Cancer Communications最新文献

{"title":"Sexual dimorphism in the antitumor immune responses elicited by the combination of fasting and chemotherapy","authors":"Andrés Pastor-Fernández, Manuel Montero Gómez de las Heras, Jose Ignacio Escrig-Larena, Marta Barradas, Cristina Pantoja, Adrian Plaza, Jose Luis Lopez-Aceituno, Esther Durán, Alejo Efeyan, Maria Mittelbrunn, Lola Martinez, Pablo Jose Fernandez-Marcos","doi":"10.1002/cac2.12535","DOIUrl":"10.1002/cac2.12535","url":null,"abstract":"<p>Fasting reduces chemotherapy toxicity [<span>1</span>], enhances immunogenic tumor cell death [<span>2, 3</span>] and increases CD8<sup>+</sup> T cell infiltration in tumors, particularly when combined with chemotherapy [<span>2, 3</span>] or immunotherapy [<span>4</span>]. Moreover, fasting exhibits a sexual dimorphism in the immune system [<span>5</span>].</p><p>The aim of our study was to elucidate the role of sex in the beneficial anti-tumoral effects of combining fasting and chemotherapy. For this, we inoculated B16-F10-derived melanoma allografts into immunocompetent male and female mice. Three days later, the mice were divided into: (1) not treated; (2) two cycles of 48-hour fasting; (3) two cycles of 10 mg/kg doxorubicin; (4) two cycles of doxorubicin and fasting for 24 hours before and 24 hours after doxorubicin inoculation (“combination treatment” or “CT”). The study methods are shown in the Supplementary Material file. Doxorubicin and fasting alone reduced tumor growth in both sexes with the same efficacy, and CT amplified this effect only in males (Figure 1A and Supplementary Figure S1A-C). Male mice bearing YUMM1.7 melanoma-derived tumors responded to fasting and doxorubicin, but females were insensitive to any of them (Figure 1B and Supplementary Figure S2A-C). Oxaliplatin did not affect B16-F10 tumor growth (Supplementary Figure S3A-D). Fasting reduced serum levels of testosterone only in males ([<span>6, 7</span>] and Supplementary Figure S4A). To explore the role of testosterone, we castrated males or implanted testosterone pellets in females. CT lost efficacy in castrated males and became efficient in females with testosterone pellets (Figure 1C and Supplementary Figure S4B-E). Next, we inoculated mice with MC38 colon carcinoma cells [<span>8</span>]. Oxaliplatin or fasting reduced tumor growth, and CT amplified this effect in both sexes (Figure 1D and Supplementary Figure S5A-C). Our findings indicate that sexual dimorphism occurs in different tumor types, is dependent on tumor and chemotherapy type, and testosterone is a key player in this sexual dimorphism.</p><p>To study the immune response in B16-F10 allografts treated with doxorubicin and/or fasting (Supplementary Figure S6A-D), we analyzed relevant immune cell types in inguinal lymph nodes (LN), peripheral blood (B) and tumors (T) (Supplementary Table S1-S4). CT increased stage II Natural Killer (NK) and Natural Killer T (NKT) cells in B16-F10 tumors only in males (Figure 1E-F and Supplementary Figure S6E-H). Females on CT had more exhausted CD8<sup>+</sup> T cells in their tumors (Figure 1G and Supplementary Figure S6I-K). Tumor-infiltrated CD8<sup>+</sup> T cells were functionally more active in CT in males (Supplementary Figure S7A-C), while serum TNFα did not change (Supplementary Figure S7D-E). Immunoablation of CD8 cells in male mice tended to reduce CT efficacy, which still improved the antitumor response (Supplementary Figure S8A-F and Supplementary Table S5), ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"508-513"},"PeriodicalIF":16.2,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12535","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183846","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":"Conserved immuno-collagenic subtypes predict response to immune checkpoint blockade","authors":"Jie Mei,&nbsp;Yun Cai,&nbsp;Rui Xu,&nbsp;Qing Li,&nbsp;Jiahui Chu,&nbsp;Zhiwen Luo,&nbsp;Yaying Sun,&nbsp;Yuxin Shi,&nbsp;Junying Xu,&nbsp;Di Li,&nbsp;Shuai Liang,&nbsp;Ying Jiang,&nbsp;Jiayu Liu,&nbsp;Zhiwen Qian,&nbsp;Jiaofeng Zhou,&nbsp;Mengyun Wan,&nbsp;Yunlong Yang,&nbsp;Yichao Zhu,&nbsp;Yan Zhang,&nbsp;Yongmei Yin","doi":"10.1002/cac2.12538","DOIUrl":"10.1002/cac2.12538","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both preclinical and clinical, underscores the pivotal role of the extracellular matrix (ECM) in modulating immune cell infiltration and behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy. This analysis led to the identification of three distinct immuno-collagenic subtypes predictive of ICB responses. We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas (TCGA) dataset and 1,084 in-house samples. Additionally, novel therapeutic targets were identified based on these established immuno-collagenic subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our categorization divided tumors into three subtypes: “soft &amp; hot” (low collagen activity and high immune infiltration), “armored &amp; cold” (high collagen activity and low immune infiltration), and “quiescent” (low collagen activity and immune infiltration). Notably, “soft &amp; hot” tumors exhibited the most robust response to ICB therapy across various cancer types. Mechanistically, inhibiting collagen augmented the response to ICB in preclinical models. Furthermore, these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types. Additionally, an unbiased approach identified B7 homolog 3 (B7-H3), an available drug target, as strongly expressed in “armored &amp; cold” tumors, relating with poor prognosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study introduces histopathology-based universal immuno-collagenic subtypes capable of predicting ICB responses across diverse cancer types. These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 5","pages":"554-575"},"PeriodicalIF":16.2,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12538","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140165459","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":"Positive regulation of cell proliferation by the miR-1290-EHHADH axis in hepatocellular carcinoma","authors":"Jinkwon Lee,&nbsp;Gyeonghwa Kim,&nbsp;Tae-Su Han,&nbsp;Eunsun Jung,&nbsp;Taesang Son,&nbsp;Kwangho Kim,&nbsp;Kiyoon Kwon,&nbsp;Yuna Roh,&nbsp;Tae Young Ryu,&nbsp;In Hwan Tae,&nbsp;Yunsang Kang,&nbsp;Byungheon Lee,&nbsp;Yu Rim Lee,&nbsp;Soo Young Park,&nbsp;Won Young Tak,&nbsp;Dae-Soo Kim,&nbsp;Mi-Young Son,&nbsp;Keun Hur,&nbsp;Hyun-Soo Cho","doi":"10.1002/cac2.12536","DOIUrl":"10.1002/cac2.12536","url":null,"abstract":"&lt;p&gt;Hepatocellular carcinoma (HCC) is the second most common cancer and the third leading cause of cancer-related death worldwide [&lt;span&gt;1&lt;/span&gt;]. Recently, HCC incidence and mortality rates have further increased due to changes in the global social environment and dietary habits [&lt;span&gt;2&lt;/span&gt;]. HCC is treated by surgical resection or combination chemotherapy, but the overall survival rate of HCC patients has not improved, and the recurrence rate is still high due to strong invasiveness and resistance to chemotherapy [&lt;span&gt;3&lt;/span&gt;]. Therefore, it is necessary to understand the pathogenesis of HCC and identify novel diagnostic biomarkers and therapeutic targets for the treatment of HCC. Recently, microRNA-1290 (miR-1290) has been reported to regulate the progression of many types of malignant cancers, such as colorectal cancer [&lt;span&gt;4&lt;/span&gt;], lung cancer [&lt;span&gt;5&lt;/span&gt;], and HCC [&lt;span&gt;6&lt;/span&gt;]. However, research on the therapeutic targets of miR-1290 is still needed. Thus, in this study, we will use HCC patient samples to assess the potential of miR-1290 as both a diagnostic marker and a therapeutic target, and we will demonstrate its oncogenic properties through functional and mechanistic studies. The methods and materials were described in Supplementary Materials andMethods.&lt;/p&gt;&lt;p&gt;To discover HCC development-specific microRNAs (miRNAs), we performed NanoString-based miRNA expression profiling in 5 steatohepatitis cirrhosis (SHC) tissues and 5 early-stage HCC tissues. Eleven miRNAs were discovered to be differentially expressed between SHC and HCC tissues (Figure 1A). Among them, miR-1290 was upregulated in HCC compared to SHC and was selected based on its cell proliferation and differentiation function in cancers [&lt;span&gt;7, 8&lt;/span&gt;]. In a subsequent validation step, the miR-1290 was found to be significantly elevated in HCC tissues compared to either SHC (&lt;i&gt;P&lt;/i&gt; = 0.043) or normal healthy liver tissues (NT) (&lt;i&gt;P&lt;/i&gt; = 0.019) (Figure 1B). In addition, miR-1290 expression was significantly upregulated as the TNM stage increased in an independent cohort of 111 HCC patients (Figure 1C; ANOVA test &lt;i&gt;P&lt;/i&gt; = 0.002). To demonstrate the clinical relevance of miR-1290 expression in patients with HCC, we determined the association between miR-1290 expression and various clinicopathological variables in a cohort of 111 HCC patients (Supplementary Table S1). The expression of miR-1290 was associated with factors reflecting disease progression, such as T stage (&lt;i&gt;P&lt;/i&gt; &lt; 0.001), M stage (&lt;i&gt;P&lt;/i&gt; = 0.011), TNM stage (&lt;i&gt;P&lt;/i&gt; = 0.003), and BCLC stage (&lt;i&gt;P&lt;/i&gt; &lt; 0.001). Moreover, the 5-year overall survival rate was significantly lower in high miR-1290-expressing HCC patients (log-rank &lt;i&gt;P&lt;/i&gt; &lt; 0.001) (Figure 1D). Next, the Univariate Cox proportional hazards analysis (Supplementary Table S2) revealed that T stage (HR 4.60; 95% CI 2.76 to 7.66; &lt;i&gt;P&lt;/i&gt; &lt; 0.001), N stage (HR 3.21; 95% CI 1.52 to 6.78; &lt;i&gt;P&lt;/i&gt; = 0.002), M stage (H","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 6","pages":"705-709"},"PeriodicalIF":20.1,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11194445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157621","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":"Disclosing the true impact of screening endoscopy in colorectal cancer prevention","authors":"Thomas Heisser,&nbsp;Carlo Senore,&nbsp;Michael Hoffmeister,&nbsp;Lina Jansen,&nbsp;Hermann Brenner","doi":"10.1002/cac2.12531","DOIUrl":"10.1002/cac2.12531","url":null,"abstract":"&lt;p&gt;Preprint: https://doi.org/10.1101/2022.11.22.22282622&lt;/p&gt;&lt;p&gt;Randomized trials, cohort and modeling studies have consistently demonstrated a major impact of screening endoscopies on reducing colorectal cancer (CRC) incidence and mortality [&lt;span&gt;1&lt;/span&gt;]. Over time, CRC mortality starts to be lower in those who underwent screening compared to those who did not due to earlier detection of prevalent, preclinical (asymptomatic) cases and lowering incidence through removing precancerous lesions. By contrast, measured incidence shows an initial apparent increase in the screening group due to the detection of preclinical (i.e., already prevalent) cancer. Only after around 4-6 years of follow-up, the measured cumulative incidence also starts to be lower in the screening group due to later manifestation of the initially preclinical cases in the control group and removal of precancerous lesions in the screening group [&lt;span&gt;2-6&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;However, measured incidence rates do not reflect true incidence rates as they are a mix of truly incident cases and cases that are already prevalent in the preclinical stage at baseline. As screening endoscopies cannot prevent prevalent CRC cases (but only remove precursor lesions at risk of developing into CRC), the commonly measured and reported effects on CRC incidence do not quantify the true endoscopy impact on CRC incidence, i.e., the impact on preventing newly developing CRC cases. In the present study, we sought to quantify the true impact of screening endoscopy on CRC incidence.&lt;/p&gt;&lt;p&gt;First, by re-calibrating the Colorectal Cancer Multistate Simulation Model (COSIMO), a thoroughly validated modeling approach, we replicated the Screening for COlon REctum trial (SCORE), a large, randomized trial (&lt;i&gt;n&lt;/i&gt; = 34,292) examining the effect of a single flexible sigmoidoscopy in reducing CRC incidence and mortality by matching the numbers of simulated subjects and allocation per group with reported baseline numbers by sex and age, also taking into account colonoscopy referral and background endoscopy use [&lt;span&gt;5&lt;/span&gt;]. Further details are provided in the Supplementary Material and Methods. The primary validation objective was the agreement between modeled and in SCORE reported incidence rate ratios (in the following: incidence rate ratio [unadjusted], IRR&lt;sub&gt;Unadjusted&lt;/sub&gt;). The results were considered consistent if modeled estimates were within the 95% confidence intervals of the corresponding outcomes reported for SCORE.&lt;/p&gt;&lt;p&gt;Then, to determine the impact of prevalent preclinical CRCs on IRR&lt;sub&gt;Unadjusted&lt;/sub&gt;, we calculated the adjusted IRR (incidence rate ratio (adjusted), IRR&lt;sub&gt;Adjusted&lt;/sub&gt;, excluding prevalent CRCs at baseline) for the screening versus control groups by omitting the sex- and age-specific number of cases arising from prevalent preclinical CRC from the model calculation of IRRs for each year of follow-up.&lt;/p&gt;&lt;p&gt;Incidence rates and IRR&lt;sub&gt;Unadjusted&lt;/sub&gt; predicted by COSIMO foll","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"504-507"},"PeriodicalIF":16.2,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12531","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142785","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":"Deciphering metastatic route-specific signals and their microenvironment interactions in peritoneal metastasis of gastric cancer","authors":"Ki Tae Kim,&nbsp;Jae Eun Lee,&nbsp;Jae-Ho Cheong,&nbsp;In Cho,&nbsp;Yoon Young Choi","doi":"10.1002/cac2.12533","DOIUrl":"10.1002/cac2.12533","url":null,"abstract":"&lt;p&gt;Gastric cancer (GC) is a pervasive global malignancy with high mortality rates due to distant metastasis [&lt;span&gt;1&lt;/span&gt;]. GC metastasis can occur via hematogenous route, peritoneal route, and specifically through ovarian spread in females [&lt;span&gt;2&lt;/span&gt;]. Among these, peritoneal metastasis is the most prevalent and challenging condition to treat [&lt;span&gt;3&lt;/span&gt;]. The Cancer Genome Atlas (TCGA) has uncovered four molecular subtypes of GC: microsatellite instability, Epstein-Barr virus-related, chromosomal instability, and genomically stable [&lt;span&gt;4&lt;/span&gt;]. These subtypes exhibit unique features and metastatic behaviors [&lt;span&gt;5&lt;/span&gt;], providing valuable insights into the molecular characteristics of GC. Nevertheless, there remains a gap in understanding gene expression feature in metastatic GC compared to corresponding primary tumors, particularly regarding its biological and clinical relevance in different metastatic patterns.&lt;/p&gt;&lt;p&gt;A whole-transcriptome sequencing analysis was conducted to investigate the characteristics of metastatic GC. We examined 66 paired primary and metastatic tumors, categorized according to their sites (38 primary, 9 hematogenous, 6 peritoneal, and 13 ovarian metastases), collected from 14 patients with GC metastasis (Supplementary Tables S1-S2 and Supplementary Figure S1). To corroborate the biological and clinical relevance of the identified metastatic GC-specific signals, we utilized publicly available databases containing expression data on primary GC, including TCGA (&lt;i&gt;n&lt;/i&gt; = 415) [&lt;span&gt;4&lt;/span&gt;], Asian Cancer Research Group (ACRG, &lt;i&gt;n&lt;/i&gt; = 300) [&lt;span&gt;6&lt;/span&gt;], and Yonsei Cancer Center (YCC, &lt;i&gt;n&lt;/i&gt; = 433) cohorts [&lt;span&gt;7&lt;/span&gt;]. For in-depth analysis at the single-cell resolution, we accessed a public dataset comprising 5 primary GC samples [&lt;span&gt;8&lt;/span&gt;] and performed a single-cell RNA sequencing (scRNA-seq) analysis on ascites obtained from 4 patients with GC (Supplementary Tables S3-S4). The flow of analysis is summarized in Supplementary Figure S2. Details of the patient demographics, samples, and data analysis methods used are outlined in the Supplementary Methods.&lt;/p&gt;&lt;p&gt;Through a differential expression analysis of the 66 paired primary and metastatic tumors, we identified 949 genes uniquely associated with metastatic GC tumors (Supplementary Figure S3). Subsequent over-representation analysis of these metastatic GC-specific genes indicated that hematogenous metastatic tumors exhibited an up-regulation of receptor tyrosine kinase-related signals, while simultaneously showing a down-regulation of pathways associated with epithelial-mesenchymal transition (EMT) (Supplementary Figure S4). Conversely, peritoneal/ovarian metastatic tumors demonstrated an upregulation of the Hedgehog pathway, a key player in EMT signaling. These findings suggest that the mechanisms underlying GC metastasis vary by route [&lt;span&gt;5&lt;/span&gt;], thus underscoring the need for route-specific clinical considerations.&lt;/p&gt;","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"514-517"},"PeriodicalIF":16.2,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12533","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140148000","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":"Impact of pre-existing cardiometabolic diseases on metastatic cancer stage at diagnosis: a prospective multinational cohort study","authors":"Anna Jansana,&nbsp;Aviane Auguste,&nbsp;Marina Kvaskoff,&nbsp;Agnès Fournier,&nbsp;Emma Fontvieille,&nbsp;Laia Peruchet-Noray,&nbsp;Carine Biessy,&nbsp;Reynalda Cordova,&nbsp;Kristina Elin Nielsen Petersen,&nbsp;Anne Tjønneland,&nbsp;Verena Katzke,&nbsp;Rudolf Kaaks,&nbsp;Fulvio Ricceri,&nbsp;Salvatore Panico,&nbsp;Paolo Contiero,&nbsp;Maria-Jose Sánchez,&nbsp;Jesus Castilla,&nbsp;Marta Crous-Bou,&nbsp;Alicia Heath,&nbsp;Elom Kouassivi Aglago,&nbsp;Elisabete Weiderpass,&nbsp;Marc James Gunter,&nbsp;Pietro Ferrari,&nbsp;Elio Riboli,&nbsp;Vivian Viallon,&nbsp;Heinz Freisling","doi":"10.1002/cac2.12526","DOIUrl":"10.1002/cac2.12526","url":null,"abstract":"&lt;p&gt;Owing to shared risk factors between cardiometabolic diseases (CMDs) and cancer, coupled with population aging, the lifetime risk of an individual developing cancer after a CMD is increasing. Furthermore, biological mechanisms such as insulin resistance or inflammation may not only predispose individuals with CMD to an elevated risk of certain types of cancer but also to a diagnosis of cancer at an advanced stage [&lt;span&gt;1, 2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Cancer stage at diagnosis strongly correlates with cancer survival rates and impacts treatment decisions. Early cancer detection is key to improving cancer outcomes, especially for cancers with poor prognosis. Factors associated with a higher risk of an advanced-stage diagnosis may differ from those associated with cancer incidence. Previous studies support an association between advanced-stage cancer at diagnosis and certain patient characteristics, such as higher body mass index (BMI), older age, smoking, comorbidities, and cancer type. Studies examining the influence of comorbidities on cancer stage at diagnosis have suggested that a CMD requiring regular medical follow-up is associated with earlier cancer detection [&lt;span&gt;3, 4&lt;/span&gt;]. However, studies have also suggested that overall participation rates in cancer screening programs may be lower among individuals with type 2 diabetes (T2D) or cardiovascular diseases (CVD), which may lead to later cancer detection and a more advanced stage at diagnosis [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;A better understanding of how CMDs prior to cancer are associated with stage at cancer diagnosis may inform cancer screening recommendations. This study aimed to investigate whether having a pre-existing CMD is associated with late-stage cancer diagnosis and to identify potential modifiers of this association in the European Prospective Investigation into Cancer and Nutrition study (EPIC).&lt;/p&gt;&lt;p&gt;This multinational prospective cohort study included 11,945 individuals diagnosed with first primary cancer between 1992 and 2012. Of all the diagnosed cancers, 64.9% were localized, 35.1% were metastatic, 53.6% were diagnosed in women, and 4.8%, a, 7.1%, and 1.3% had a history of CVD, of T2D, and of both CVD and T2D, respectively (Supplementary Figure S1, Supplementary Table S1). In addition to overall cancer, breast and colorectal cancers (38.1% of all cancers) were also investigated separately because of the well-established population-based cancer screening programs for these two cancers at the time of cancer diagnosis in the countries included in this study (i.e., Denmark, Germany, Italy, Spain, Sweden, and the UK). Detailed methods are described in Supplementary Materials.&lt;/p&gt;&lt;p&gt;We found that the adjusted odds ratios (ORs) of developing metastatic cancer (vs. localized) comparing individuals with pre-existing CVD, T2D or both to those without a CMD prior to cancer were 0.92 (95% confidence interval [CI] = 0.65-1.01), 1.04 (95% CI = 0.83-1.18) and 1.06 (95% CI = 0.60-1.36), respectively ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 5","pages":"593-597"},"PeriodicalIF":16.2,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12526","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130795","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 mechanism of resistance to CDK4/6 inhibition and novel combination therapy with RNR inhibition for chemo-resistant bladder cancer","authors":"Zhichao Tong,&nbsp;Yubo Zhao,&nbsp;Shiyu Bai,&nbsp;Benedikt Ebner,&nbsp;Lou Lienhard,&nbsp;Yuling Zhao,&nbsp;Ziqi Wang,&nbsp;Qi Pan,&nbsp;Pengyu Guo,&nbsp;Thilo Bracht,&nbsp;Barbara Sitek,&nbsp;Jürgen E. Gschwend,&nbsp;Wanhai Xu,&nbsp;Roman Nawroth","doi":"10.1002/cac2.12532","DOIUrl":"10.1002/cac2.12532","url":null,"abstract":"&lt;p&gt;Bladder cancer (BCa) is the most prevalent urological cancer worldwide [&lt;span&gt;1&lt;/span&gt;]. A significant proportion of BCa (89%) exhibits molecular alterations in the cell cycle pathway, and targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is deemed as a promising therapeutic strategy [&lt;span&gt;2&lt;/span&gt;]. Selective inhibitors of CDK4/6 (CDK4/6is) have been approved by the US Food and Drug Administration (FDA) [&lt;span&gt;3&lt;/span&gt;]. They could induce cell cycle arrest in BCa immediately, and after this “sensitive stage”, unknown compensatory mechanism may cause acquired resistance [&lt;span&gt;4, 5&lt;/span&gt;]. To address this issue, our study employed multi-omics and identified ribonucleotide reductase regulatory subunit M2 (RRM2), a crucial component of the ribonucleotide reductase (RNR) complex [&lt;span&gt;6&lt;/span&gt;], as a key mediator in conferring acquired resistance. We further investigated whether Palbociclib activates proteolysis of RRM2 by the ubiquitin-proteasome system (UPS) and the ubiquitin-like proteins (UBLs) during the sensitive stage. Additionally, we explored whether RRM2 is controlled by E2F transcription factor 3 (E2F3) when acquired resistance is established. Interestingly, upregulation of RRM2 may also cause chemotherapy resistance [&lt;span&gt;7&lt;/span&gt;]. Thus, we verified if concurrent inhibition of RNR and CDK4/6 holds promise as a novel therapeutic strategy for BCa patients, especially those exhibit resistance to chemotherapy. All the study designs and methods are described in the Supplementary file.&lt;/p&gt;&lt;p&gt;Retinoblastoma (RB)-positive BCa elicits a sequential progression from sensitivity to resistance to Palbociclib [&lt;span&gt;8&lt;/span&gt;]. We utilized multi-omics to identify key regulators of this process (Figure 1A, Supplementary Tables S1-S5). The only candidate matching all three high-throughput screening approaches was RRM2, and pathway analysis further demonstrated related mechanisms (Supplementary Figures S1-S2). To validate this finding, we examined the cell cycle distribution and expression levels of the other RNR subunit RRM1 and RRM2 in a time kinetic (Figure 1B-C, Supplementary Figure S3A-D). Transcript levels were initially downregulated, followed by a partial recovery, while the decline and recovery pattern of proteins mirrored this. We then transduced single-guide RNAs of RRM1 and RRM2 into T24 synergistic activation mediator (SAM) cells and confirmed partial resistance (Figure 1D-E, Supplementary Figure S3E). However, degradation of RRM2 was still observed at early time points (Supplementary Figure S3F), indicating that proteolysis might be essential for therapy response. We then applied the proteasome inhibitors Epoxomicin/MG-132 in combination with Palbociclib. As shown, protein degradation of RRM2 was effectively blocked, but only partially for RRM1 (Figure 1F, Supplementary Figure S4A-B). We next tested the combination of Palbociclib with ubiquitin-like proteins (UBLs) inhibitor MLN4924 and proved that the initial degradation of RRM1/2","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 6","pages":"700-704"},"PeriodicalIF":20.1,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11194448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101078","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":"Revealing the secret behind Epstein-Barr virus-specific tumor immune contexture","authors":"Chu-Xia Deng","doi":"10.1002/cac2.12529","DOIUrl":"10.1002/cac2.12529","url":null,"abstract":"&lt;p&gt;Immune checkpoint inhibitor (ICI) therapy has significantly revolutionized cancer treatment across various malignancies, offering distinct and enduring clinical advantages [&lt;span&gt;1&lt;/span&gt;]. Gastric cancer (GC) represents a widespread and life-threatening malignancy with substantial global health implications [&lt;span&gt;2&lt;/span&gt;]. However, ICI therapy has not produced satisfactory therapeutic responses in GC patients. Presently, monotherapy targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway demonstrates clinical efficacy in approximately 10% of GC patients [&lt;span&gt;3&lt;/span&gt;]. Exploration of novel immunotherapeutic targets is urgently needed. Notably, Epstein-Barr virus (EBV)-positive GC constitutes a distinct GC subset, exhibiting a remarkably higher objective response rate to anti-PD-1 inhibitors—an intriguing phenomenon [&lt;span&gt;4&lt;/span&gt;]. Several studies have found that EBV-positive GC has more innate and adaptive immune cell infiltration than EBV-negative GC [&lt;span&gt;5, 6&lt;/span&gt;]. In their recent publication titled “Dynamic single-cell mapping reveals Epstein-Barr virus-imprinted T-cell exhaustion and on-treatment response”, Qiu &lt;i&gt;et al.&lt;/i&gt; [&lt;span&gt;7&lt;/span&gt;] unveiled, for the first time, the cellular basis underlying these remarkably heightened responses in EBV-positive GC patients undergoing immunochemotherapy. Leveraging single-cell profiling technologies, this study deepened our comprehension of the intricate and heterogeneous tumor microenvironment in GC.&lt;/p&gt;&lt;p&gt;In this study, the authors conducted a comprehensive characterization of the cellular dynamics of tumor-infiltrating immune cells in GC patients, distinguishing between those with EBV-positive and EBV-negative statuses. EBV-positive GC exhibited a heightened immune phenotype characterized by elevated infiltration of T cells and B cells, highlighting the intricate interplay among EBV infection, multi-cellular ecosystems, and tumor development. EBV-negative GC exhibited an immune-suppressive tumor microenvironment characterized by an abundance of plasma cells, myeloid cells, and mast cells. After treatment, the evaluation of the dynamic changes in EBV-positive GC showed an increased presence of cytotoxic CD8&lt;sup&gt;+&lt;/sup&gt; T cells and effector memory/memory CD8&lt;sup&gt;+&lt;/sup&gt; T cells. Notably, there was clear evidence of clonal revival and reinvigoration of CD8&lt;sup&gt;+&lt;/sup&gt; T cells in EBV-positive GC patients, indicating an active T cell-mediated immune reaction enhancing treatment responses.&lt;/p&gt;&lt;p&gt;Furthermore, the authors observed a distinct EBV-imprinted CD8&lt;sup&gt;+&lt;/sup&gt; T cell population, ISG-15&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt; T cells, which exhibited significantly higher expression of interferon-stimulated genes, such as ISG-15, IFIT1-3, RASD2, and MX1. Significantly, ISG-15&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt; T cells demonstrated the ability to recognize EBV antigens and coordinated exhausted T cell responses. STARTRAC-tran analysis revealed a robust association bet","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"491-494"},"PeriodicalIF":16.2,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12529","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038740","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":"Unveiling quality of clinical trial in China: from concern to confirmation","authors":"Huiyao Huang,&nbsp;Yiru Hou,&nbsp;Hong Fang,&nbsp;Ling Xu,&nbsp;Yue Yu,&nbsp;Huifang Zhang,&nbsp;Jing Zhang,&nbsp;Yu Tang,&nbsp;Gongtao Lan,&nbsp;Wenbao Zhang,&nbsp;Ning Li","doi":"10.1002/cac2.12528","DOIUrl":"10.1002/cac2.12528","url":null,"abstract":"&lt;p&gt;The cornerstone of scientifically valid and ethically sound clinical trials is in compliance with established global quality requirements. Although China has made significant progress over the past 20 years in terms of the clinical trial quantity [&lt;span&gt;1&lt;/span&gt;], quality and participation in multiregional trials [&lt;span&gt;2&lt;/span&gt;], there still remain concerns regarding the trial quality, which could be associated with the self-inspection initiative in 2015 [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In fact, the clinical trial quality in China has improved significantly during the past decade, which is reflected in the harmonized development trends of industry quality systems and regulatory quality promotion systems (Figure 1). In 2003, the China Good Clinical Practice (GCP) guidelines have been released, which identified the subject protection and data integrity as two basic principles of clinical trials. Four rigorous management policies started to implement in 2015, which required sponsors to re-evaluate the authenticity, integrity, and compliance of trial data before new drug application [&lt;span&gt;4&lt;/span&gt;]. A series of high-profile policies were subsequently announced by the National Medical Products Administration, to improve quality ecosystem [&lt;span&gt;5&lt;/span&gt;]. The regulatory supervision of trial quality in China has been significantly strengthened since then. In the meantime, a vital shift occurred since the quality culture in the industry emerged, and the approaches and tools of quality management systems were launched through information exchange and training.&lt;/p&gt;&lt;p&gt;Another milestone of trial quality progress in China was that China officially joined the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and began to integrate into the international drug regulatory system. This alliance initiated a proactive and harmonized process with China pledging to gradually transform its pharmaceutical regulatory authorities, industry and institutions to implement the international coalition's technical standards and guidelines [&lt;span&gt;6&lt;/span&gt;]. Universal quality standard GCP guidelines and ideas, such as quality by design (QbD) and risk-based inspection, could be implemented almost simultaneously in China. Gradually, trial quality culture has been embedded in the full life cycle of drug research and development (R&amp;D) in China.&lt;/p&gt;&lt;p&gt;All four regions, including China, the European Union (EU), the United States (US) and Japan, have a common consensus and harmonized standards to ensure the participants’ safety, data integrity and GCP compliance, and all have established similar regulatory frameworks for quality compliance (Supplementary Table S1). For example, local and international GCP standards and principles should be established, then inspection processes and checklists with key points for investigational drugs should be employed. In terms of inspection objects, types, requirements and disclosure, we observed cons","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 5","pages":"576-579"},"PeriodicalIF":16.2,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12528","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038741","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":"Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study","authors":"Jing Zheng,&nbsp;Tao Wang,&nbsp;Yunpeng Yang,&nbsp;Jie Huang,&nbsp;Jifeng Feng,&nbsp;Wu Zhuang,&nbsp;Jianhua Chen,&nbsp;Jun Zhao,&nbsp;Wei Zhong,&nbsp;Yanqiu Zhao,&nbsp;Yiping Zhang,&nbsp;Yong Song,&nbsp;Yi Hu,&nbsp;Zhuang Yu,&nbsp;Youling Gong,&nbsp;Yuan Chen,&nbsp;Feng Ye,&nbsp;Shucai Zhang,&nbsp;Lejie Cao,&nbsp;Yun Fan,&nbsp;Gang Wu,&nbsp;Yubiao Guo,&nbsp;Chengzhi Zhou,&nbsp;Kewei Ma,&nbsp;Jian Fang,&nbsp;Weineng Feng,&nbsp;Yunpeng Liu,&nbsp;Zhendong Zheng,&nbsp;Gaofeng Li,&nbsp;Huijie Wang,&nbsp;Shundong Cang,&nbsp;Ning Wu,&nbsp;Wei Song,&nbsp;Xiaoqing Liu,&nbsp;Shijun Zhao,&nbsp;Lieming Ding,&nbsp;Giovanni Selvaggi,&nbsp;Yang Wang,&nbsp;Shanshan Xiao,&nbsp;Qian Wang,&nbsp;Zhilin Shen,&nbsp;Jianya Zhou,&nbsp;Jianying Zhou,&nbsp;Li Zhang","doi":"10.1002/cac2.12524","DOIUrl":"10.1002/cac2.12524","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (<i>ALK</i>)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline <i>ALK</i> or tumor protein 53 (<i>TP53</i>) mutation. In addition, patients with concurrent <i>TP53</i> mutations had shorter OS than those without concurrent <i>TP53</i> mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated <i>ALK</i> mutation abundance at 6 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and <i>ALK</i>-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"455-468"},"PeriodicalIF":16.2,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12524","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995723","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}