Cancer Communications最新文献

{"title":"Unraveling the effects of screening colonoscopy on colorectal cancer early detection and prevention: the NordICC trial revisited","authors":"Hermann Brenner, Tim Holland-Letz, Annette Kopp-Schneider, Thomas Heisser, Michael Hoffmeister","doi":"10.1002/cac2.12642","DOIUrl":"10.1002/cac2.12642","url":null,"abstract":"<p>Based on intriguing findings from observational studies [<span>1, 2</span>], colonoscopy has since long been recommended for colorectal cancer (CRC) screening, long before evidence on its effectiveness in reducing CRC incidence and mortality was demonstrated by a randomized controlled trial (RCT). Such evidence has only recently been provided by the Nordic-European Initiative on Colorectal Cancer (NordICC) trial [<span>3</span>]. In this RCT, the risk of CRC was lower among those invited to undergo screening colonoscopy than among those not invited to screening. However, reported CRC risk reduction was smaller than anticipated: The authors derived risk ratios of 0.82 (95% confidence interval [CI] = 0.70-0.93) and 0.69 (95% CI = 0.55-0.83) in intention-to-screen analysis and adjusted per-protocol analysis, respectively, suggesting an 18% risk reduction of CRC among those invited for screening and a 31% risk reduction among screening attenders. These results have prompted major concerns and debate about the effectiveness and cost-effectiveness of screening colonoscopy [<span>4</span>], which had so far been considered as a particularly effective and cost-effective, if not cost-saving CRC preventive measure. However, the “incident” cases in the published NordICC trial results included CRCs that were already prevalent at recruitment and could not possibly have been prevented [<span>5</span>]. Such cases were early detected by screening among screening attenders, an additional desired screening effect. In the following, we demonstrate how to disentangle screening effects on CRC early detection and prevention.</p><p>Details on the design of the NordICC trial have been reported elsewhere [<span>3</span>]. Briefly, this trial was run in 4 Northern European countries (Poland, Norway, Sweden, and the Netherlands), but data from the Netherlands were not included for legal reasons in the first report on long-term effect estimates, published in October 2022. The study population for that analysis, which was drawn from population registries, included 84,585 presumptively healthy men and women 55-64 years of age who were randomized in a 1:2 ratio to either receive an invitation for a single colonoscopy or to usual-care. Recruitment was performed between 2009 and 2014. Of 28,220 participants in the invited group, 11,843 (42.0%) followed the invitation. Primary endpoints were risk of CRC incidence and death. Follow-up was performed by record linkage with cancer registries and cause-of-death registries.</p><p>During a median follow-up time of 10 years, 259 and 622 CRC cases were registered in the invited group and the usual-care group, respectively (Figure 1). Among the 259 CRC cases in the invited group, 102 were registered among attenders of screening colonoscopy, of which 62 were prevalent, screening-detected cases and 40 were truly incident cases. However, in the estimation of screening effects in the NordICC trial, no distinction was made between early det","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 3","pages":"205-208"},"PeriodicalIF":20.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12642","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neoadjuvant HER2 inhibition induces ESR1 DNA methylation alterations resulting in clinically relevant ER expression changes in breast cancers","authors":"Gavin P. Dowling, Gordon R. Daly, Aisling Hegarty, Michael Flanagan, Mihaela Ola, Ramón Fallon, Sinéad Cocchiglia, Vikrant Singh, Katherine M. Sheehan, Fiona Bane, Jason McGrath, Louise Watson, Sandra Hembrecht, Bryan Hennessy, Patrick G. Morris, Arnold D. K. Hill, Damir Varešlija, Leonie S. Young","doi":"10.1002/cac2.12640","DOIUrl":"10.1002/cac2.12640","url":null,"abstract":"<p>The expression of estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) in breast cancer can change in response to treatment and pivotally influence tumor behavior and clinical management [<span>1</span>]. Receptor discordance has been observed at various distant metastatic site (bone, lung, liver, and brain), with a routine loss of ER and gains in HER2 reported [<span>2</span>]. This receptor discordance can influence tumor responsiveness to both HER2 inhibitor and endocrine therapies. Although the mechanisms underlying receptor expression changes are not fully understood, we recently reported gains in <i>ESR1</i> promoter hypermethylation as a potential driver of ER loss during disease progression [<span>3</span>]. In this study, mechanisms underlying altered receptor expression and associated disease outcomes were examined following neoadjuvant trastuzumab treatment.</p><p>We investigated the impact of HER2 inhibition on ER expression. From a cohort of 2,917 patients, 527 tumors were HER2-positive. Of these, 161 patients received neoadjuvant trastuzumab with systemic chemotherapy (Supplementary Figure S1, Supplementary Table S1). In this cohort (<i>n</i> = 161), 89 patients (55.3%) achieved pathological complete response (pCR), while 72 patients (44.7%) had residual disease, and 18 patients developed metastases (Clinical Cohort, Figure 1A, Supplementary Table S1). A statistically significant higher proportion of patients with ER-negative tumors achieved pCR compared to their ER-positive counterparts (<i>P</i> = 0.016, Supplementary Table S1), consistent with previous studies [<span>4</span>]. In patients with residual disease, the most notable finding was the observed gain of ER protein expression and loss of HER2 in a number of patients (33% and 17%, respectively; Figure 1B). ER protein status remained unchanged in 38 patients (53%), with a loss of ER observed in 8 patients (11%) (Figure 1B).</p><p>Epigenetic modifications are a potential mechanism underlying this observed receptor discordance. In this study, the role of DNA methylation in altered receptor expression was investigated (DNA methylation cohort, Figure 1A). Global DNA methylation was assessed in pre- and post-treatment samples (<i>n</i> = 16; Supplementary Table S2), of which 7 patient tumors were matched (biopsy and resection). Differentially methylated gene (DMG) analysis segregated patient tumors into pre- or post-treatment groups, illustrating the dominance of hypomethylation in post-treatment patient tumors (Figure 1C). Notably, pathway analysis identified <i>Estrogen Response Early</i>, <i>Epithelial Mesenchymal Transition</i> (<i>EMT</i>), <i>ERRB</i>, <i>AMPK</i>, and <i>RAS</i> signaling (<i>P</i> < 0.05) as statistically significant pathways (Supplementary Figure S2A-B). Network graph analysis revealed <i>Estrogen Response Early</i>, <i>Estrogen Response Late</i> and <i>EMT</i> as hub pathways (Figure 1D). Estrogen-responsive genes such as <i>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"198-202"},"PeriodicalIF":20.1,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12640","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer situation in China: an analysis based on the global epidemiological data released in 2024","authors":"Xiayao Diao,&nbsp;Chao Guo,&nbsp;Yukai Jin,&nbsp;Bowen Li,&nbsp;Xuehan Gao,&nbsp;Xin Du,&nbsp;Zhenchong Chen,&nbsp;Minju Jo,&nbsp;Yi Zeng,&nbsp;Chao Ding,&nbsp;Wenwu Liu,&nbsp;Jianrong Guo,&nbsp;Shanqing Li,&nbsp;Haibo Qiu","doi":"10.1002/cac2.12627","DOIUrl":"10.1002/cac2.12627","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer remains a major cause of mortality and a significant economic burden in China. Exploring the disparities in cancer patterns and control strategies between China and developed countries may offer valuable insights for policy formulation and enhance cancer management efforts. This study examined the incidence, mortality, and disability-adjusted life year (DALY) burden of cancer in China, and compared these metrics with those observed in the United States (US) and the United Kingdom (UK).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data on cancer incidence, mortality, and DALYs for China, the US, and the UK were sourced from the GLOBOCAN 2022 online database and the Global Burden of Disease 2021 study (GBD 2021). We utilized Joinpoint regression models to analyze trends in cancer incidence and mortality across these countries, calculating annual percent changes (APCs) and determining the optimal joinpoints.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In 2022, China recorded around 4,824,703 new cancer cases and 2,574,176 cancer-related deaths, contributing to 71,037,170 DALYs. China exhibited a lower cancer incidence rate compared to the US and the UK. Although cancer-related mortality in China is slightly lower than that in the UK, it is significantly higher than that in the US. Additionally, China experienced significantly higher DALY rates compared to both the US and UK. The cancer landscape in China was also undergoing significant changes, with a rapid rise in the incidence and burden of lung, colorectal, breast, cervical, and prostate cancers. Meanwhile, the incidence and burden of stomach cancer continued to decline. Although the incidence of liver and esophageal cancers was decreasing, the burden of liver cancer was increasing, while the burden of esophageal cancer remained largely unchanged.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The cancer profile of China is shifting from that of a developing country to one more typical of a developed country. The ongoing population aging and the rise in unhealthy lifestyles are expected to further escalate the cancer burden in China. Consequently, it is crucial for Chinese authorities to revise the national cancer control program, drawing on successful strategies from developed countries, while also accounting for the regional diversity in cancer types across China.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"178-197"},"PeriodicalIF":20.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12627","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interplay between natural killer cells and pancreatic stellate cells in pancreatic ductal adenocarcinoma","authors":"Rachel Elizabeth Ann Fincham,&nbsp;Parthiban Periasamy,&nbsp;Craig Ryan Joseph,&nbsp;Jia Meng,&nbsp;Jeffrey Chun Tatt Lim,&nbsp;Felicia Wee,&nbsp;Konstantinos Stasinos,&nbsp;Michelle Rodrigues Goulart,&nbsp;Jiangfeng Ye,&nbsp;Li Yen Chong,&nbsp;Bijin Veonice Au,&nbsp;Denise Goh,&nbsp;Joe Poh Sheng Yeong,&nbsp;Hemant Mahendrakumar Kocher","doi":"10.1002/cac2.12638","DOIUrl":"10.1002/cac2.12638","url":null,"abstract":"&lt;p&gt;Pancreatic ductal adenocarcinoma (PDAC) remains one of medicine's most urgent areas of unmet need. With 5-year survival rates of ∼11%, PDAC is set to become the second leading cause of cancer related deaths by 2040 [&lt;span&gt;1&lt;/span&gt;]. The complex tumour microenvironment (TME) in PDAC, responsible for poor prognosis, is comprised of extracellular matrix (ECM) proteins and multiple cell types; with pancreatic stellate cells (PSCs), which become activated cancer associated fibroblasts (CAFs), being regarded as key orchestrators of the TME. We have demonstrated that treatment with all-trans retinoic acid (ATRA) can render activated PSCs (aPSC) to a quiescent (qPSC) phenotype (shift to G1 phase of cell cycle and other features [&lt;span&gt;2&lt;/span&gt;]), resulting in stromal remodelling and thus, influencing cancer cell co-targeting with chemotherapy in patients [&lt;span&gt;3&lt;/span&gt;]. This has resulted in the use of ATRA along with standard-of-care chemotherapy in the Stromal TARgeting for PAncreatic Cancer (STARPAC) clinical trial, with promising results [&lt;span&gt;4&lt;/span&gt;]. These clinically relevant [&lt;span&gt;5&lt;/span&gt;], exciting potential therapeutic benefits of stromal co-targeting through rendering PSCs quiescent [&lt;span&gt;6&lt;/span&gt;], along with predictive inflammation-related biomarkers [&lt;span&gt;7&lt;/span&gt;], and increased focus on cellular therapeutics such as NK cells, led us to postulate potential targetable PSC-immune cell interactions which may uncover a comprehensive therapeutic strategy for treating hitherto, incurable PDAC.&lt;/p&gt;&lt;p&gt;We identified differential NK-92 (a cell line representing NK cells) cytotoxicity against qPSCs (telomerase reverse transcriptase (hTERT) immortalised PS1 cell line rendered quiescent by administering ATRA for seven days at 1 µmol/L daily [&lt;span&gt;2&lt;/span&gt;]) and aPSC phenotypes as assessed by surface expression of CD107a/b, and Calcein Acetyoxymethyl (AM) cytotoxicity assays (Supplementary Figure S1A-B). Furthermore, qPSC or aPSC education of NK-92 cells resulted in altered and distinct cytotoxicity towards pancreatic cancer cells (BxPC3, Capan2, MiaPaca2) as indicated by surface CD107a/b expression (Figure 1A) and complemented by Calcein AM cytotoxicity assays (data not shown).&lt;/p&gt;&lt;p&gt;Surface and intracellular markers for CAF subtypes (pCAFassigner subtypes A-D [&lt;span&gt;3&lt;/span&gt;]; CD105&lt;sup&gt;+/−&lt;/sup&gt; CAFs [&lt;span&gt;8&lt;/span&gt;]) and surface activating/inhibitory receptors and intracellular functional markers for NK cells, as assessed by spectral flow cytometry and Luminex ELISA secretome analysis, demonstrated that this interaction is, indeed, bidirectional. We demonstrated stellate cell polarisation to a myofibroblastic activation state [&lt;span&gt;2&lt;/span&gt;] in response to direct contact with NK cells as assessed by alpha-SMA abundance (geometric mean fluorescence intensity (MFI)), as well as upregulation of CD105 expression, a CAF marker of anti-tumour immunity [&lt;span&gt;8&lt;/span&gt;], irrespective of previous PSC activation status (Figure 1B), a fact not obse","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"172-177"},"PeriodicalIF":20.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12638","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reciprocal tumor-platelet interaction through the EPHB1-EFNB1 axis in the liver metastatic niche promotes metastatic tumor outgrowth in pancreatic ductal adenocarcinoma","authors":"Lin-Li Yao,&nbsp;Wei-Ting Qin,&nbsp;Li-Peng Hu,&nbsp;Tie-Zhu Shi,&nbsp;Jian Yu Yang,&nbsp;Qing Li,&nbsp;Hui-Zhen Nie,&nbsp;Jun Li,&nbsp;Xu Wang,&nbsp;Lei Zhu,&nbsp;De-Jun Liu,&nbsp;Yan-Li Zhang,&nbsp;Shu-Heng Jiang,&nbsp;Zhi-Gang Zhang,&nbsp;Xiao-Mei Yang,&nbsp;Dong-Xue Li,&nbsp;Xue-Li Zhang","doi":"10.1002/cac2.12637","DOIUrl":"10.1002/cac2.12637","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The interaction between the metastatic microenvironment and tumor cells plays an important role in metastatic tumor formation. Platelets play pivotal roles in hematogenous cancer metastasis through tumor cell-platelet interaction in blood vessels. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy distinguished by its notable tendency to metastasize to the liver. However, the role of platelet in the liver metastatic niche of PDAC remains elusive. This study aimed to elucidate the role of platelets and their interactions with tumor cells in the liver metastatic niche of PDAC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An mCherry niche-labeling system was established to identify cells in the liver metastatic niche of PDAC. Platelet depletion in a liver metastasis mouse model was used to observe the function of platelets in PDAC liver metastasis. Gain-of-function and loss-of-function of erythropoietin-producing hepatocellular receptor B1 (<i>Ephb1</i>), tumor cell-platelet adhesion, recombinant protein, and tryptophan hydroxylase 1 (<i>Tph1</i>)-knockout mice were used to study the crosstalk between platelets and tumor cells in the liver metastatic niche.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The mCherry metastatic niche-labeling system revealed the presence of activated platelets in the liver metastatic niche of PDAC patients. Platelet depletion decreased liver metastatic tumor growth in mice. Mechanistically, tumor cell-expressed EPHB1 and platelet-expressed Ephrin B1 (EFNB1) mediated contact-dependent activation of platelets via reverse signaling-mediated AKT signaling activation, and in turn, activated platelet-released 5-HT, further enhancing tumor growth.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We revealed the crosstalk between platelets and tumor cells in the liver metastatic niche of PDAC. Reciprocal tumor-platelet interaction mediated by the EPHB1-EFNB1 reverse signaling promoted metastatic PDAC outgrowth via 5-HT in the liver. Interfering the tumor-platelet interaction by targeting the EPHB1-EFNB1 axis may represent a promising therapeutic intervention for PDAC liver metastasis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"143-166"},"PeriodicalIF":20.1,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12637","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular smooth muscle cell plasticity in the tumor microenvironment","authors":"Caitlin F. Bell,&nbsp;Richard A. Baylis,&nbsp;Nicolas G. Lopez,&nbsp;Wei Feng Ma,&nbsp;Hua Gao,&nbsp;Fudi Wang,&nbsp;Sharika Bamezai,&nbsp;Changhao Fu,&nbsp;Yoko Kojima,&nbsp;Shaunak S. Adkar,&nbsp;Lingfeng Luo,&nbsp;Clint L. Miller,&nbsp;Nicholas J. Leeper","doi":"10.1002/cac2.12635","DOIUrl":"10.1002/cac2.12635","url":null,"abstract":"&lt;p&gt;Smooth muscle cell (SMC) plasticity plays a prominent role in the pathogenesis of multiple diseases. This phenomenon is characterized by the loss of canonical SMC marker gene expression (such as &lt;i&gt;Acta2&lt;/i&gt; and &lt;i&gt;Myh11&lt;/i&gt;), increased proliferation and migration, and the upregulation of genes typically associated with other cell types, such as macrophages [&lt;span&gt;1-3&lt;/span&gt;]. This process is best described in atherosclerosis, where phenotype switching, clonal expansion, and the aberrant expression of inflammatory and matrix proteins contribute to lesion progression and plaque instability [&lt;span&gt;1-4&lt;/span&gt;]. However, this phenomenon has not been studied in the context of tumorigenesis. Here, we investigated whether SMC diversity and plasticity play a role in the tumor microenvironment (TME) using well-established SMC-lineage tracing mouse models, single cell RNA sequencing (scRNA-seq), and in silico ligand-receptor predictions. Detailed study methods are described in the supplementary materials and methods section. The goal of this work was to determine if vascular SMC plasticity should be prioritized as a translational target in oncology.&lt;/p&gt;&lt;p&gt;Two-colored &lt;i&gt;Myh11&lt;/i&gt; lineage tracing mice have native cells that express tdTomato at baseline. Following tamoxifen administration, any cell expressing MYH11 will lose tdTomato and instead express eGFP (Supplementary Figure S1A-B). Syngeneic colon cancers (MC38) implanted subcutaneously into the flanks of these two-colored mice showed a marked and progressive investment of SMCs into the tumor over an 11-day period (Figure 1A-B, Supplementary Figure S1C). High-resolution fluorescent microscopy revealed the loss of the canonical SMC marker ACTA2 in the eGFP&lt;sup&gt;+&lt;/sup&gt; lineage traced cells, indicating that they may have been misidentified using traditional histological approaches (Figure 1C). eGFP&lt;sup&gt;+&lt;/sup&gt; cells were noted far from discernible vasculature within the TME (Figure 1D-E), suggesting their migration away from endothelial networks into the tumor interstitium. Experiments using a separate Rainbow lineage tracer revealed that the expansion of these cells did not occur in a clonal fashion (Supplementary Figure S1D-E) [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To more precisely define the diversity of these cells, scRNA-seq was performed. Unbiased clustering and uniform manifold approximation and projection (UMAP) analysis of the tumor data showed the representation of all anticipated cell types, identified by their gene expression profiles (Supplementary Figure S1F). As expected, eGFP-expressing cells were concentrated in the SMC cluster but were also surprisingly prevalent within the larger macrophage cluster (Figure 1F), representing 10% of eGFP&lt;sup&gt;+&lt;/sup&gt; cells in total. To define the diversity of SMC-derived cells in the TME, all cells expressing an eGFP transcript ≥ 1 were subset and reanalyzed, identifying eight distinct groups of tumor-associated lineage-traced SMCs (Figure 1G). We then used Monocle3 ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"167-171"},"PeriodicalIF":20.1,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SYNCRIP promotes cell cycle progression and lung tumorigenesis by modulating AURKB translation","authors":"Hyeon Ji Kim,&nbsp;Hye Guk Ryu,&nbsp;Mingyu Kang,&nbsp;Namgyu Lee,&nbsp;Hyo-Jin Kim,&nbsp;Dahye Lee,&nbsp;Chaeuk Chung,&nbsp;Sangjune Kim,&nbsp;Kyung-Ha Lee,&nbsp;Wanil Kim,&nbsp;Jin-Seok Byun,&nbsp;Kyong-Tai Kim,&nbsp;Do-Yeon Kim","doi":"10.1002/cac2.12634","DOIUrl":"10.1002/cac2.12634","url":null,"abstract":"&lt;p&gt;Dysregulation of cellular processes, such as cell division and proliferation, is a hallmark of cancer and is driven by the aberrant expression of cell cycle-related genes [&lt;span&gt;1&lt;/span&gt;]. Aurora kinase B (AURKB), due to its pivotal role in mitotic progression, has been implicated in various cancers. Overexpression or hyperactivation of AURKB significantly contributes to tumorigenesis and cancer progression [&lt;span&gt;2&lt;/span&gt;]. Although mechanisms that enhance AURKB activity, including binding to INCENP, autophosphorylation [&lt;span&gt;3&lt;/span&gt;], and ubiquitination by TRAF6 [&lt;span&gt;4&lt;/span&gt;], have been extensively investigated, regulation of AURKB synthesis, particularly mRNA translation, remains unclear. The translation of eukaryotic mRNAs typically occurs either through cap-dependent scanning or through direct ribosomal binding to specialized RNA elements known as internal ribosome entry sites (IRES). IRES-mediated translation is strongly influenced by specific RNA-binding proteins, known as IRES trans-acting factors (ITAFs). SYNCRIP (Synaptotagmin-binding cytoplasmic RNA-interacting protein), also known as hnRNP Q, has been identified as an ITAF [&lt;span&gt;5&lt;/span&gt;], integrating various aspects of RNA metabolism with key cellular processes. Here, we aim to elucidate the mechanism of &lt;i&gt;AURKB&lt;/i&gt; mRNA translation and investigate whether SYNCRIP regulates &lt;i&gt;AURKB&lt;/i&gt; mRNA translation in lung cancer.&lt;/p&gt;&lt;p&gt;To investigate the mechanisms underlying &lt;i&gt;AURKB&lt;/i&gt; mRNA translation, we analyzed AURKB protein levels following treatment with rapamycin, an inhibitor of eIF4E-mediated cap-dependent translation, and cycloheximide (CHX), an inhibitor of the elongation phase of translation. Treatment with CHX significantly reduced AURKB protein production, whereas rapamycin had no effect, suggesting that &lt;i&gt;AURKB&lt;/i&gt; can be translated via a cap-independent mechanism (Figure 1A, Supplementary Figure S1A-B). To further validate this finding, we used a bicistronic reporter containing the 5′-UTR of &lt;i&gt;AURKB&lt;/i&gt; mRNA positioned between the coding sequences for Renilla (RLUC) and Firefly (FLUC) luciferases (Supplementary Figure S1C). This experiment confirmed that the &lt;i&gt;AURKB&lt;/i&gt; 5’-UTR facilitates translation of a downstream cistron in a cap-independent manner (Figure 1B, Supplementary Figure S1D).&lt;/p&gt;&lt;p&gt;We next examined the correlation between AURKB and SYNCRIP protein expression in human lung cancer tissues. Utilizing the LinkedOmics database, we identified 11,466 genes associated with SYNCRIP in lung adenocarcinoma (LUAD) and 11,928 genes in lung squamous cell carcinoma (LSCC) (Supplementary Figure S2A-B) [&lt;span&gt;6&lt;/span&gt;]. Gene set enrichment analysis revealed a strong positive correlation between AURKB and SYNCRIP in both LUAD and LSCC (Supplementary Figure S2C-G). Additionally, immunoblot analysis revealed higher expression levels of both proteins in tumor tissues compared to adjacent normal tissues (Figure 1C). We further validated the correlation between these prot","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"138-142"},"PeriodicalIF":20.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12634","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotinamide N-methyltransferase negatively regulates metastasis-promoting property of cancer-associated fibroblasts in lung adenocarcinoma","authors":"Peiyu Wang,&nbsp;Guangxi Wang,&nbsp;Haoran Li,&nbsp;Yuyao Yuan,&nbsp;Haiming Chen,&nbsp;Shaodong Wang,&nbsp;Zewen Sun,&nbsp;Fanjie Meng,&nbsp;Yun Li,&nbsp;Fan Yang,&nbsp;Jun Wang,&nbsp;Kezhong Chen,&nbsp;Mantang Qiu","doi":"10.1002/cac2.12633","DOIUrl":"10.1002/cac2.12633","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Recurrence and metastasis remain significant challenges in lung adenocarcinoma (LUAD) after radical resection. The mechanisms behind the recurrence and metastasis of LUAD remain elusive, and deregulated cellular metabolism is suspected to play a significant role. This study explores the metabolic and epigenetic regulation mediated by nicotinamide N-methyl transferase (NNMT) in LUAD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Untargeted metabolomic analyses were performed to detect metabolism irregularities. Single-cell RNA sequencing (RNA-seq) databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment. The biological functions of NNMT were investigated both in vitro and in vivo, with RNA-seq and chromatin immunoprecipitation-PCR providing insights into underlying mechanisms. Finally, single-cell RNA-seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Untargeted metabolomic analyses revealed metabolic aberrations in amino acids, organic acids, lipids, and nicotinamide pathways, which are linked to metastasis of non-small cell lung cancer. NNMT is a key enzyme in nicotinamide metabolism, and we found the bulk tissue mRNA level of &lt;i&gt;NNMT&lt;/i&gt; gene was inversely associated with LUAD metastasis. NNMT was proved to be predominantly expressed in cancer-associated fibroblasts (CAFs) within the stromal regions of LUAD, and a low stromal NNMT expression was identified as a predictor of poor disease-free survival following radical resection of LUAD. The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments, which confirmed that NNMT negatively regulated the metastasis-promoting properties of CAFs in LUAD. Mechanistically, the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle, resulting in heightened methylation at H3K4me3. This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs, including those encoding collagens, integrins, laminins, and matrix metalloproteinases, thereby facilitating cancer cell invasion and metastasis. Reanalysis of single-cell RNA-seq data and immunohistochemistry assays of primary LUAD tissues substantiated NNMT's negative regulation of these genes in CAFs.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study provides novel insights into the metabolic and epigenetic regulatory ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"110-137"},"PeriodicalIF":20.1,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12633","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in cervical cancer: current insights and future directions","authors":"Miaochun Xu,&nbsp;Canhui Cao,&nbsp;Peng Wu,&nbsp;Xiaoyuan Huang,&nbsp;Ding Ma","doi":"10.1002/cac2.12629","DOIUrl":"10.1002/cac2.12629","url":null,"abstract":"<p>In alignment with the World Health Organization's strategy to eliminate cervical cancer, substantial progress has been made in the treatment of this malignancy. Cervical cancer, largely driven by human papillomavirus (HPV) infection, is considered preventable and manageable because of its well-established etiology. Advancements in precision screening technologies, such as DNA methylation triage, HPV integration detection, liquid biopsies, and artificial intelligence-assisted diagnostics, have augmented traditional screening methods such as HPV nucleic acid testing and cytology. Therapeutic strategies aimed at eradicating HPV and reversing precancerous lesions have been refined as pivotal measures for disease prevention. The controversy surrounding surgery for early-stage cervical cancer revolves around identifying optimal candidates for minimally invasive and conservative procedures without compromising oncological outcomes. Recent clinical trials have yielded promising results for the development of systemic therapies for advanced cervical cancer. Immunotherapies, such as immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and targeted therapy have demonstrated significant effectiveness, marking a substantial advancement in cervical cancer management. Various combination therapies have been validated, and ongoing trials aim to enhance outcomes through the development of novel drugs and optimized combination regimens. The prospect of eradicating cervical cancer as the first malignancy to be eliminated is now within reach. In this review, we provide a comprehensive overview of the latest scientific insights, with a particular focus on precision managements for various stages of cervical disease, and explore future research directions in cervical cancer.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"77-109"},"PeriodicalIF":20.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12629","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTPN9 regulates HER3 phosphorylation during trastuzumab treatment and loss of PTPN9 is a potential biomarker for trastuzumab resistance in HER2 positive breast cancer","authors":"Abul Azad,&nbsp;Maryam Arshad,&nbsp;Daniele Generali,&nbsp;Katharina Feldinger,&nbsp;Merel Gijsen,&nbsp;Carla Strina,&nbsp;Mariarosa Cappelletti,&nbsp;Daniele Andreis,&nbsp;Russell Leek,&nbsp;Syed Haider,&nbsp;Pirkko-Liisa Kellokumpu-Lehtinen,&nbsp;Ioannis Roxanis,&nbsp;Adrian Llewellyn Harris,&nbsp;Abeer Mahmoud Shaaban,&nbsp;Heikki Joensuu,&nbsp;Anthony Kong","doi":"10.1002/cac2.12632","DOIUrl":"10.1002/cac2.12632","url":null,"abstract":"&lt;p&gt;Although trastuzumab does not bind to human epidermal growth factor receptor 3 (HER3), it dephosphorylates HER3 through a previously unknown mechanism. In addition, HER3 is reactivated during prolonged trastuzumab treatment and upon resistance [&lt;span&gt;1&lt;/span&gt;]. Previous study showed that tyrosine-protein phosphatase non-receptor type 9 (PTPN9) inhibits STAT3/STAT5 signalling by dephosphorylation of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in breast cancer [&lt;span&gt;2&lt;/span&gt;], but how this would affect HER3 was not analyzed especially in relation to trastuzumab treatment. We investigated the role of PTPN9 in HER3 signaling in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. The materials and methods applied in this research were described in the supplementary materials.&lt;/p&gt;&lt;p&gt;We showed that PTPN9 was upregulated after trastuzumab treatment in both SKBR3 and BT474 cells (Figure 1A), but this is not the case for two other PTPs which are known to regulate EGFR and HER2 respectively, PTP1B and PTPN13 [&lt;span&gt;3, 4&lt;/span&gt;] (Supplementary Figure S1A). The upregulation of PTPN9 occurred concomitantly with a decrease in the phosphorylation of HER3 and its downstream effector protein kinase B (PKB or Akt), but not HER2 and EGFR (Figure 1A and Supplementary Figure S1B). Moreover, HER3 and Akt were reactivated in trastuzumab-resistant SKBR3 and BT474 cells with a concomitant decreased PTPN9 expression. In contrast, EGFR and HER2 phosphorylation was not decreased by trastuzumab treatment but was further increased during trastuzumab resistance, which was previously shown to be due to a disintegrin and metalloproteinase 10/17 (ADAM10/17) mediated HER ligand activation [&lt;span&gt;1, 5&lt;/span&gt;]. In immunofluorescence studies, PTPN9 expression was upregulated in cytoplasm and co-localized with the cytoplasmic HER3 following trastuzumab treatment for 4 hours in both SKBR3 and BT474 cells (Supplementary Figure S1C), correlated with a decrease of pHER3 seen in the western blot at this time point. PTPN9 expression was decreased again in trastuzumab-resistant BT474 and SKBR3 cells (Supplementary Figure S1C) which was correlated with a reactivation of HER3. Similarly, PTPN9 expression and pHER3 levels were seen to be inversely correlated during trastuzumab treatment in MDA-MB-453 and MDA-MB-361 cells (Supplementary Figure S1D). In relation to other anti-HER2 therapies, trastuzumab and ado-trastuzumab emtansine (T-DM1) (and to much lesser extent for trastuzumab deruxtecan [TDxd] but not neratinib and pertuzumab monotherapy) could increase PTPN9 expression (Supplementary Figure S1E), although decreased HER3 and Akt phosphorylation was seen in all drugs, which may reflect the different mechanisms of action of these drugs. The trastuzumab-based combination treatment also upregulated PTPN9 expression with concomitant decrease in HER3 and Akt phosphorylation (Supplementary Figure S1E).&lt;/p&gt;&lt;p&gt;Next, we ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"68-73"},"PeriodicalIF":20.1,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}