Carcinogenesis最新文献

The phenomenon of tumor immune escape involves multiple mechanisms that enable tumor cells to evade recognition and assault by the host's immune system, facilitating their survival and growth within the organism. Furthermore, tumor immune escape represents a critical mechanism in tumor progression and significantly contributes to the unsuccessful outcomes of immunotherapy. Tumor-associated macrophages (TAMs) are recruited into the tumor microenvironment, serving a pivotal role in modulating tumor immune escape. An increasing body of research has demonstrated that TAMs are linked to unfavorable cancer prognosis and drug resistance. They suppress immune cell activity, hinder antigen presentation, and inhibit T cell activation, thereby helping tumor cells evade immune attacks. Consequently, elucidating the mechanisms by which TAMs promote tumor immune escape is crucial for developing novel immunotherapeutic strategies and improving the efficacy of cancer immunotherapy. In terms of clinical relevance, studies on TAMs have revealed their significant roles in various types of cancer. In recent years, transformational therapies such as CSF-1R inhibitors and CD40 agonists targeting TAMs have entered clinical trials and are expected to reverse immunosuppression and enhance immunotherapy response. These studies provide new directions for improving the effectiveness of existing immunotherapies and overcoming drug resistance.

Transgelins (TAGLNs) are actin-binding proteins within the calponin family, playing a crucial role in modulating actin-myosin interactions and maintaining actin filament stability. These proteins are expressed in both smooth and non-smooth muscle cells, contributing to the regulation of muscle contractility and cell migration. TAGLNs family has three isoforms that differ in their isoelectric point, namely: TAGLN1, TAGLN2, and TAGLN3. TAGLNs regulation is involved in the development of many diseases, such as pulmonary arterial hypertension, asthma, atherosclerosis, obstructive nephropathy, diabetes, and cancer. Recent research indicates TAGLNs involvement in carcinogenesis and chemoresistance. This review investigates TAGLNs as potential cancer biomarkers, exploring their versatile tissue-specific impact on patient outcomes. We also highlight their roles as, tumor suppressor agents and tumor progression oncogenes depending on the tumor type, tumor genetic variations, and TAGLNs expression profiles. Furthermore, emerging evidence suggests that the interplay between TAGLN2 and chemoresistance to anticancer drugs is mediated by its interaction with the chemoresistance double agent MT-2, with possible bidirectional implications. TAGLNs present a promising avenue for novel therapeutic strategies against cancer, owing to their tissue-specific duality in promoting/suppressing tumor growth and cell migration in cancer cells. Thus, they can serve as a potential prognostic/diagnostic biomarker. The focus should be on leveraging, in future therapeutics, the interplay between TAGLNs and MTs to reverse tumor progression and chemoresistance, transforming them into tumor suppression.

Tumor cells produce/release tumor-derived exosomes (TEX) which promote tumor growth, drive immune suppression, and interfere with immune therapies. Amlodipine, a calcium flux inhibitor, may block TEX release by tumor cells. Amlodipine's potential as a drug blocking TEX release was evaluated. We measured tumor growth, TEX numbers, phenotype, and molecular content in murine SCCVII and human cancer cell lines. Cell lysates and TEX were tested for expression of autophagy-related proteins by western blots (WBs). Tumor growth in mice, histopathology, T-cell infiltrations, and TEX production by SCCVII treated with amlodipine were measured. Numbers and protein content of TEX eluted from tumor explants were studied by flow cytometry and WBs. Amlodipine used in vitro at 0.5-5 µM was nontoxic, did not impair tumor cell viability, reduced cell proliferation, and decreased TEX production. It reduced PD-L1 and Rab11 content of TEX, altered tumor cell size/shape, induced vesicle accumulations in the cytosol, and upregulated expression levels of autophagy-related proteins, ATG7, Beclin-1, and LC3. In vivo, daily treatment of established SCCVII with amlodipine (10 mg/kg) inhibited tumor growth (P < 0.001), increased CD8+ T-cell infiltration into tumor, decreased TEX production, and altered PD-L1, Rab11, and FasL content of TEX. Amlodipine delivered in vitro to tumor cells or in vivo to tumor-bearing mice interferes with tumor growth and TEX production, induces tumor autophagy, reduces circulating TEX numbers, and alters the TEX immunosuppressive signature. Amlodipine emerges as a potentially promising drug for removing immunosuppressive TEX in cancer subjects who are candidates for immune therapies.

Reproductive factors and sex hormones are tightly linked to systemic immunity. However, no studies have examined whether reproductive factors and hormone use modulate the immune microenvironment of breast tissue. We prospectively evaluated the associations of reproductive factors and exogenous hormone use with breast tumor and normal-adjacent tissue immune cell markers among 935 breast cancer cases in the Nurses' Health Studies. We deconvoluted immune cell abundance using CIBERSORTx and derived gene expression signatures of markers for immune checkpoint (PD1, PDL1, and CTLA4), co-regulatory signal and antigen presentation (MHC class I/ II and T cell receptor), and mammary cytokine signaling. Linear regression was used adjusting for confounders. Patterns of associations between reproductive factors and immune profile differed between tumor and normal-adjacent tissues and by estrogen receptor (ER) status. Tumors from postmenopausal women had significantly higher pro-inflammatory cytokine signaling and antigen presentation compared with tumors from premenopausal women (FDR ≤ 0.05). Several reproductive factors were nominally associated with immune profiles of normal-adjacent tissues. For example, parous women had higher CD8 T cell infiltration, higher PDL1 expression, and lower cytokine signaling (P ≤ .05); women who ever breastfed showed higher infiltration of NK cells and T helper cells in normal-adjacent tissue of ER+ tumors but lower infiltration of CD8 T cell and monocyte, and higher expression of cytokine signaling in normal-adjacent tissue of ER- tumors (P ≤ .05). Our study demonstrates for the first time in a large epidemiologic study that reproductive factors may influence breast tumor immune microenvironment and sheds light on potential immune regulation for breast cancer prevention.

Macrophage migration inhibitory factor (MIF) emerged in recent years as an important cytokine with a pleiotropic spectrum of biological functions implicated in the pathogenesis of inflammatory diseases and malignancies. A growing body of research indicates that the overexpression of MIF is prevalent across a variety of solid tumors. Howbeit, there are fewer studies regarding the expression and clinical significance of serum MIF in multiple myeloma (MM) patients. In this study, we investigated the clinical significance of serum MIF in newly diagnosed MM (NDMM) patients and explored the effect of exogenous MIF on the proliferation, migration, and invasion of MM cells in vitro. Herein, our study revealed that NDMM patients exhibited markedly elevated serum MIF levels compared to healthy adults. High levels of MIF were associated with advanced International Staging System (ISS) stage and the Second Revision of the International Staging System (R2-ISS) stage. Besides, NDMM patients with high levels of MIF were prone to have a higher incidence of hypercalcemia, renal insufficiency, high tumor burden, and extramedullary lesions. Moreover, we found that serum MIF, creatinine, and lactate dehydrogenase levels were independent risk factors for predicting poor progression-free survival and overall survival in NDMM patients. Meanwhile, in vitro experiments revealed that MIF can promote the proliferation of MM cells and enhance their migration and invasion. Our study confirmed that NDMM patients with high serum MIF levels showed poor clinical characteristics and inferior prognosis. Therefore, MIF may serve as a promising biomarker in the clinical practice of MM.

Currently, research on ferroptosis-related prognostic models for gastric cancer is limited, whereas traditional predictive models often have a narrow perspective and low accuracy. In this study, we systematically analyzed the expression patterns of ferroptosis-related genes in patients with gastric adenocarcinoma and evaluated their prognostic value. Using data from The Cancer Genome Atlas (TCGA) and the FerrDb database, we developed a ferroptosis-related prognostic risk model based on four genes: hydroxycarboxylic acid receptor 1 (HCAR1), branched-chain amino acid transaminase 1 (BCAT1), ceruloplasmin (CP), and dickkopf-1 (DKK1). This model demonstrated strong prognostic value and potential clinical relevance in stratifying gastric cancer patients by overall survival outcomes. ferroptosis-related prognostic risk model. Compared to traditional clinicopathological features, the risk score derived from this model exhibited superior predictive accuracy for overall survival in patients with gastric cancer and served as an independent prognostic factor. Functional enrichment analysis revealed that the risk score was primarily enriched for extracellular matrix-related pathways. Additionally, the risk score was significantly correlated with TME signature genes, immune checkpoint expression, and immune cell infiltration in stomach adenocarcinoma (STAD). Mechanistic studies revealed that HCAR1 is abnormally overexpressed in gastric cancer tissues and is associated with a poor prognosis. It exerted its effects by regulating the GPX4/SLC7A11 axis to inhibit lipid peroxidation and malondialdehyde accumulation, thereby obstructing ferroptosis. Experimental validation demonstrated that the downregulation of HCAR1 promoted ferroptosis and suppressed malignant tumor phenotypes, suggesting that both the gene and its associated risk model hold significant clinical value as potential therapeutic targets and prognostic biomarkers.

Most studies suggest that B vitamins can reduce the risk of colorectal cancer (CRC), and research in this field has been growing. Focusing on 2617 articles in the field, this study used CiteSpace and VOSviewer software to evaluate the contributions of various countries/regions, institutions, authors, and journals. The United States and Harvard University were identified as the most productive nation and institution, respectively, with Edward L. Giovannucci (Harvard) being the top contributor. Cancer Epidemiology Biomarkers & Prevention was recognized as the leading journal. Through the analysis of keywords and citations, we found that the potential of B vitamins (B1, B2, B6, B9, and B12) in the prevention and treatment of CRC and their mechanisms including regulation of gene expression, anti-inflammatory and antioxidant, and modulation of gut microenvironment are hot topics of research in this field. Burst detection analysis further revealed that the application of nanoparticle-based targeted drug delivery systems (such as folate-conjugated nanocarriers) in the treatment of CRC represents both a current hotspot and a future trend. This study offers a comprehensive overview of the field, highlights research hotspots and trends, and offers valuable information for researchers to further grasp the research direction.

Lung cancer is among the leading causes of cancer-related death in the US Cigarette smoking remains the leading risk factor for lung cancer and can cause somatic mutations in the critical tumor suppressor gene TP53, among others. Mutations in TP53 not only cause loss of wild-type function but may also introduce oncogenic, gain-of-function (GOF) properties. The frequency of missense mutations at residues p.V157 and p.R158 in p53 increases dramatically in lung cancer relative to other cancers. These p53 mutants exhibit both loss of wild-type p53 function and GOF properties, including broadly rewiring gene expression programs in lung cancer cells. Several pan-cancer hotspot mutations in p53 impart GOF activities that reprogram cellular metabolism. To refine our understanding of the GOF properties conferred by the lung-enriched p53 mutants, the cellular metabolism of cells containing mutant p53 (V157F) was investigated. Untargeted metabolomics revealed that glutathione metabolism is among the top altered metabolic pathways related to mutant p53 (V157F). p53 mutants V157F and R158L provided resistance to oxidative stress induced by both menadione and cigarette smoke extract. The cell death experienced in the absence of mutant p53 (V157F; R158L) was due to the increase in reactive oxygen species (ROS). These findings suggest that the lung-enriched mutations in p53 (V157F; R158L) confer lung cancer cells with resistance to ROS, and ROS accumulation in the absence of mutant p53 causes cell death.

DNA adducts are central in the carcinogenic process because they can cause miscoding leading to permanent mutations in important genes involved in carcinogenesis. While it is known that tobacco smoking leads to increased levels of multiple DNA adducts, most DNA adducts detected to date in humans cannot be explicitly attributed to smoking but instead have various possible exogenous and endogenous sources. We plan to probe the tobacco source of DNA adducts by providing carbon-13 labelled ([13C]-labelled) cigarettes to smokers and analyzing [13C]-labelled DNA adducts in their oral cells to determine which adducts arise from smoking. Prior to conducting studies in humans, we first report here proof-of-principle machine smoking experiments to evaluate carbon isotopologues of (a) selected carbonyls and (b) DNA adducts resulting from direct exposure of cigarette smoke vapour-phase to calf-thymus DNA. The smoke of the study cigarettes, made from a 50:50 mixture of [13C]-labelled tobacco and a popular commercial tobacco, yielded similar concentrations of carbonyl compounds and their respective DNA adducts compared with the smoke of 1R6F reference cigarettes and the popular brand of cigarettes. We detected [13C]-isotopologues of DNA adducts such as 1,N6-etheno-dA, (8R/S)-3-(2'-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dG), and (6S,8S and 6R,8R)-3-(2'-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)-one [(6S,8S)-γ-OH-Cro-dG and (6R,8R)-γ-OH-Cro-dG], proving that they have a direct source from tobacco smoke and providing important new insights regarding their mechanisms of formation. These unique results form the basis for further studies in cell culture and in cigarette smokers to establish how carcinogens in tobacco smoke cause DNA adduct formation.

Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, metastasis, and recurrence and play a crucial role in androgen deprivation therapy resistance, yet how sphingolipid metabolism promotes CSC maintenance remains exclusive. Here, we conducted gene expression profiling of sphere-derived castration-resistant prostate cancer stem cells (PCSCs) and identified enhanced sphingolipid de novo biosynthesis with upregulated DEGS2 expression in PCSCs. Silencing of DEGS2 significantly suppressed prostate cancer stem-like traits, cell growth, clonogenicity, and metastasis, while ectopic overexpression of DEGS2 showed the opposite effects. Mechanistically, DEGS2-synthesized phytoceramide activates PI3K-AKT signaling pathway to promote cancer stem-like characteristics, and activation of AKT reversed DEGS2-depletion-inhibited cancer stem-like properties. Clinically, prostate cancer tissues expressed higher levels of DEGS2 compared with adjacent normal tissue, and DEGS2 expression exhibits strong correlations with SOX2, CD133, and Snail expression in primary prostate carcinomas. Collectively, our data illustrate that DEGS2 dictates prostate cancer stem-like properties via the PI3K-AKT pathway, and disruption of this pathway provides potential therapeutic strategies for prostate cancer.