosis and over-treatment. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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15 pages, 3464 KiB

Open AccessArticle

Scopoletin Reactivates Latent HIV-1 by Inducing NF-κB Expression without Global T Cell Activation

by Yuqi Zhu, Zhengtao Jiang, Lin Liu, Xinyi Yang, Min Li, Yipeng Cheng, Jianqing Xu, Chunhua Yin and Huanzhang Zhu

Int. J. Mol. Sci. 2023, 24(16), 12649; https://doi.org/10.3390/ijms241612649 - 10 Aug 2023

Cited by 2 | Viewed by 1374

Abstract

Reversing HIV-1 latency promotes the killing of infected cells and is essential for cure strategies. However, current latency-reversing agents (LRAs) are not entirely effective and safe in activating latent viruses in patients. In this study, we investigated whether Scopoletin (6-Methoxy-7-hydroxycoumarin), an important coumarin [...] Read more.

Reversing HIV-1 latency promotes the killing of infected cells and is essential for cure strategies. However, current latency-reversing agents (LRAs) are not entirely effective and safe in activating latent viruses in patients. In this study, we investigated whether Scopoletin (6-Methoxy-7-hydroxycoumarin), an important coumarin phytoalexin found in plants with multiple pharmacological activities, can reactivate HIV-1 latency and elucidated its underlying mechanism. Using the Jurkat T cell model of HIV-1 latency, we found that Scopoletin can reactivate latent HIV-1 replication with a similar potency to Prostratin and did so in a dose- and time-dependent manner. Moreover, we provide evidence indicating that Scopoletin-induced HIV-1 reactivation involves the nuclear factor kappa B (NF-κB) signaling pathway. Importantly, Scopoletin did not have a stimulatory effect on T lymphocyte receptors or HIV-1 receptors. In conclusion, our study suggests that Scopoletin has the potential to reactivate latent HIV-1 without causing global T-cell activation, making it a promising treatment option for anti-HIV-1 latency strategies. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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18 pages, 1839 KiB

Open AccessArticle

In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer

by Ana Alfano, Eduardo G. A. Cafferata, Mariela Gangemi, Alejandro Nicola Candia, Cristian M. Malnero, Ismael Bermudez, Mauricio Vargas Lopez, Gregorio David Ríos, Cecilia Rotondaro, Nicasio Cuneo, David T. Curiel, Osvaldo L. Podhajcer and Maria Veronica Lopez

Int. J. Mol. Sci. 2023, 24(12), 9992; https://doi.org/10.3390/ijms24129992 - 10 Jun 2023

Cited by 1 | Viewed by 2311

Abstract

More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such [...] Read more.

More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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25 pages, 4511 KiB

Open AccessArticle

Preconditioned Chorionic Villus Mesenchymal Stem/Stromal Cells (CVMSCs) Minimize the Invasive Phenotypes of Breast Cancer Cell Line MDA231 In Vitro

by Abdullah Al Subayyil, Yasser S. Basmaeil, Hayaa Bin Kulayb, Maha Alrodayyan, Lama Abdulaziz A. Alhaber, Taghreed N. Almanaa and Tanvir Khatlani

Int. J. Mol. Sci. 2023, 24(11), 9569; https://doi.org/10.3390/ijms24119569 - 31 May 2023

Cited by 2 | Viewed by 1872

Abstract

Among the newer choices of targeted therapies against cancer, stem cell therapy is gaining importance because of their antitumor properties. Stem cells suppress growth, metastasis, and angiogenesis, and induce apoptosis in cancer cells. In this study, we have examined the impact of the [...] Read more.

Among the newer choices of targeted therapies against cancer, stem cell therapy is gaining importance because of their antitumor properties. Stem cells suppress growth, metastasis, and angiogenesis, and induce apoptosis in cancer cells. In this study, we have examined the impact of the cellular component and the secretome of preconditioned and naïve placenta-derived Chorionic Villus Mesenchymal Stem Cells (CVMSCs) on the functional characteristics of the Human Breast Cancer cell line MDA231. MDA231 cells were treated with preconditioned CVMSCs and their conditioned media (CM), followed by an evaluation of their functional activities and modulation in gene and protein expression. Human Mammary Epithelial Cells (HMECs) were used as a control. CM obtained from the preconditioned CVMSCs significantly altered the proliferation of MDA231 cells, yet no change in other phenotypes, such as adhesion, migration, and invasion, were observed at various concentrations and time points tested. However, the cellular component of preconditioned CVMSCs significantly inhibited several phenotypes of MDA231 cells, including proliferation, migration, and invasion. CVMSCs-treated MDA231 cells exhibited modulation in the expression of various genes involved in apoptosis, oncogenesis, and Epithelial to Mesenchymal Transition (EMT), explaining the changes in the invasive behavior of MDA231 cells. These studies reveal that preconditioned CVMSCs may make useful candidate in a stem cell-based therapy against cancer. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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17 pages, 3279 KiB

Open AccessArticle

Neuropilin-1 Knockout and Rescue Confirms Its Role to Promote Metastasis in MDA-MB-231 Breast Cancer Cells

by Noura Al-Zeheimi, Yan Gao, Peter A. Greer and Sirin A. Adham

Int. J. Mol. Sci. 2023, 24(9), 7792; https://doi.org/10.3390/ijms24097792 - 25 Apr 2023

Cited by 6 | Viewed by 2851

Abstract

Breast cancer (BC) metastasis remains a leading cause of female mortality. Neuropilin-1 (NRP-1) is a glycoprotein receptor that plays ligand-dependent roles in BC. Clinical studies indicate its correlation with metastatic disease; however, its functional role in BC metastasis remains uncertain. CRISPR-Cas9 was used [...] Read more.

Breast cancer (BC) metastasis remains a leading cause of female mortality. Neuropilin-1 (NRP-1) is a glycoprotein receptor that plays ligand-dependent roles in BC. Clinical studies indicate its correlation with metastatic disease; however, its functional role in BC metastasis remains uncertain. CRISPR-Cas9 was used to knockout the NRP-1 gene in MDA-MB-231 BC cells, and the effects on metastasis were determined using an orthotopic mouse engraftment model. NRP-1 expression in knockout cells was rescued using a recombinant cDNA with a silent mutation in the sgRNA target-adjacent PAM sequence. Differentially expressed genes between NRP-1 knockout and control cells were determined using whole-transcriptome sequencing and validated using real-time PCR. NRP-1KO cells showed a pronounced reduction in the metastasis to the lungs. KEGG pathway analysis of the transcriptome data revealed that PI3K and ECM receptor interactions were among the top altered pathways in the NRP-1KO cells. In addition, reduction in metastasis enhancers proteins, Integrin-β3 and Tenascin-C, and genes CCL20 and FN1 and upregulation of metastasis suppressor genes, ACVRL and GPX3 in NRP-1KO were detected. These findings provide evidence for a functional role for NRP-1 in BC metastasis, supporting further exploration of NRP-1 and the identified genes as targets in treating metastatic BC. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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9 pages, 868 KiB

Open AccessCommunication

Frequencies of an Immunogenic HER-2/neu Epitope of CD8+ T Lymphocytes Predict Favorable Clinical Outcomes in Prostate Cancer

by Maria Goulielmaki, Savvas Stokidis, Theodoros Anagnostou, Ioannis F. Voutsas, Angelos D. Gritzapis, Constantin N. Baxevanis and Sotirios P. Fortis

Int. J. Mol. Sci. 2023, 24(6), 5954; https://doi.org/10.3390/ijms24065954 - 22 Mar 2023

Cited by 3 | Viewed by 1807

Abstract

HER-2/neu is the human epidermal growth factor receptor 2, which is associated with the progression of prostate cancer (PCa). HER-2/neu-specific T cell immunity has been shown to predict immunologic and clinical responses in PCa patients treated with HER-2/neu peptide [...] Read more.

HER-2/neu is the human epidermal growth factor receptor 2, which is associated with the progression of prostate cancer (PCa). HER-2/neu-specific T cell immunity has been shown to predict immunologic and clinical responses in PCa patients treated with HER-2/neu peptide vaccines. However, its prognostic role in PCa patients receiving conventional treatment is unknown, and this was addressed in this study. The densities of CD8+ T cells specific for the HER-2/neu_(780–788) peptide in the peripheral blood of PCa patients under standard treatments were correlated with TGF-β/IL-8 levels and clinical outcomes. We demonstrated that PCa patients with high frequencies of HER-2/neu_(780–788)-specific CD8+ T lymphocytes had better progression-free survival (PFS) as compared with PCa patients with low frequencies. Increased frequencies of HER-2/neu_(780–788)-specific CD8+ T lymphocytes were also associated with lower levels of TGF-β and IL-8. Our data provide the first evidence of the predictive role of HER-2/neu-specific T cell immunity in PCa. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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16 pages, 5590 KiB

Open AccessArticle

Chemokine Receptors CCR6 and PD1 Blocking scFv E27 Enhances Anti-EGFR CAR-T Therapeutic Efficacy in a Preclinical Model of Human Non-Small Cell Lung Carcinoma

by Jing Wang, Yanan Wang, Hanyu Pan, Lin Zhao, Xinyi Yang, Zhiming Liang, Xiaoting Shen, Jing Zhang, Jinlong Yang, Yuqi Zhu, Jingna Xun, Yue Liang, Qinru Lin, Huitong Liang, Min Li and Huanzhang Zhu

Int. J. Mol. Sci. 2023, 24(6), 5424; https://doi.org/10.3390/ijms24065424 - 12 Mar 2023

Cited by 5 | Viewed by 2741

Abstract

Chimeric antigen receptor (CAR)-T cells, a therapeutic agent for solid tumors, are not completely effective due to a lack of infiltration of T cells into the tumor site and immunity caused by Programmed Death Receptor 1(PD1). Here, an epidermal growth factor receptor (EGFR) [...] Read more.

Chimeric antigen receptor (CAR)-T cells, a therapeutic agent for solid tumors, are not completely effective due to a lack of infiltration of T cells into the tumor site and immunity caused by Programmed Death Receptor 1(PD1). Here, an epidermal growth factor receptor (EGFR) CAR-T cell was engineered to express the chemokine receptor CCR6 and secrete PD1 blocking Single-chain antibody fragment (scFv) E27 to enhance their anti-tumor effects. The findings showed that CCR6 enhanced the migration of EGFR CAR-E27-CCR6 T cells in vitro by the Transwell migration assay. When incubated with tumor cells, EGFR CAR-E27-CCR6 T cells specifically exerted potent cytotoxicity and produced high levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), and interferon-γ (IFN-γ). A non-small cell lung carcinoma (NSCLC) cell line-derived xenograft model was constructed by implanting modified A549 cell lines into immunodeficient NOD.Prkdc^scidIl2rg^em1/Smoc (NSG) mice. In comparison with traditional EGFR CAR-T cells, live imaging indicated that EGFR CAR-E27-CCR6 T cells displayed superior anti-tumor function. In addition, the histopathological examination of mouse organs showed no obvious organic damage. Our findings confirmed that PD1 blocking and CCR6 can enhance the anti-tumor function of EGFR CAR-T cells in an NSCLC xenograft model, providing an effective treatment strategy to improve the efficacy of CAR-T in NSCLC. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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Review

Jump to: Research, Other

14 pages, 1093 KiB

Open AccessReview

Infant Acute Lymphoblastic Leukemia—New Therapeutic Opportunities

by Marika Kulczycka, Kamila Derlatka, Justyna Tasior, Maja Sygacz, Monika Lejman and Joanna Zawitkowska

Int. J. Mol. Sci. 2024, 25(7), 3721; https://doi.org/10.3390/ijms25073721 - 27 Mar 2024

Viewed by 2058

Abstract

Infant acute lymphoblastic leukemia (Infant ALL) is a kind of pediatric ALL, diagnosed in children under 1 year of age and accounts for less than 5% of pediatric ALL. In the infant ALL group, two subtypes can be distinguished: KMT2A-rearranged ALL, known [...] Read more.

Infant acute lymphoblastic leukemia (Infant ALL) is a kind of pediatric ALL, diagnosed in children under 1 year of age and accounts for less than 5% of pediatric ALL. In the infant ALL group, two subtypes can be distinguished: KMT2A-rearranged ALL, known as a more difficult to cure form and KMT2A- non-rearranged ALL with better survival outcomes. As infants with ALL have lesser treatment outcomes compared to older children, it is pivotal to provide novel treatment approaches. Progress in the development of molecularly targeted therapies and immunotherapy presents exciting opportunities for potential improvement. This comprehensive review synthesizes the current literature on the epidemiology, clinical presentation, molecular genetics, and therapeutic approaches specific to ALL in the infant population. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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14 pages, 1331 KiB

Open AccessReview

Exploring Tumor–Immune Interactions in Co-Culture Models of T Cells and Tumor Organoids Derived from Patients

by So-Ra Jeong and Minyong Kang

Int. J. Mol. Sci. 2023, 24(19), 14609; https://doi.org/10.3390/ijms241914609 - 27 Sep 2023

Cited by 10 | Viewed by 8334

Abstract

The use of patient-derived tumor tissues and cells has led to significant advances in personalized cancer therapy and precision medicine. The advent of genomic sequencing technologies has enabled the comprehensive analysis of tumor characteristics. The three-dimensional tumor organoids derived from self-organizing cancer stem [...] Read more.

The use of patient-derived tumor tissues and cells has led to significant advances in personalized cancer therapy and precision medicine. The advent of genomic sequencing technologies has enabled the comprehensive analysis of tumor characteristics. The three-dimensional tumor organoids derived from self-organizing cancer stem cells are valuable ex vivo models that faithfully replicate the structure, unique features, and genetic characteristics of tumors. These tumor organoids have emerged as innovative tools that are extensively employed in drug testing, genome editing, and transplantation to guide personalized therapy in clinical settings. However, a major limitation of this emerging technology is the absence of a tumor microenvironment that includes immune and stromal cells. The therapeutic efficacy of immune checkpoint inhibitors has underscored the importance of immune cells, particularly cytotoxic T cells that infiltrate the vicinity of tumors, in patient prognosis. To address this limitation, co-culture techniques combining tumor organoids and T cells have been developed, offering diverse avenues for studying individualized drug responsiveness. By integrating cellular components of the tumor microenvironment, including T cells, into tumor organoid cultures, immuno-oncology has embraced this technology, which is rapidly advancing. Recent progress in co-culture models of tumor organoids has allowed for a better understanding of the advantages and limitations of this novel model, thereby exploring its full potential. This review focuses on the current applications of organoid-T cell co-culture models in cancer research and highlights the remaining challenges that need to be addressed for its broader implementation in anti-cancer therapy. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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18 pages, 1974 KiB

Open AccessReview

The Dilemma of HSV-1 Oncolytic Virus Delivery: The Method Choice and Hurdles

by Guijin Tang, Dawei Wang, Xiangqian Zhao, Zhihua Feng, Qi Chen and Yangkun Shen

Int. J. Mol. Sci. 2023, 24(4), 3681; https://doi.org/10.3390/ijms24043681 - 12 Feb 2023

Cited by 13 | Viewed by 4185

Abstract

Oncolytic viruses (OVs) have emerged as effective gene therapy and immunotherapy drugs. As an important gene delivery platform, the integration of exogenous genes into OVs has become a novel path for the advancement of OV therapy, while the herpes simplex virus type 1 [...] Read more.

Oncolytic viruses (OVs) have emerged as effective gene therapy and immunotherapy drugs. As an important gene delivery platform, the integration of exogenous genes into OVs has become a novel path for the advancement of OV therapy, while the herpes simplex virus type 1 (HSV-1) is the most commonly used. However, the current mode of administration of HSV-1 oncolytic virus is mainly based on the tumor in situ injection, which limits the application of such OV drugs to a certain extent. Intravenous administration offers a solution to the systemic distribution of OV drugs but is ambiguous in terms of efficacy and safety. The main reason is the synergistic role of innate and adaptive immunity of the immune system in the response against the HSV-1 oncolytic virus, which is rapidly cleared by the body’s immune system before it reaches the tumor, a process that is accompanied by side effects. This article reviews different administration methods of HSV-1 oncolytic virus in the process of tumor treatment, especially the research progress in intravenous administration. It also discusses immune constraints and solutions of intravenous administration with the intent to provide new insights into HSV-1 delivery for OV therapy. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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12 pages, 966 KiB

Open AccessReview

CD96 as a Potential Immune Regulator in Cancers

by Shikai Feng, Orkhan Isayev, Jens Werner and Alexandr V. Bazhin

Int. J. Mol. Sci. 2023, 24(2), 1303; https://doi.org/10.3390/ijms24021303 - 9 Jan 2023

Cited by 10 | Viewed by 3501

Abstract

The discovery of CTLA-4 and PD-1 checkpoints has prompted scientific researchers and the pharmaceutical industry to develop and conduct extensive research on tumor-specific inhibitors. As a result, the list of potential immune checkpoint molecules is growing over time. Receptors for nectin and nectin-like [...] Read more.

The discovery of CTLA-4 and PD-1 checkpoints has prompted scientific researchers and the pharmaceutical industry to develop and conduct extensive research on tumor-specific inhibitors. As a result, the list of potential immune checkpoint molecules is growing over time. Receptors for nectin and nectin-like proteins have recently emerged as promising targets for cancer immunotherapy. Potential immune checkpoints, including CD226, TIGIT, and CD96, belong to this receptor class. Among them, CD96 has received little attention. In this mini-review, we aim to discuss the basic biology of CD96 as well as the most recent relevant research on this as a promising candidate for cancer immunotherapy. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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Other

Jump to: Research, Review

12 pages, 1611 KiB

Open AccessCase Report

Comprehensive Genetic Study of Malignant Cervical Paraganglioma

by Anastasiya Snezhkina, Vladislav Pavlov, Maria Fedorova, Dmitry Kalinin, Elena Pudova, Anastasiya Kobelyatskaya, Ildar Bakhtogarimov, George Krasnov and Anna Kudryavtseva

Int. J. Mol. Sci. 2023, 24(9), 8220; https://doi.org/10.3390/ijms24098220 - 4 May 2023

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Abstract

Malignant middle ear paraganglioma (MEPGL) is an exceedingly rare tumor of the neuroendocrine system. In general, MEPGLs represent as slow growing and hypervascularized benign neoplasms. The genetic basis of MEPGL tumorigenesis has been poorly investigated. We report a case of malignant MEPGL accompanied [...] Read more.

Malignant middle ear paraganglioma (MEPGL) is an exceedingly rare tumor of the neuroendocrine system. In general, MEPGLs represent as slow growing and hypervascularized benign neoplasms. The genetic basis of MEPGL tumorigenesis has been poorly investigated. We report a case of malignant MEPGL accompanied by the comprehensive genetic analysis of the primary tumor and metastasis. Based on whole-exome sequencing data, the germline pathogenic mutation p.R230H in the SDHB gene, encoding for subunit B of mitochondrial complex II, was found in a patient. Analysis of somatic mutation spectra revealed five novel variants in different genes, including a potentially deleterious variant in UNC13C that was common for the tumor and metastasis. Identified somatic variants clustered into SBS1 and SBS5 mutational signatures. Of note, the primary tumor was characterized by Ki-67 4% and had an elevated mutational load (1.4/Mb); the metastasis’ mutational load was about 4.5 times higher (6.4/Mb). In addition, we revealed somatic loss of the wild-type SDHB allele, as well as loss of heterozygosity (LOH) at the 11p locus. Thus, germline mutation in SDHB combined with somatic LOH seem to be drivers that lead to the tumor’s initiation and progression. Other somatic changes identified can be additional disease-causing factors. Obtained results expand our understanding of molecular genetic mechanisms associated with the development of this rare tumor. Full article

(This article belongs to the Special Issue Research Progress in Molecular and Cellular Therapy of Cancer)

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