Cancer Science最新文献

Double expression (DE) is a World Health Organization-recognized adverse prognostic factor in diffuse large B-cell lymphoma (DLBCL). However, the prognostic value of DE in the genetic subtyping era and potential mechanisms remain to be explored. We enrolled 246 DLBCL patients diagnosed between December 2021 and September 2023 in a Jiangsu Province Hospital cohort and included 930 DLBCL patients from three published studies in an external cohort. Double-expression DLBCL (DEL) in the external cohort was mainly distributed in the OTHER subtype (42.0%), EZB subtype (28.3%), and MCD subtype (15.0%), whereas the MCD subtype exhibited the highest ratio of DEL. DEL was significantly related to unfavorable overall survival (OS) and progression-free survival (PFS) in DLBCL, but only in EZB and OTHER subtypes that DEL retained remarkably adverse impacts on survivals compared to non-DEL. We explored the prognostic value of clinical and genetic parameters in DEL patients and found only ST2 showed better OS than A53 in DEL patients, whereas the other subtypes showed no significant difference. DEL showed similarities with the MCD subtype in mutation profiles. Furthermore, RNA-sequencing analyses exhibited upregulation in tumor proliferation-related pathways in DEL patients, but downregulation in extracellular matrix organization, T-cell activation and proliferation, type II interferon production, and pathways associated with cell death might contribute to the poor outcomes of DEL patients.

Fibrocytes were identified as bone marrow-derived myeloid cells that also have fibroblast-like phenotypes, such as ECM production and differentiation to myofibroblasts. Although fibrocytes are known to contribute to various types of tissue fibrosis, their functions in the tumor microenvironment are unclear. We focused on fibrocytes as pivotal regulators of tumor progression. Our previous studies have indicated that fibrocytes induce angiogenesis and cancer stem cell-like phenotypes by secreting various growth factors. In contrast, immune checkpoint inhibitor (ICI)-treated fibrocytes demonstrated antigen-presenting capacity and enhanced antitumor T cell proliferation. Taken together, these findings indicate that fibrocytes have multiple effects on tumor progression. However, the detailed phenotypes of fibrocytes have not been fully elucidated because the isolation of distinct fibrocyte clusters has not been achieved without culturing in ECM-coated conditions or intracellular staining of ECM. The development of single-cell analyses partially resolves these problems. Single-cell RNA sequences in CD45⁺ immune cells from tumor tissue identified ECM-expressing myeloid-like cells as distinct fibrocyte clusters. In addition, these findings enabled the isolation of tumor-infiltrating fibrocytes as CD45⁺CD34⁺ cells. These tumor-infiltrating fibrocytes demonstrated both antigen-presenting ability and differentiation into myofibroblast-like cancer-associated fibroblasts. Considering these functions of fibrocytes in tumor progression, molecular-targeting agents for the migration, activity, and differentiation of fibrocytes are promising therapeutic strategies. Furthermore, identification of specific cell surface markers and master regulators of fibrocytes will advance novel fibrocyte-targeting therapies. In this review, we discuss the multiple roles of tumor-infiltrating fibrocytes and novel cancer therapeutic strategies.

Stemness is a key factor contributing to treatment failure in gastric cancer (GC). Methyltransferase-like 14 (METTL14) has been linked to various cancers, though its specific role in regulating stemness in GC remains undefined. In this study, we assessed METTL14 expression levels in GC tissues using public datasets and clinical specimens and investigated its impact on cell proliferation, metastasis, and stemness both in vitro and in vivo. Through m6A RNA immunoprecipitation (MeRIP) and luciferase reporter assays, we identified downstream targets of METTL14. Rescue assays were performed to examine whether METTL14 overexpression could reverse stemness in GC. We also explored the underlying mechanisms using chromatin immunoprecipitation (ChIP) and western blot analysis, focusing on the role of ATF5 and the upstream regulation of METTL14. Our findings show that lower METTL14 expression is associated with poorer overall survival in GC patients. Functionally, METTL14 knockdown enhanced stemness traits in GC cells. Mechanistically, METTL14 facilitated m6A modification, promoting the degradation of ATF5 mRNA. Overexpression of ATF5 reversed the stemness inhibition caused by METTL14 overexpression by increasing WDR74 transcription and enhancing β-catenin nuclear translocation. Furthermore, histone H3 lactylation at Lys18 was found to upregulate METTL14 expression. In conclusion, METTL14 knockdown promotes stemness in GC by mediating m6A modification of ATF5 mRNA, which activates the WDR74/β-catenin axis, making METTL14 a potential therapeutic target for gastric cancer treatment.

The efficacy of combined chemotherapy and immunotherapy has previously been demonstrated in patients with biliary tract cancer. The aim of this study was to assess the efficacy and safety of camrelizumab in combination with gemcitabine and apatinib as a first- or second-line treatment for advanced programmed death-ligand 1 (PD-L1)-positive biliary tract cancer. This prospective, single-arm, and exploratory clinical trial aimed at recruiting 20 PD-L1-positive patients (tumor proportion score ≥1% or combined positive score ≥1) who met the inclusion criteria. Camrelizumab (200 mg) was administered in combination with gemcitabine (800 mg/m²) and apatinib (250 mg). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Fourteen patients were enrolled between September 2, 2020, and December 15, 2022. At the data cutoff on August 16, 2023, the median follow-up time was 11.4 months (interquartile range, 4.5-15.4), with one patient still undergoing treatment. Among the enrolled patients, six achieved a partial response, and four had stable disease. The ORR was 42.9% (95% confidence interval [CI], 17.7-71.1), and the DCR was 71.4% (95% CI, 41.9-91.6). The median PFS was 5.4 months (95% CI, 2.8-not reached), and the median OS was 13.5 months (95% CI, 5.7-not reached). The most frequent grade 3 or 4 treatment-related adverse event was neutropenia (n = 4, 29%). The combination of camrelizumab, gemcitabine, and apatinib showed promising efficacy and acceptable safety in patients with advanced PD-L1-positive biliary tract cancer.

Viruses are widely recognized to be intricately associated with both solid and hematological malignancies in humans. The primary goal of this research is to elucidate the interplay of genes between SARS-CoV-2 infection and lung adenocarcinoma (LUAD), with a preliminary investigation into their clinical significance and underlying molecular mechanisms. Transcriptome data for SARS-CoV-2 infection and LUAD were sourced from public databases. Differentially expressed genes (DEGs) associated with SARS-CoV-2 infection were identified and subsequently overlapped with TCGA-LUAD DEGs to discern the crosstalk genes (CGs). In addition, CGs pertaining to both diseases were further refined using LUAD TCGA and GEO datasets. Univariate Cox regression was conducted to identify genes associated with LUAD prognosis, and these genes were subsequently incorporated into the construction of a prognosis signature using 10 different machine learning algorithms. Additional investigations, including tumor mutation burden assessment, TME landscape, immunotherapy response assessment, as well as analysis of sensitivity to antitumor drugs, were also undertaken. We discovered the risk stratification based on the prognostic signature revealed that the low-risk group demonstrated superior clinical outcomes (p < 0.001). Gene set enrichment analysis results predominantly exhibited enrichment in pathways related to cell cycle. Our analyses also indicated that the low-risk group displayed elevated levels of infiltration by immunocytes (p < 0.001) and superior immunotherapy response (p < 0.001). In our study, we reveal a close association between CGs and the immune microenvironment of LUAD. This provides preliminary insight for further exploring the mechanism and interaction between the two diseases.

High tissue density of the mammary gland is considered a pro-tumorigenic factor, hence suppressing the stimuli that induce matrix buildup carries the potential for cancer interception. We found that in non-malignant mammary epithelial cells the combination of the chemopreventive agents bexarotene (Bex) and carvedilol (Carv) suppresses the zymogen granule protein 16B (ZG16B, PAUF) through an interaction of ARID1A with a proximal enhancer. Bex + Carv also reduced ZG16B levels in vivo in normal breast tissue and MDA-MB231 tumor xenografts. The relevance of ZG16B is underscored by ongoing clinical trials targeting ZG16B in pancreatic cancers, but its role in breast cancer development is unclear. In immortalized mammary epithelial cells, secreted recombinant ZG16B stimulated mitogenic kinase phosphorylation, detachment and mesenchymal characteristics, and promoted proliferation, motility and clonogenic growth. Highly concerted induction of specific laminin, collagen and integrin isoforms indicated a shift in matrix properties toward increased density and cell-matrix interactions. Exogenous ZG16B alone blocked Bex + Carv-mediated control of cell growth and migration, and antagonized Bex + Carv-induced gene programs regulating cell adhesion and migration. In breast cancer cells ZG16B induced colony formation and anchorage-independent growth, and stimulated migration in a PI3K/Akt-dependent manner. In contrast, Bex + Carv inhibited colony formation, reduced Ki67 levels, ZG16B expression and glucose uptake in MDA-MB231 xenografts. These data establish ZG16B as a druggable pro-tumorigenic target in breast cell transformation and suggest a key role of the matrisome network in rexinoid-dependent antitumor activity.

Elucidating the mechanisms underlying cancer development and proliferation is important for the development of therapeutic methods for the complete cure of cancer. In particular, the identification of diagnostic markers for early detection and new therapeutic strategies for refractory gastrointestinal cancers are needed. Various abnormal phenomena occur in cancer cells, such as functional changes of proteins, led by genomic mutations, and changes in gene expression due to dysregulation of epigenetic regulation. This is no exception for noncoding RNA (ncRNA), which do not encode proteins. Recent reports have revealed that microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) are deeply involved in cancer progression. These ncRNAs have attracted attention as gene expression regulatory molecules. Recent advances in technology have made it possible not only to read DNA and RNA sequences but also to study the modification state of each base. In particular, comprehensive analysis of N6-methyladenosine (m⁶A) has been performed by many research groups, with multiple studies reporting that m⁶A modifications of specific genes are associated with cancer progression. Based on the above, this review examines how ncRNA modifications are related to cancer progression in gastrointestinal cancers such as colorectal and pancreatic cancer. We also discuss enzyme inhibitors that have been reported to have drug discovery potential targeting m⁶A modifications. By utilizing the new perspective of ncRNA modification, we may be able to accumulate knowledge on the molecular biology of cancer and contribute to human health through diagnosis and treatment.

Cancer cells rely on mitochondrial oxidative phosphorylation (OXPHOS) and the noncanonical tricarboxylic acid (TCA) cycle. In this paper, we shed light on the vital role played by the noncanonical TCA cycle in a host-side concession to mitochondria, especially in highly energy-demanding malignant tumor cells. Inhibition of ATP-citrate lyase (ACLY), a key enzyme in the noncanonical TCA cycle, induced apoptosis by increasing reactive oxygen species levels and DNA damage while reducing mitochondrial membrane potential. The mitochondrial membrane citrate transporter inhibitor, CTPI2, synergistically enhanced these effects. ACLY inhibition reduced cytosolic citrate levels and CTPI2 lowered ACLY activity, suggesting that the noncanonical TCA cycle is sustained by a positive feedback mechanism. These inhibitions impaired ATP production, particularly through OXPHOS. Metabolomic analysis of mitochondrial and cytosolic fractions revealed reduced levels of glutathione pathway-related and TCA cycle-related metabolite, except fumarate, in mitochondria following noncanonical TCA cycle inhibition. Despite the efficient energy supply to the cell by mitochondria, this symbiosis poses challenges related to reactive oxygen species and mitochondrial maintenance. In conclusion, the noncanonical TCA cycle is indispensable for the canonical TCA cycle and mitochondrial integrity, contributing to mitochondrial domestication.

Retraction: C. Di Stefano, G. Marfe, M. M. Trawinska, P. Sinibaldi-Salimei, R. Silvestri, S. Amadori and E. Abruzzese, "Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) Exert Their Anti-proliferative Activity by Interfering With Akt-mTOR Signaling and bax:bcl-2 Ratio Modulation in Cells From Chronic Myeloid Leukemic Patients," Cancer Science 101, no. 4 (2010): 991-1000, https://doi.org/10.1111/j.1349-7006.2010.01490.x. The above article, published online on 07 January 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley & Sons Australia, Ltd. The retraction has been agreed due to several instances of duplications of western blot bands observed in Figures 3, 4, 5 and 8. Furthermore, splicing and deletion of bands was uncovered in Figures 4 and 7 respectively. Finally, western blot bands presented in Figure 4 was also found published earlier in another article. The authors provided partial raw data but the inconsistencies found could not be resolved on this basis. Due to the extent and nature of the duplications, the editors consider the results and conclusions of this study invalid.