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17 pages, 7181 KiB

Open AccessArticle

Immunohistochemical Expression Levels of Epidermal Growth Factor Receptor, Cyclooxygenase-2, and Ki-67 in Canine Cutaneous Squamous Cell Carcinomas

by João Miguel Luís, Rita Files, Cláudia Cardoso, José Pimenta, Gabriela Maia, Filipe Silva, Felisbina L. Queiroga, Justina Prada and Isabel Pires

Curr. Issues Mol. Biol. 2024, 46(5), 4951-4967; https://doi.org/10.3390/cimb46050297 - 19 May 2024

Viewed by 1250

Abstract

Squamous cell carcinoma (SCC) stands as the second most prevalent skin cancer in dogs, primarily attributed to UV radiation exposure. Affected areas typically include regions with sparse hair and pale or depigmented skin. The significance of spontaneous canine cutaneous SCC as a model [...] Read more.

Squamous cell carcinoma (SCC) stands as the second most prevalent skin cancer in dogs, primarily attributed to UV radiation exposure. Affected areas typically include regions with sparse hair and pale or depigmented skin. The significance of spontaneous canine cutaneous SCC as a model for its human counterpart is underscored by its resemblance. This study assesses the expression of key markers—Epidermal Growth Factor Receptor (EGFR), Cyclooxygenase-2 (Cox-2), and Ki-67—in canine cutaneous SCC. Our objective is to investigate the association between their expression levels and classical clinicopathological parameters, unraveling the intricate relationships among these molecular markers. In our retrospective analysis of 37 cases, EGFR overexpression manifested in 43.2% of cases, while Cox-2 exhibited overexpression in 97.3%. The EGFR, Cox-2 overexpression, and Ki-67 proliferation indices, estimated through immunohistochemistry, displayed a significant association with the histological grade, but only EGFR labeling is associated with the presence of lymphovascular emboli. The Ki-67 labeling index expression exhibited an association with EGFR and Cox-2. These findings propose that EGFR, Cox-2, and Ki-67 hold promise as valuable markers in canine SCC. EGFR, Cox-2, and Ki-67 may serve as indicators of disease progression, offering insights into the malignancy of a lesion. The implications extend to the potential therapeutic targeting of EGFR and Cox-2 in managing canine SCC. Further exploration of these insights is warranted due to their translational relevance and the development of targeted interventions in the context of canine SCC. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)

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14 pages, 5768 KiB

Open AccessArticle

Arsenic Trioxide Decreases Lymphangiogenesis by Inducing Apoptotic Pathways and Inhibition of Important Endothelial Cell Receptors

by Igor Hrgovic, Eva Zöller, Monika Doll, Tsige Hailemariam-Jahn, Thilo Jakob, Roland Kaufmann, Markus Meissner and Johannes Kleemann

Curr. Issues Mol. Biol. 2024, 46(1), 67-80; https://doi.org/10.3390/cimb46010006 - 21 Dec 2023

Cited by 3 | Viewed by 1396

Abstract

Tumor-induced lymphangiogenesis is strongly associated with the formation of tumor metastasis. Therefore, the regulation of lymphangiogenesis offers a promising target in cancer therapy. Arsenic trioxide (ATO) is highly effective in the treatment of patients with acute promyelocytic leukemia (APL). As ATO mediates anti-angiogenic [...] Read more.

Tumor-induced lymphangiogenesis is strongly associated with the formation of tumor metastasis. Therefore, the regulation of lymphangiogenesis offers a promising target in cancer therapy. Arsenic trioxide (ATO) is highly effective in the treatment of patients with acute promyelocytic leukemia (APL). As ATO mediates anti-angiogenic effects on endothelial and tumor cells, we aimed to explore the impact of ATO on lymphangiogenesis in human lymphatic endothelial cells (LEC). The BrdU assay and flow cytometry analysis were used to evaluate the influence of ATO on the proliferation and cell cycle distribution of LECs. The lymphatic suppression effects of ATO were investigated in vitro using the lymphatic tube formation assay. The effects of ATO on apoptosis, mitochondrial membrane potential and endothelial cell receptors were investigated by Western blotting, ELISA, flow cytometry and qRT-PCR. The treatment of LECs with ATO attenuated cell proliferation, blocked tube formation and induced subG0/G1 arrest in LECs, thus suggesting enhanced apoptosis. Although subG0/G1 arrest was accompanied by the upregulation of p21 and p53, ATO treatment did not lead to visible cell cycle arrest in LECs. In addition, ATO caused apoptosis via the release of cytochrome c from mitochondria, activating caspases 3, 8 and 9; downregulating the anti-apoptotic proteins survivin, XIAP and cIAP-2; and upregulating the pro-apoptotic protein Fas. Furthermore, we observed that ATO inhibited the VEGF-induced proliferation of LECs, indicating that pro-survival VEGF/VEGFR signaling was affected by ATO treatment. Finally, we found that ATO inhibited the expression of the important endothelial cell receptors VEGFR-2, VEGFR-3, Tie-2 and Lyve-1. In conclusion, we demonstrate that ATO inhibits lymphangiogenesis by activating apoptotic pathways and inhibiting important endothelial cell receptors, which suggests that this drug should be further evaluated in the treatment of tumor-associated lymphangiogenesis. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)

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14 pages, 4471 KiB

Open AccessArticle

SUMO-Activating Enzyme Subunit 1 Is Associated with Poor Prognosis, Tumor Progression, and Radio-Resistance in Colorectal Cancer

by Yueh-Jung Wu, Siang-Ting Huang, Ya-Hui Chang, Shih-Yi Lin, Weng-Ling Lin, Ying-Jung Chen and Shang-Tao Chien

Curr. Issues Mol. Biol. 2023, 45(10), 8013-8026; https://doi.org/10.3390/cimb45100506 - 30 Sep 2023

Cited by 2 | Viewed by 1603

Abstract

Concurrent chemoradiotherapy is an effective treatment option for patients with low-grade colorectal cancer (CRC) in the local disease stage. At present, the principle of the Taiwan Medical Center is to treat CRC patients with combination radiotherapy and chemotherapy (high-dose 5-FU) for a period [...] Read more.

Concurrent chemoradiotherapy is an effective treatment option for patients with low-grade colorectal cancer (CRC) in the local disease stage. At present, the principle of the Taiwan Medical Center is to treat CRC patients with combination radiotherapy and chemotherapy (high-dose 5-FU) for a period of about five weeks prior to surgery. Radical resection of the tumor is performed at least six to eight weeks after concurrent chemoradiotherapy (CCRT). However, this approach fails to produce the desired therapeutic effect in approximately 20% to 30% of patients, and such patients are unnecessarily exposed to the risks of radiation and drug toxicity posed by this therapy. Therefore, it is crucial to explore new biomarkers to predict the prognosis of CRC. SUMO-activating enzyme subunit 1 (SAE1) plays an important role in SUMOylation, a post-translational modification involved in cellular functions, such as cell proliferation, cell cycle, and apoptosis. In our study, to explore the clinical–pathological role of SAE1 protein in CRC, we evaluated the clinical data and paraffin sections from CRC patients. The expression of SAE1 was evaluated using immunohistochemical analysis, and clinical parameters were analyzed using chi-square and Kaplan–Meier survival tests. The results of in vitro proliferation and radiosensitive assays were compared between control groups and SAE1 siRNA groups. Western blotting was also used to detect the expressions of the SAE1, PARP, cyclin D1, p-NF-κB, and NF-κB proteins. Flow cytometry and colony formation assays were used to detect the effect of SAE-1 on radiosensitivity. In vivo, we detected the growth curve in a mouse xenograft model. The results showed that SAE-1 was revealed to be an independent prognostic biomarker of CRC. SAE1 knockdown inhibited CRC proliferation in vitro and in vivo, and led to the cleavage of PARP, downregulation of cyclin D1 protein expression, and downregulation of p-NF-κB/NF-κB. Additionally, SAE1 knockdown promoted radiosensitivity in CRC cells. Therefore, it was inferred that SAE1 may be used as a potential therapeutic target in CRC treatment. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)

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15 pages, 4692 KiB

Open AccessArticle

Defucosylated Monoclonal Antibody (H₂Mab-139-mG_2a-f) Exerted Antitumor Activities in Mouse Xenograft Models of Breast Cancers against Human Epidermal Growth Factor Receptor 2

by Hiroyuki Suzuki, Tomokazu Ohishi, Ren Nanamiya, Manabu Kawada, Mika K. Kaneko and Yukinari Kato

Curr. Issues Mol. Biol. 2023, 45(10), 7734-7748; https://doi.org/10.3390/cimb45100488 - 23 Sep 2023

Cited by 1 | Viewed by 1233

Abstract

The clinically approved human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibodies (mAbs), trastuzumab, and pertuzumab, target domains IV and II, respectively. Trastuzumab is now the standard treatment for HER2-overexpressed breast and gastric cancers, and trastuzumab in combination with pertuzumab showed clinical benefit. [...] Read more.

The clinically approved human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibodies (mAbs), trastuzumab, and pertuzumab, target domains IV and II, respectively. Trastuzumab is now the standard treatment for HER2-overexpressed breast and gastric cancers, and trastuzumab in combination with pertuzumab showed clinical benefit. However, there still exist patients who do not respond to the therapy. Furthermore, HER2 mutants that cannot be recognized by pertuzumab were found in tumors. Therefore, novel anti-HER2 mAbs and modalities have been desired. In our previous study, we developed a novel anti-HER2 domain I mAb, H₂Mab-139 (mouse IgG₁, kappa). We herein produced a defucosylated mouse IgG_2a type of mAb against HER2 (H₂Mab-139-mG_2a-f) to enhance antibody-dependent cellular cytotoxicity (ADCC)-mediated antitumor activity. H₂Mab-139-mG_2a-f exhibits a high binding affinity in flow cytometry with the dissociation constant (K_D) determined to be 3.9 × 10⁻⁹ M and 7.7 × 10⁻⁹ M against HER2-overexpressed Chinese hamster ovary (CHO)-K1 (CHO/HER2) and HER2-positive BT-474 cells, respectively. Moreover, we showed that H₂Mab-139-mG_2a-f exerted ADCC and complement-dependent cytotoxicity against CHO/HER2 and BT-474 in vitro and exhibited potent antitumor activities in mouse xenograft models. These results indicated that H₂Mab-139-mG_2a-f exerts antitumor effects against HER2-positive human breast cancers and is useful as an antibody treatment for HER2-positive human cancers. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)

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Review

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18 pages, 1288 KiB

Open AccessReview

Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer

by Dimitrios Stefanoudakis, Maximos Frountzas, Dimitrios Schizas, Nikolaos V. Michalopoulos, Alexandra Drakaki and Konstantinos G. Toutouzas

Curr. Issues Mol. Biol. 2024, 46(4), 2827-2844; https://doi.org/10.3390/cimb46040177 - 23 Mar 2024

Cited by 8 | Viewed by 4325

Abstract

The present review demonstrates the major tumor suppressor genes, including TP53, CDKN2A and SMAD4, associated with pancreatic cancer. Each gene’s role, prevalence and impact on tumor development and progression are analyzed, focusing on the intricate molecular landscape of pancreatic cancer. In addition, this [...] Read more.

The present review demonstrates the major tumor suppressor genes, including TP53, CDKN2A and SMAD4, associated with pancreatic cancer. Each gene’s role, prevalence and impact on tumor development and progression are analyzed, focusing on the intricate molecular landscape of pancreatic cancer. In addition, this review underscores the prognostic significance of specific mutations, such as loss of TP53, and explores some potential targeted therapies tailored to these molecular signatures. The findings highlight the importance of genomic analyses for risk assessment, early detection and the design of personalized treatment approaches in pancreatic cancer. Overall, this review provides a comprehensive analysis of the molecular intricacies of pancreatic tumors, paving the way for more effective and tailored therapeutic interventions. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)

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14 pages, 568 KiB

Open AccessReview

Anti-Tumor Potential of Post-Translational Modifications of PD-1

by Xiaoming Xi and Wuli Zhao

Curr. Issues Mol. Biol. 2024, 46(3), 2119-2132; https://doi.org/10.3390/cimb46030136 - 6 Mar 2024

Cited by 2 | Viewed by 1887

Abstract

Programmed cell death protein-1 (PD-1) is a vital immune checkpoint molecule. The location, stability, and protein–protein interaction of PD-1 are significantly influenced by post-translational modification (PTM) of proteins. The biological information of PD-1, including its gene and protein structures and the PD-1/PD-L1 signaling [...] Read more.

Programmed cell death protein-1 (PD-1) is a vital immune checkpoint molecule. The location, stability, and protein–protein interaction of PD-1 are significantly influenced by post-translational modification (PTM) of proteins. The biological information of PD-1, including its gene and protein structures and the PD-1/PD-L1 signaling pathway, was briefly reviewed in this review. Additionally, recent research on PD-1 post-translational modification, including the study of ubiquitination, glycosylation, phosphorylation, and palmitoylation, was summarized, and research strategies for PD-1 PTM drugs were concluded. At present, only a part of PD-1/PD-L1 treated patients (35–45%) are benefited from immunotherapies, and novel strategies targeting PTM of PD-1/PD-L1 may be important for anti-PD-1/PD-L1 non-responders (poor responders). Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)

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34 pages, 518 KiB

Open AccessReview

Recruiting In Vitro Transcribed mRNA against Cancer Immunotherapy: A Contemporary Appraisal of the Current Landscape

by Androulla N. Miliotou, Sofia K. Georgiou-Siafis, Charikleia Ntenti, Ioannis S. Pappas and Lefkothea C. Papadopoulou

Curr. Issues Mol. Biol. 2023, 45(11), 9181-9214; https://doi.org/10.3390/cimb45110576 - 16 Nov 2023

Cited by 2 | Viewed by 3618

Abstract

Over 100 innovative in vitro transcribed (IVT)-mRNAs are presently undergoing clinical trials, with a projected substantial impact on the pharmaceutical market in the near future. Τhe idea behind this is that after the successful cellular internalization of IVT-mRNAs, they are subsequently translated into [...] Read more.

Over 100 innovative in vitro transcribed (IVT)-mRNAs are presently undergoing clinical trials, with a projected substantial impact on the pharmaceutical market in the near future. Τhe idea behind this is that after the successful cellular internalization of IVT-mRNAs, they are subsequently translated into proteins with therapeutic or prophylactic relevance. Simultaneously, cancer immunotherapy employs diverse strategies to mobilize the immune system in the battle against cancer. Therefore, in this review, the fundamental principles of IVT-mRNA to its recruitment in cancer immunotherapy, are discussed and analyzed. More specifically, this review paper focuses on the development of mRNA vaccines, the exploitation of neoantigens, as well as Chimeric Antigen Receptor (CAR) T-Cells, showcasing their clinical applications and the ongoing trials for the development of next-generation immunotherapeutics. Furthermore, this study investigates the synergistic potential of combining the CAR immunotherapy and the IVT-mRNAs by introducing our research group novel, patented delivery method that utilizes the Protein Transduction Domain (PTD) technology to transduce the IVT-mRNAs encoding the CAR of interest into the Natural Killer (NK)-92 cells, highlighting the potential for enhancing the CAR NK cell potency, efficiency, and bioenergetics. While IVT-mRNA technology brings exciting progress to cancer immunotherapy, several challenges and limitations must be acknowledged, such as safety, toxicity, and delivery issues. This comprehensive exploration of IVT-mRNA technology, in line with its applications in cancer therapeutics, offers valuable insights into the opportunities and challenges in the evolving landscape of cancer immunotherapy, setting the stage for future advancements in the field. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)

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25 pages, 1861 KiB

Open AccessReview

An Overview of Systemic Targeted Therapy in Renal Cell Carcinoma, with a Focus on Metastatic Renal Cell Carcinoma and Brain Metastases

by Liliana Eleonora Semenescu, Amira Kamel, Vasile Ciubotaru, Silvia Mara Baez-Rodriguez, Mircea Furtos, Alexandra Costachi, Anica Dricu and Ligia Gabriela Tătăranu

Curr. Issues Mol. Biol. 2023, 45(9), 7680-7704; https://doi.org/10.3390/cimb45090485 - 21 Sep 2023

Cited by 6 | Viewed by 1956

Abstract

The most commonly diagnosed malignancy of the urinary system is represented by renal cell carcinoma. Various subvariants of RCC were described, with a clear-cell type prevailing in about 85% of all RCC tumors. Patients with metastases from renal cell carcinoma did not have [...] Read more.

The most commonly diagnosed malignancy of the urinary system is represented by renal cell carcinoma. Various subvariants of RCC were described, with a clear-cell type prevailing in about 85% of all RCC tumors. Patients with metastases from renal cell carcinoma did not have many effective therapies until the end of the 1980s, as long as hormonal therapy and chemotherapy were the only options available. The outcomes were unsatisfactory due to the poor effectiveness of the available therapeutic options, but then interferon-alpha and interleukin-2 showed treatment effectiveness, providing benefits but only for less than half of the patients. However, it was not until 2004 that targeted therapies emerged, prolonging the survival rate. Currently, new technologies and strategies are being developed to improve the actual efficacy of available treatments and their prognostic aspects. This article summarizes the mechanisms of action, importance, benefits, adverse events of special interest, and efficacy of immunotherapy in metastatic renal cell carcinoma, with a focus on brain metastases. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)

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