Cancer Cell International

Our medical research library holds 17 studies published in Cancer Cell International (2003–2025). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 17 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: BioMed Central
• Published: 2001 to the present, England
• Language: English
• ISSN: 1475-2867 (electronic)
• Its record in the NLM Catalog

2020s

• A novel mesothelioma molecular classification based on malignant cell differentiation. J. Liu, Y. Liu, Y. Lu, et al. 2025;25(1):235. PubMed · Publisher · Free full text

  Abstract

  Background: The high heterogeneity and multi-directional poor differentiation of tumor cells in mesothelioma (MESO) contributes to tumor growth and malignant biological behaviors. However, a molecular classification based on differentiated states of tumor cells remains void.

  Methods: We performed dimensionality reduction analysis on the single-cell RNA sequencing profiles available from the GEO database, to visualize the cell types in MESO. Multi-omics analysis was done to supplement the plausibility of classification. We also constructed regulatory networks to detect the function of important tumor cell differential genes (TCDGs) in the MESO.

  Results: Following twice dimensionality reduction analysis and clustering, eight malignant cell subtypes in the MESO were visualized. According to the expression of TCDGs, MESO was classified into three subtypes (Malignant differentiation-related MESO, Benign differentiation-related MESO, and Neutral differentiation-related MESO) with prognostic differences. The prediction model was built by 12 key TCDGs (ALDH2, HP, CASP1, RTP4, PDZK1IP1, TOP2A, LOXL2, CKS2, SPARC, TLCD3A, C6orf99, and SERPINH1) and validated with high accuracy. In the regulatory networks of MESO subtypes, RTP4, CASP1, MYO1B, SLC7A5, LOXL2, and GHR were labeled as key genes. A total of 14 potential inhibitors were predicted. Clinical specimens validated the reliability of the clinical subtyping of MESO patients.

  Conclusion: The novel molecular classification system and the prognostic prediction model might benefit the management of MESO patients.

  © 2025. The Author(s).

• Restoration of BAP1 activity via base editing suppresses anchorage-independent survival in kidney cancer. D. Lee, B. Lee, J. Lee, et al. 2025;25(1):444. PubMed · Publisher · Free full text

  Abstract

  BAP1, a deubiquitinase with a ubiquitin C-terminal hydrolase domain, functions as a tumor suppressor involved in diverse cellular processes, including DNA repair, genome stability, and apoptosis. Inactivating mutations in BAP1-particularly missense and deletion variants-are recurrent across multiple cancers, with a high prevalence in clear cell renal cell carcinoma (ccRCC), mesothelioma, and uveal melanoma. Among these, the Glu31Lys mutation in ccRCC impairs BAP1's enzymatic activity, protein stability, and DNA repair functions. Here, we investigated the physiological impact of this recurrent mutation using isogenic KMRC-20 ccRCC cell clones in which the Glu31Lys substitution was precisely corrected to wild-type glutamate via CRISPR-Cas9-mediated adenine base editing. BAP1 reactivation restored anchorage-dependent growth in KMRC-20 cells-a hallmark of non-transformed epithelial cells-and increased apoptosis under non-adherent conditions, indicating reinstated sensitivity to anoikis. Mechanistically, this phenotypic switch was accompanied by post-transcriptional downregulation of N-cadherin and β-catenin under anchorage-free conditions, implicating BAP1 in the regulation of adhesion- and Wnt-related survival pathways. Furthermore, transcriptomic profiling revealed broad gene expression changes upon BAP1 restoration, suggesting that these combined alterations contribute to the re-establishment of anchorage-dependent growth in KMRC-20 cells. These findings uncover a previously unrecognized role for BAP1 in suppressing anchorage-independent survival, providing new insights into BAP1-driven tumorigenesis and underscoring the therapeutic potential of precise gene editing to restore tumor suppressor function in ccRCC.

  © 2025. The Author(s).

• Immune modulation in malignant pleural effusion: from microenvironment to therapeutic implications. S. Ge, Y. Zhao, J. Liang, et al. 2024;24(1):105. Review PubMed · Publisher · Free full text

  Abstract

  Immune microenvironment and immunotherapy have become the focus and frontier of tumor research, and the immune checkpoint inhibitors has provided novel strategies for tumor treatment. Malignant pleural effusion (MPE) is a common end-stage manifestation of lung cancer, malignant pleural mesothelioma and other thoracic malignancies, which is invasive and often accompanied by poor prognosis, affecting the quality of life of affected patients. Currently, clinical therapy for MPE is limited to pleural puncture, pleural fixation, catheter drainage, and other palliative therapies. Immunization is a new direction for rehabilitation and treatment of MPE. The effusion caused by cancer cells establishes its own immune microenvironment during its formation. Immune cells, cytokines, signal pathways of microenvironment affect the MPE progress and prognosis of patients. The interaction between them have been proved. The relevant studies were obtained through a systematic search of PubMed database according to keywords search method. Then through screening and sorting and reading full-text, 300 literatures were screened out. Exclude irrelevant and poor quality articles, 238 literatures were cited in the references. In this study, the mechanism of immune microenvironment affecting malignant pleural effusion was discussed from the perspectives of adaptive immune cells, innate immune cells, cytokines and molecular targets. Meanwhile, this study focused on the clinical value of microenvironmental components in the immunotherapy and prognosis of malignant pleural effusion.

  © 2024. The Author(s).

• Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling. I. Dell'Anno, F. Morani, S. Patergnani, et al. 2024;24(1):226. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous drug screening, we identified thonzonium bromide (TB) as one of the most active compounds against MPM cells. Since the biological effects of TB are poorly known, in this work we departed from some hints of previous studies and investigated several hypotheses. Moreover, we evaluated the efficacy of TB in an in vivo xenograft rodent model.

  Methods: In vitro assessment was made on five MPM (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A). We evaluated TB ability to affect proliferation, apoptosis, mitochondrial functions and metabolism, and the mevalonate pathway. In vivo assay was carried out on MPM-xenograft NOD-SCID mice (4 mg/kg delivered intraperitoneally, twice a week for 4 weeks) and the overall survival was analysed with Kaplan-Meier curves.

  Results: After TB treatment, we observed the suppression of ERK 1/2 phosphorylation, the increase of BAX expression and p38 phosphorylation. TB affected Ca2+ homeostasis in both mitochondrial and cytosolic compartments, it regulated the mitochondrial functioning, respiration, and ATP production as well as the mevalonate pathway. The in vivo study showed an increased overall survival for TB treated group vs. vehicle control group (P = 0.0076).

  Conclusions: Both in vitro and in vivo results confirmed the effect of TB on MPM and unravelled novel targets with translational potential.

  © 2024. The Author(s).

• DNA repair and damage pathways in mesothelioma development and therapy. F. Malakoti, N. Targhazeh, E. Abadifard, et al. 2022;22(1):176. Review PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MMe) is an aggressive neoplasm that occurs through the transformation of mesothelial cells. Asbestos exposure is the main risk factor for MMe carcinogenesis. Other important etiologies for MMe development include DNA damage, over-activation of survival signaling pathways, and failure of DNA damage response (DDR). In this review article, first, we will describe the most important signaling pathways that contribute to MMe development and their interaction with DDR. Then, the contribution of DDR failure in MMe progression will be discussed. Finally, we will review the latest MMe therapeutic strategies that target the DDR pathway.

  © 2022. The Author(s).

• Pan-cancer analysis of oncogenic role of Programmed Cell Death 2 Like (PDCD2L) and validation in colorectal cancer. H. Gao, C. Xu, J. Liang, et al. 2022;22(1):100. PubMed · Publisher · Free full text

  Abstract

  Background: Programmed Cell Death 2 Like (PDCD2L) correlates with cell proliferation, apoptosis and mouse embryonic development. However, the role of PDCD2L in human cancers is unclear.

  Methods: Multiple bioinformatic methods, in vitro function experiments and validation were performed to clarify the oncogenic role of PDCD2L in human cancers.

  Results: Our study found that PDCD2L was aberrantly expressed in multiple types of human cancers, and associated with clinical stage and molecular subtype. Furthermore, overexpression of PDCD2L predicted poor overall survival in adrenocortical carcinoma(ACC), kidney chromophobe(KICH), acute myeloid leukemia(LAML), brain lower grade glioma(LGG),liver hepatocellular carcinoma(LIHC), mesothelioma(MESO), uveal melanoma(UVM) and poor diseases free survival in ACC, bladder urothelial carcinoma(BLCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), kidney renal clear cell carcinoma(KIRC), kidney renal papillary cell carcinoma(KIRP), LGG, LIHC, and UVM. PDCD2L expression was negatively associated with cancer associated fibroblast in breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), sarcoma (SARC), stomach adenocarcinoma (STAD) and testicular germ cell tumors (TGCT). Mechanically, we found that PDCD2L expression was associated with apoptosis, invasion and cell cycle by investigating single cell sequencing data. For further validation, PDCD2Lwas highly expressed in colorectal cancer (CRC) cell lines and tissue samples compared with the normal colon cell line and non-tumor adjacent colorectal mucosa tissues. PDCD2L knockdown induced the apoptosis and proliferation of CRC cells.

  Conclusions: Our study shows that the oncogenic role of PDCD2L in various cancers and PDCD2L could be served as a biomarker of CRC.

  © 2022. The Author(s).

• Prognostic value of maximum standard uptake value, metabolic tumour volume, and total lesion glycolysis of 18F-FDG PET/CT in patients with malignant pleural mesothelioma: a systematic review and meta-analysis. W. Wen, D. Xu, Y. Piao, et al. 2022;22(1):60. Review PubMed · Publisher · Free full text

  Abstract

  Purpose: Present work systematically reviewed relevant literature based on 18F-FDG PET parameters and conducted a meta-analysis to examine the prognostic value of maximal standard uptake value (SUVmax), total lesional glycolysis (TLG), and metabolic tumour volume (MTV) in the prognosis of malignant pleural mesothelioma (MPM).

  Methods: The relevant literature published in English were searched on PubMed, Cochrane Library, and EMBASE databases. We also evaluated the significance of SUVmax, TLG, and MTV in prognosis prediction using pooled hazard ratios (HRs).

  Results: The current study comprised 12 primary studies with a total of 1307 MPM cases. According to our results, the pooled HR (95% confidence interval [CI]) of increased SUVmax for overall survival (OS) was 1.30 (95% CI 1.13-1.49, P = 0.000), whereas the increased TLG was 1.81(95% CI 1.25-2.61, P = 0.089). The increased MTV was not significantly related to OS (1.14 [95% CI 0.87-1.50, P = 0.18]).However, study design-stratified subgroup analysis suggested that differences in OS of retrospective and prospective subgroups were statistically significant, and no significant heterogeneity among different studies was observed.

  Conclusion: Based on the findings from the present work, PET/CT can significantly affect the prognosis prediction in MPM cases. Also, the increased SUVmax and TLG values predict an increased risk of mortality.

  © 2022. The Author(s).

• Thrombospondin-2 acts as a bridge between tumor extracellular matrix and immune infiltration in pancreatic and stomach adenocarcinomas: an integrative pan-cancer analysis. X. Liao, W. Wang, B. Yu, et al. 2022;22(1):213. PubMed · Publisher · Free full text

  Abstract

  Background: Thrombospondin-2 (THBS2) is a versatile glycoprotein that regulates numerous biological functions, including the apoptosis-proliferation balance in endothelial cells, and it has been linked to tumor angiogenesis. However, the exact role of THBS2 in human cancer remains unknown. This study aimed to determine THBS2 expression in a pan-cancer analysis and its association with pan-cancer prognosis and to further identify its possible roles in tumor immunity and the extracellular matrix (ECM).

  Methods: Data on THBS2 expression in cancers and normal tissues were downloaded from the Genotype-Tissue Expression portal and UCSC Xena visual exploration tool and analyzed using the ONCOMINE database, Perl programming language, and Gene Expression Profiling and Interactive Analyses vision 2 webserver. In addition, survival prognosis was analyzed using the survival, survminer, limma, and forestplot packages in R v. 4.0.3.Immune and matrix components were also analyzed using R v. 4.0.3. Most importantly, we partially validated the role and mechanism of THBS2 in pancreatic and gastric cancers in vitro using PANC1 and BGC-823 cell lines.

  Results: THBS2 was significantly overexpressed in 17 of the 33 investigated cancers and linked to a poor prognosis in pan-cancer survival analysis. High THBS2 expression was an independent unfavorable prognostic factor in kidney renal papillary cell, mesothelioma, and stomach and pancreatic adenocarcinomas. Immune infiltration and THBS2 expression were also related. THBS2 expression has been linked to immune and stromal scores and immune checkpoint markers in various cancers. The protein-protein interaction network revealed that THBS2 is associated with multiple ECM and immune proteins. THBS2 knockdown decreased the expression of CD47 and matrix metallopeptidase 2 (MMP-2) as well as the proliferation, migration, and invasion of PANC1 and BGC-823 cells in vitro.

  Conclusions: Our findings suggested that THBS2 might promote cancer progression by remodeling the tumor microenvironment, affecting CD47-mediated signaling pathways, activating the pro-tumor functions of a disintegrin and metalloproteinase with thrombospondin motifs, and enhancing MMP-2 expression. Furthermore, it functions as a bridge between the ECM and immune infiltration in cancer and serves as a potential prognostic biomarker for several cancers, especially pancreatic and gastric adenocarcinomas.

  © 2022. The Author(s).

• Three newly established immortalized mesothelial cell lines exhibit morphological phenotypes corresponding to malignant mesothelioma epithelioid, intermediate, and sarcomatoid types, respectively. T. Sato, H. Nakanishi, K. Akao, et al. 2021;21(1):546. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant mesothelioma (MM) is a very aggressive tumor that develops from mesothelial cells, mainly due to asbestos exposure. MM is categorized into three major histological subtypes: epithelioid, sarcomatoid, and biphasic, with the biphasic subtype containing both epithelioid and sarcomatoid components. Patients with sarcomatoid mesothelioma usually show a poorer prognosis than those with epithelioid mesothelioma, but it is not clear how these morphological phenotypes are determined or changed during the oncogenic transformation of mesothelial cells.

  Methods: We introduced the E6 and E7 genes of human papillomavirus type 16 and human telomerase reverse transcriptase gene in human peritoneal mesothelial cells and established three morphologically different types of immortalized mesothelial cell lines.

  Results: HOMC-B1 cells exhibited epithelioid morphology, HOMC-A4 cells were fibroblast-like, spindle-shaped, and HOMC-D4 cells had an intermediate morphology, indicating that these three cell lines closely mimicked the histological subtypes of MM. Gene expression profiling revealed increased expression of NOD-like receptor signaling-related genes in HOMC-A4 cells. Notably, the combination treatment of HOMC-D4 cells with TGF-β and IL-1β induced a morphological change from intermediate to sarcomatoid morphology.

  Conclusions: Our established cell lines are useful for elucidating the fundamental mechanisms of mesothelial cell transformation and mesothelial-to-mesenchymal transition.

  © 2021. The Author(s).

• Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma. Z. Lin, Y.Z. Xie, M.C. Zhao, et al. 2021;21(1):475. PubMed · Publisher · Free full text

  Abstract

  Background: Xanthine dehydrogenase (XDH) is a critical enzyme involved in the oxidative metabolism of purines, pterin and aldehydes and a central component of the innate immune system. However, the prognostic value of XDH in predicting tumor-infiltrating lymphocyte abundance, the immune response, and survival in different cancers, including hepatocellular carcinoma (HCC), is still unclear.

  Methods: XDH expression was analyzed in multiple databases, including Oncomine, the Tumor Immune Estimation Resource (TIMER), the Kaplan-Meier plotter database, the Gene Expression Profiling Interactive Analysis (GEPIA) database, and The Cancer Genome Atlas (TCGA). XDH-associated transcriptional profiles were detected with an mRNA array, and the levels of infiltrating immune cells were validated by immunohistochemistry (IHC) of HCC tissues. A predictive signature containing multiple XDH-associated immune genes was established using the Cox regression model.

  Results: Decreased XDH mRNA expression was detected in human cancers originating from the liver, bladder, breast, colon, bile duct, kidney, and hematolymphoid system. The prognostic potential of XDH mRNA expression was also significant in certain other cancers, including HCC, breast cancer, kidney or bladder carcinoma, gastric cancer, mesothelioma, lung cancer, and ovarian cancer. In HCC, a low XDH mRNA level predicted poorer overall survival, disease-specific survival, disease-free survival, and progression-free survival. The prognostic value of XDH was independent of the clinical features of HCC patients. Indeed, XDH expression in HCC activated several immune-related pathways, including the T cell receptor, PI3K-AKT, and MAPK signaling pathways, which induced a cytotoxic immune response. Importantly, the microenvironment of XDHhigh HCC tumors contained abundant infiltrating CD8 + T cells but not exhausted T cells. A risk prediction signature based on multiple XDH-associated immune genes was revealed as an independent predictor in the TCGA liver cancer cohort.

  Conclusion: These findings suggest that XDH is a valuable prognostic biomarker in HCC and other cancers and indicate that it may function in tumor immunology. Loss of XDH expression may be an immune evasion mechanism for HCC.

  © 2021. The Author(s).

• Demonstration of anti-tumour bystander killing with prodrug-preloaded suicide gene-engineered tumour cells: a potential improvement for cancer therapeutics. J. Zweiri, S.E. Christmas. 2020;20:26. PubMed · Publisher · Free full text

  Abstract

  Background: Therapeutic approaches for cancer rely on careful consideration of finding the optimal way of delivering the pro-drug for cellular-based cancer treatment. Cell lines and cell cultures have been used in these studies to compare the in vitro and in vivo efficacy of autologous vs. allogeneic tumour cellular gene therapy. Here we have investigated and are reporting for the first time the effect of prodrug ganciclovir (GCV)-preloading (pre-treatment) in suicide gene therapy of cancer.

  Methods: This study examines the effect of GCV-preloading (pre-treatment) on a range of tumour cell lines in conjunction with suicide gene therapy of cancer. To determine the efficacy of this modality, a series of in vitro and in vivo experiments were conducted using genetically modified and unmodified tumour cell lines.

  Results: Following co-culture of herpes simplex virus thymidine kinase (HSV-TK) modified tumour cells and unmodified tumour cells both in vitro and in vivo, GCV-preloading (pre-treatment) of TK-modified human and mouse mesothelioma cells and ovarian tumour cells allowed them to mediate efficiently bystander killing of neighbouring unmodified tumour cells in vitro. In contrast, GCV-preloading of TK-modified human and mouse mesothelioma cells and ovarian tumour cells abolished their in vivo ability to induce bystander killing of unmodified tumour cells, although there was some tumour regression compared to control groups but this was not statistically significant. These results suggest that preloading TK modified tumour cells with GCV needs further study to define the most effective strategy for an in vivo application to retain their bystander killing potential after exposure to lethal doses of GCV in vitro.

  Conclusions: This study highlights the promising possibility of improving the efficacy of pro-drug system to prevent any damage to the immune system and enhancing this type of suicide gene therapy of cancer, as well as the need for further studies to explore the discrepancies between in vitro and in vivo results.

  © The Author(s) 2020.

2010s

• Augmented expression of cardiac ankyrin repeat protein is induced by pemetrexed and a possible marker for the pemetrexed resistance in mesothelioma cells. Y. Qin, I. Sekine, M. Fan, et al. 2017;17:120. PubMed · Publisher · Free full text

  Abstract

  Background: Pemetrexed (PEM) is an anti-cancer agent targeting DNA and RNA synthesis, and clinically in use for mesothelioma and non-small cell lung carcinoma. A mechanism of resistance to PEM is associated with elevated activities of several enzymes involved in nucleic acid metabolism.

  Methods: We established two kinds of PEM-resistant mesothelioma cells which did not show any increase of the relevant enzyme activities. We screened genes enhanced in the PEM-resistant cells with a microarray analysis and confirmed the expression levels with Western blot analysis. A possible involvement of the candidates in the PEM-resistance was examined with a WST assay after knocking down the expression with si-RNA. We also analyzed a mechanism of the up-regulated expression with agents influencing AMP-activated protein kinase (AMPK) and p53.

  Results: We found that expression of cardiac ankyrin repeat protein (CARP) was elevated in the PEM-resistant cells with a microarray and Western blot analysis. Down-regulation of CARP expression with si-RNA did not however influence the PEM resistance. Parent and PEM-resistant cells treated with PEM increased expression of CARP, AMPK, p53 and histone H2AX. The CARP up-regulation was however irrelevant to the p53 genotypes and not induced by an AMPK activator. Augmented p53 levels with nutlin-3a, an inhibitor for p53 degradation, and DNA damages were not always associated with the enhanced CARP expression.

  Conclusions: These data collectively suggest that up-regulated CARP expression is a potential marker for development of PEM-resistance in mesothelioma and that the PEM-mediated enhanced expression is not directly linked with immediate cellular responses to PEM.

• The impact of γ-irradiation on the induction of bystander killing by genetically engineered ovarian tumor cells: implications for clinical use. J. Zweiri, S.E. Christmas. 2017;17:96. PubMed · Publisher · Free full text

  Abstract

  Background: Cellular based therapeutic approaches for cancer rely on careful consideration of finding the optimal cell to execute the cellular goal of cancer treatment. Cell lines and primary cell cultures have been used in some studies to compare the in vitro and in vivo efficacy of autologous vs allogeneic tumour cell vaccines.

  Methods: This study examines the effect of γ-irradiation on a range of tumor cell lines in conjunction with suicide gene therapy of cancer. To determine the efficacy of this modality, a series of in vitro and in vivo experiments were conducted using genetically modified and unmodified tumor cell lines.

  Results: Following co-culture of HSV-TK modified tumor cells and unmodified tumor cells both in vitro and in vivo we observed that the PA-STK ovarian tumor cells were sensitive to γ-irradiation, completely abolishing their ability to induce bystander killing of unmodified tumor cells. In contrast, TK-modified human and mouse mesothelioma cells were found to retain their in vitro and in vivo bystander killing effect after γ-irradiation. Morphological evidence was consistent with the death of PA-STK cells being by pyknosis after γ-irradiation. These results suggest that PA-STK cells are not suitable for clinical application of suicide gene therapy of cancer, as lethal γ-irradiation (100 Gy) interferes with their bystander killing activity. However, the human mesothelioma cell line CRL-5830-TK retained its bystander killing potential after exposure to similarly lethal γ-irradiation (100 Gy). CRL-5830 may therefore be a suitable vehicle for HSV-TK suicide gene therapy.

  Conclusions: This study highlights the diversity among tumor cell lines and the careful considerations needed to find the optimal tumor cell line for this type of suicide gene therapy of cancer.

• A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition. M. Hayashi, H. Madokoro, K. Yamada, et al. 2016;16:35. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant Mesothelioma (MM) is a highly aggressive tumor with poor prognosis. Multimodal treatments and novel molecular targeted therapies against MM are in high demand in order treat this disease effectively. We have developed a humanized monoclonal antibody YS110 against CD26 expressed in 85 % of MM cases. CD26 is thought to be involved in tumor growth and invasion by interacting with collagen and fibronectin, or affecting signal transduction processes.

  Methods: We evaluated the direct anti-tumor effect of YS110 against MM cell lines, NCI-H2452 and JMN, and investigated its effects on cell cycle and on the cell cycle regulator molecules. In addition, we investigated synergistic effects of YS110 and anti-tumor agent pemetrexed (PMX) against MM cell line both in vitro and in vivo.

  Results: YS110 suppressed the proliferation of NCI-H2452 cells by approximately 20 % in 48 h. Based on cell cycle analysis, percentage of cells in G2/M phase increased 8.0 % on the average after YS110 treatment; in addition, cell cycle regulator p21 cip/waf1 was increased and cyclin B1 was decreased after YS110 treatment. Inhibitory phosphorylation of both cdc2 (Tyr15) and cdc25C (Ser216) were elevated. Furthermore, activating phosphorylation of p38 MAPK (Thr180/Tyr182) and ERK1/2 (Thr202/Tyr204) were augmented at 24 h after YS110 treatment. PMX rapidly induced CD26 expression on cell surface and the treatment with both YS110 and PMX inhibited in vivo tumor growth accompanied by a synergistic reduction in the MIB-1 index.

  Conclusion: This is a first report of a novel anti-proliferative mechanism of the humanized anti-CD26 monoclonal antibody YS110, which resulted in G2/M cell cycle delay through regulation of quantity and activity of various cell cycle regulating molecules.

• EGCG induces human mesothelioma cell death by inducing reactive oxygen species and autophagy. M. Satoh, Y. Takemura, H. Hamada, et al. 2013;13(1):19. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma is an asbestos-related fatal disease with no effective cure. We studied whether a green tea polyphenol, epigallocathechin-3-gallate (EGCG), could induce cell death in five human mesothelioma cell lines. We found that EGCG induced apoptosis in all five mesothelioma cell lines in a dose-dependent manner. We further clarified the cell killing mechanism. EGCG induced reactive oxygen species (ROS), and impaired the mitochondrial membrane potential. As treatment with ROS scavengers, catalase and tempol, significantly inhibited the EGCG-induced apoptosis, ROS is considered to be responsible for the EGCG-induced apoptosis. Further, we found that EGCG induced autophagy, and that when autophagy was suppressed by chloroquine, the EGCG-induced cell death was enhanced. Taken together, these results suggest that EGCG has a great potential for the treatment of mesothelioma by inducing apoptosis and autophagy.

2000s

• Localization of CD26/DPPIV in nucleus and its nuclear translocation enhanced by anti-CD26 monoclonal antibody with anti-tumor effect. K. Yamada, M. Hayashi, W. Du, et al. 2009;9:17. PubMed · Publisher · Free full text

  Abstract

  Background: CD26 is a type II, cell surface glycoprotein known as dipeptidyl peptidase (DPP) IV. Previous studies have revealed CD26 expression in T cell leukemia/lymphoma and malignant mesothelioma, and an inhibitory effect of anti-CD26 monoclonal antibody (mAb) against the growth of CD26+ cancer cells in vitro and in vivo. The function of CD26 in tumor development is unknown and the machinery with which the CD26 mAb induces its anti-tumor effect remains uncharacterized.

  Results: The localization of CD26 in the nucleus of T cell leukemia/lymphoma cells and mesothelioma cells was shown by biochemical and immuno-electron microscopic analysis. The DPPIV enzyme activity was revealed in the nuclear fraction of T cell leukemia/lymphoma cells. These expressions of intra-nuclear CD26 were augmented by treatment with the CD26 mAb, 1F7, with anti-tumor effect against the CD26+ T cell leukemia/lymphoma cells. In contrast, the CD26 mAb, 5F8, without anti-tumor effect, did not augment CD26 expressions in the nucleus. Biotin-labeled, cell surface CD26 translocated into the nucleus constantly, and this translocation was enhanced with 1F7 treatment but not with 5F8.

  Conclusion: These results indicate that the intra-nuclear CD26 which moves from plasma membrane may play certain roles in cell growth of human cancer cells.

• Phorbol myristate acetate and Bryostatin 1 rescue IFN-gamma inducibility of MHC class II molecules in LS1034 colorectal carcinoma cell line. Y. Kudinov, C.L. Wiseman, A.I. Kharazi. 2003;3:4. PubMed · Publisher · Free full text

  Abstract

  Background: The expression of major histocompatibility complex class II (MHCII) antigens in both mouse and human tumors is rare, and these antigens are not easily inducible by IFN-gamma (IFNg). Since MHCII may play an important role in the development of host antitumor immune response, we explored the possibility of restoring MHCII inducibility in several IFNg-resistant tumor cell lines using protein kinase C (PKC) agonists phorbol myristate acetate (PMA) or Bryostatin.

  Results: Tumor cells were co-cultured with various concentrations of PMA and IFNg for 48 hr. The expression of MHCII antigens and receptors IFNgR1 and IFNgR2 was determined by flow cytometry. We showed that the presence of as little as 0.1 ng/ml of PMA in tissue culture restored the ability of weakly inducible LS1034 colon carcinoma cells to express MHCII in response to IFNg (100 - 10,000 IU/ml) in a dose-dependent manner. Likewise, Bryostatin 1, as low as 10 ng/ml produced a 5-6 fold upregulation of MHCII. The effect of PMA was not observed in two other poorly responding cell lines, MSTO-211H mesothelioma and HepG2 hepatocellular carcinoma, and was abrogated by relatively high concentrations of PKC inhibitors staurosporine (100 nM) and GF 109203X (1,000 nM). Both surface and intracellular staining of all cell lines with antibodies against IFNgR1 and IFNgR2 failed to detect any increase in IFNg receptor expression following incubation with PMA.

  Conclusion: In this study we showed that IFNg-inducibility of MHCII antigens in weakly inducible LS1034 colorectal carcinoma cell line can be rescued by concomitant incubation with PKC agonists. Bryostatin 1 may be considered for further investigation of IFNg-dependent MHCII induction in resistant tumors in vivo.

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