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Abstract Progressive carcinogenesis of a gastric polyp with transformation to gastric adenocarcinoma and subsequent development of leptomeningeal carcinomatosis is described in an adult male Scottish terrier. Presenting clinical signs consisted of vomiting with intermittent hematemesis. Surgical biopsies over the course of 14 months documented the progression from gastric polyp to minimally invasive gastric carcinoma to invasive gastric adenocarcinoma, a pathogenesis not previously documented in veterinary oncology. The patient ultimately developed neurologic pathology and was euthanized, and necropsy evaluation identified widespread carcinomatosis with accompanying leptomeningeal metastasis. As in humans, gastric polyps in dogs rarely have malignant potential.

ABSTRACT Breast cancer is a common form of cancer among women characterized by the growth of malignant cells in the breast tissue. The most common treatments for this condition include chemotherapy, surgical intervention, radiation therapy, hormone therapy, and biological therapy. The primary issues associated with chemotherapy and radiation therapy are their adverse events and significant financial burden among patients in underdeveloped countries. This highlights the need to explore and develop superior therapeutic options that are less detrimental and more economically efficient. Plants provide an abundant supply of innovative compounds and present a promising new avenue for investigating cancer. Plants and their derivations are undergoing a revolution due to their reduced toxicity, expediency, cost‐effectiveness, safety, and simplicity in comparison to conventional treatment methods. Natural products are considered promising candidates for the development of anticancer drugs, due perhaps to the diverse pleiotropic effects on target events. The effects of plant‐derived products are limited to cancer cells while leaving healthy cells unaffected. Identification of compounds with strong anticancer properties and development of plant‐based medications for cancer treatment might be crucial steps in breast cancer therapy. Although bioactive compounds have potent anticancer properties, they also have drawbacks that need to be resolved before their application in clinical trials and improved for the approved drugs. This study aims to give comprehensive information on known anticancer compounds, including their sources and molecular mechanisms of actions, along with opportunities and challenges in plant‐based anticancer therapies.

ABSTRACT Objectives Oxidative stress, an imbalance between the body's natural antioxidant defenses and the production of reactive oxygen species (ROS), can result in serious oral diseases, including oral cancer, periodontal diseases, and oral lichen planus, through the activation of the redox‐sensitive transcription factors and inflammation. The purpose of this study was to assess the potential effects of a removable complete denture on the levels of oxidative stress markers, such as lipid peroxidation (MDA), advanced oxidation protein products (AOPP), and catalase, and the quantitative expression of the redox‐sensitive transcription factor NF‐κB p65 subunit. Materials and Methods This interventional follow‐up study enrolled 40 participants of both sexes aged 28–78 years, with a median age of 56 years, where unstimulated saliva was collected before denture placement, immediately after the denture placement, and 24 h, 7 days, and 30 days after the denture placement. The most prominent ROS overproduction was reported on the seventh day (p

Abstract Circadian rhythms are oscillations in physiology and behavior caused by the circadian regulator. Cryptochromes, Periods, and Bmal1 are circadian clock genes that have been linked to aging and cancer. Human pathologies alter circadian clock gene expression, and transgenic rats with clock gene defects progress to cancer and age prematurely. In the growth of age‐linked pathologies and carcinogenesis, cell proliferation and genome integrity play critical roles. The relationship concerning the cell cycle regulation and circadian clock is discussed in this article. The circadian clock controls the behavior and countenance of many main cell cycle and cell cycle check‐point proteins, and cell cycle‐associated proteins, in turn, control the activity and expression of circadian clock proteins. The circadian clock can be reset by DNA disruption, providing a molecular mechanism for mutual control amid the cell cycle and the clock. This circadian clock‐dependent regulation of cell proliferation, composed with other circadian clock‐dependent physiological functions including metabolism control, genotoxic and oxidative stress response, and DNA repair, unlocks new avenues for studying the processes of aging and carcinogenesis.

Abstract Background The tetraspanin (TSPAN) family comprises 33 membrane receptors involved in various physiological processes in humans. Tetrasapanins are surface proteins expressed in cells of various organisms. They are localised to the cell membrane by four transmembrane domains (TM4SF). These domains bind several cell surface receptors and signalling proteins to tetraspanin‐enriched lipid microdomains (TERM or TEM). Tetraspanins play a critical role in anchoring many proteins. They also act as a scaffold for cell signalling proteins. Aim To summarise how tetraspanins 6, 7 and 8 contribute to the carcinogenesis process in different types of cancer. Methods To provide a comprehensive review of the role of tetraspanins 6, 7 and 8 in cancer biology, we conducted a thorough search in PubMed, Embase and performed manual search of reference list to collect and extract data. Discussion The assembly of tetraspanins covers an area of approximately 100–400 nm. Tetraspanins are involved in various biological processes such as membrane fusion, aggregation, proliferation, adhesion, cell migration and differentiation. They can also regulate integrins, cell surface receptors and signalling molecules. Tetraspanins form direct bonds with proteins and other members of the tetraspanin family, forming a hierarchical network of interactions and are thought to be involved in cell and membrane compartmentalisation. Tetraspanins have been implicated in cancer progression and have been shown to have multiple binding partners and to promote cancer progression and metastasis. Clinical studies have documented a correlation between the level of tetraspanin expression and the prediction of cancer progression, including breast and lung cancer. Conclusions Tetraspanins are understudied in almost all cell types and their functions are not clearly defined. Fortunately, it has been possible to identify the basic mechanisms underlying the biological role of these proteins. Therefore, the purpose of this review is to describe the roles of tetraspanins 6, 7 and 8.

Abstract With the deepening of the genome project study, attention on noncoding RNAs is increasing. Long noncoding RNAs (lncRNAs) have become a new research hotspot. A growing number of studies have revealed that lncRNAs are involved in tumorigenesis and tumor suppressor pathways. Aberrant expressions of lncRNAs have been found in a variety of human tumors including hepatocellular carcinoma (HCC). In this review, we provide a brief introduction to lncRNA and highlight recent research on the functions and clinical significance of lncRNAs in HCC.

Abstract Introduction Tumor‐associated bacteria and gut microbiota have gained significant attention in recent years due to their potential role in cancer development and therapeutic response. This review aims to discuss the contributions of intratumor bacteria outside the gastrointestinal tract, in addition to exploring the mechanisms, functions, and implications of these bacteria in cancer therapy. Methods We reviewed current literature on intratumor bacteria and their impact on tumorigenesis, progression, metastasis, drug resistance, and anti‐tumor immune modulation. Additionally, we examined techniques used to detect intratumor bacteria, precautions necessary when handling low microbial biomass tumor samples, and the recent progress in bacterial manipulation for tumor treatment. Results Research indicates that each type of cancer uniquely interacts with its microbiome, and bacteria can be detected even in non‐gastrointestinal tumors with low bacterial abundance. Intracellular bacteria have the potential to regulate tumor cells' biological behavior and contribute to critical aspects of tumor development. Furthermore, bacterial‐based anti‐tumor therapies have shown promising results in cancer treatment. Conclusions Understanding the complex interactions between intratumor bacteria and tumor cells could lead to the development of more precise cancer treatment strategies. Further research into non‐gastrointestinal tumor‐associated bacteria is needed to identify new therapeutic approaches and expand our knowledge of the microbiota's role in cancer biology.

Abstract Gamma‐aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain of adult mammals. Several studies have demonstrated that the GABAergic system may regulate tumor development via GABA receptors, downstream cyclic adenosine monophosphate (cAMP) pathway, epithelial growth factor receptor (EGFR) pathway, AKT pathway, mitogen‐activated protein kinase (MAPK) or extracellular signal‐related kinases (ERK) pathway, and matrix metalloproteinase (MMP) pathway, although the exact mechanism is unclear. Pioneering studies reported that GABA signaling exists and functions in the cancer microenvironment and has an immunosuppressive effect that contributes to metastasis and colonization. This article reviews the molecular structures and biological functions of GABAergic components correlated with carcinogenesis, the mechanisms underlying GABAergic signaling that manipulate the proliferation and invasion of cancer cells, and the potential GABA receptor agonists and antagonists for cancer therapy. These molecules may provide an avenue for the development of specific pharmacological components to prevent the growth and metastasis of various cancers.

Abstract Objectives Molecular‐level research has linked RING finger (RNF) protein family members to carcinogenesis and tumor progression. Among them, RNF128 is related to tumor progression, but reports on its association with lung cancer are few. This study aimed to clarify the unknown association between RNF128 expression and clinical outcomes in patients with lung adenocarcinoma. Methods Clinical data of 545 patients with therapy‐naïve lung adenocarcinoma who underwent lobectomy with systematic lymph node dissection between 1999 and 2016 were retrospectively reviewed. Histological and immunohistochemical analyses were conducted to evaluate the relationship between RNF128 expression and prognosis. Results Among adenocarcinoma histologic types, acinar, micropapillary, and solid tumors did not express RNF128 compared with other histologic types (p

Abstract Background Oral leukoplakia (OL) is associated with an increased risk for oral cancer (OC) development. Prediction of OL cancer progression may contribute to decreased OC morbidity and mortality by favoring early intervention. Current OL progression risk assessment approaches face large interobserver variability and is weakly prognostic. We hypothesized that convolutional neural networks (CNN)‐based histology image analyses could accelerate the discovery of better OC progression risk models. Methods Our CNN‐based oral mucosa risk stratification model (OMRS) was trained to classify a set of nondysplastic oral mucosa (OM) and a set of OC H&E slides. As a result, the OMRS model could identify abnormal morphological features of the oral epithelium. By applying this model to OL slides, we hypothesized that the extent of OC‐like features identified in the OL epithelium would correlate with its progression risk. The OMRS model scored and categorized the OL cohort (n = 62) into high‐ and low‐risk groups. Results OL patients classified as high‐risk (n = 31) were 3.98 (95% CI 1.36–11.7) times more likely to develop OC than low‐risk ones (n = 31). Time‐to‐progression significantly differed between high‐ and low‐risk groups (p = 0.003). The 5‐year OC development probability was 21.3% for low‐risk and 52.5% for high‐risk patients. The predictive power of the OMRS model was sustained even after adjustment for age, OL site, and OL dysplasia grading (HR = 4.52, 1.5–13.7). Conclusion The ORMS model successfully identified OL patients with a high risk of OC development and can potentially benefit OC early diagnosis and prevention policies.

Abstract Background Normal adult mammalian cells can respond to oncogenic somatic mutations by committing suicide through a well‐described, energy dependent process termed apoptosis. Cancer cells avoid oncogene promoted apoptosis. Oncogenic somatic mutations are widely acknowledged to be the cause of the relentless unconstrained cell proliferation which characterises cancer. But how does the normal cell with the very first oncogenic mutation survive to proliferate without undergoing apoptosis? New findings The phenomena of malignant transformation by somatic mutation, apoptosis, aneuploidy, aerobic glycolysis and Cdk4 upregulation in carcinogenesis have each been extensively discussed separately in the literature but an overview explaining how they may be linked at the initiation of the cancer process has not previously proposed. Conclusion A hypothesis is presented to explain how in addition to the initial oncogenic mutation, the expression of certain key normal genes is, counter‐intuitively, also required for successful malignant transformation from a normal cell to a cancer cell. The hypothesis provides an explanation for how the cyclic amphiphilic peptide HILR‐056, derived from peptides with homology to a hexapeptide in the C‐terminal region of Cdk4, kill cancer cells but not normal cell by necrosis rather than apoptosis.

A prevalence of around 26% of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has been previously reported. HPV induced oncogenesis mainly involving E6 and E7 viral oncoproteins. In some cases, HPV viral DNA has been detected to integrate with the host genome and possibly contributes to carcinogenesis by affecting the gene expression. We retrospectively assessed HPV integration sites and signatures in 80 HPV positive patients with HNSCC, by using a double capture‐HPV method followed by next‐generation Sequencing. We detected HPV16 in 90% of the analyzed cohort and confirmed five previously described mechanistic signatures of HPV integration [episomal (EPI), integrated in a truncated form revealing two HPV‐chromosomal junctions colinear (2J‐COL) or nonlinear (2J‐NL), multiple hybrid junctions clustering in a single chromosomal region (MJ‐CL) or scattered over different chromosomal regions (MJ‐SC) of the human genome]. Our results suggested that HPV remained episomal in 38.8% of the cases or was integrated/mixed in the remaining 61.2% of patients with HNSCC. We showed a lack of association of HPV genomic signatures to tumour and patient characteristics, as well as patient survival. Similar to other HPV associated cancers, low HPV copy number was associated with worse prognosis. We identified 267 HPV‐human junctions scattered on most chromosomes. Remarkably, we observed four recurrent integration regions: PDL1/PDL2/PLGRKT (8.2%), MYC/PVT1 (6.1%), MACROD2 (4.1%) and KLF5/KLF12 regions (4.1%). We detected the overexpression of PDL1 and MYC upon integration by gene expression analysis. In conclusion, we identified recurrent targeting of several cancer genes such as PDL1 and MYC upon HPV integration, suggesting a role of altered gene expression by HPV integration during HNSCC carcinogenesis.

Abstract Background The mechanism underlying colorectal cancer (CRC) initiation and progression remains elusive, and overall survival is far from satisfactory. Previous studies have shown that PDGFA‐associated protein 1 (PDAP1) is upregulated in several cancers including CRC. Here, we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target. Methods Multi‐omics data analysis was performed to identify potential key players in CRC initiation and progression. Immunohistochemistry (IHC) staining was applied to determine the expression pattern of PDAP1 in CRC tissues. Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models. RNA sequencing, a phosphoprotein antibody array, western blotting, histological analysis, 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation assay, and interactome analysis were applied to identify the underlying mechanisms of PDAP1. A human patient‐derived xenograft (PDX) model was used to assess the potential of PDAP1 as a therapeutic target. Results PDAP1 was identified as a potential key player in CRC development using multi‐omics data analysis. PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival. Further investigation showed that PDAP1 was critical for the regulation of cell proliferation, migration, invasion, and metastasis. Significantly, depletion of Pdap1 in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt‐induced colitis and inhibited tumor initiation and growth in colitis‐associated cancers. Mechanistic studies showed that c‐Myc directly transactivated PDAP1, which contributed to the high PDAP1 expression in CRC cells. PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor (EGFR) and facilitated EGFR‐mitogen‐activated protein kinase (MAPK) signaling activation, which resulted in FOS‐related antigen 1 (FRA‐1) expression, thereby facilitating CRC progression. Notably, silencing of PDAP1 could hinder the growth of patient‐derived xenografts that sustain high PDAP1 levels. Conclusions PDAP1 facilitates mucosal restitution and carcinogenesis in colitis‐associated cancer. c‐Myc‐driven upregulation of PDAP1 promotes proliferation, migration, invasion, and metastasis of CRC cells via the EGFR‐MAPK‐FRA‐1 signaling axis. These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression.

Abstract Colonies formed by bacteria, archaea, fungi, and viral groups and their genomes, metabolites, and expressed proteins constitute complex human microbiomes. An increasing evidences showed that carcinogenesis and disease progression were link to microbiomes. Different organ sources, their microbial species, and their metabolites are different; the mechanisms of carcinogenic or procancerous are also different. Here, we summarize how microbiomes contribute to carcinogenesis and disease progression in cancers of the skin, mouth, esophagus, lung, gastrointestinal, genital, blood, and lymph malignancy. We also insight into the molecular mechanisms of triggering, promoting, or inhibiting carcinogenesis and disease progress induced by microbiomes or/and their secretions of bioactive metabolites. And then, the strategies of application of microorganisms in cancer treatment were discussed in detail. However, the mechanisms by which human microbiomes function are still poorly understood. The bidirectional interactions between microbiotas and endocrine systems need to be clarified. Probiotics and prebiotics are believed to benefit human health via a variety of mechanisms, in particular, in tumor inhibition. It is largely unknown how microbial agents cause cancer or how cancer progresses. We expect this review may open new perspectives on possible therapeutic approaches of patients with cancer.

The high‐order chromatin structure, together with DNA methylation and other epigenetic marks, plays a vital role in gene regulation and displays abnormal status in cancer cells. Theoretical analyses are expected to provide a more unified understanding of the multi‐omics data on the large variety of samples, and hopefully a common picture of carcinogenesis. In particular, we are interested in the question of whether an underlying origin DNA sequence exists for these epigenetic alterations. The human genome consists of two types of megabase‐sized domain based on the distribution of CpG islands (CGIs) that show distinct structural, epigenetic, and transcriptional properties: CGI‐rich and CGI‐poor domains. Through an integrated analysis of chromatin structure, DNA methylation, and RNA sequencing data, we found that, in carcinogenesis, the two different types of domain display different structural changes and have an increased number of DNA methylation differences and transcriptional‐level differences, compared with in noncancer cells. We also compared the structural features among carcinogenesis, senescence, and mitosis, showing the possible connection between chromatin structure and cell state, which could affect vital cancer‐related properties. In summary, chromatin structure, DNA methylation, and gene expression, as well as their changes observed in several types of cancers, show a dependence on multiscale DNA sequence heterogeneity.

Objectives: Oxidative stress, an imbalance between the body's natural antioxidant defenses and the production of reactive oxygen species (ROS), can result in serious oral diseases, including oral cancer, periodontal diseases, and oral lichen planus, through the activation of the redox-sensitive transcription factors and inflammation. The purpose of this study was to assess the potential effects of a removable complete denture on the levels of oxidative stress markers, such as lipid peroxidation (MDA), advanced oxidation protein products (AOPP), and catalase, and the quantitative expression of the redox-sensitive transcription factor NF-κB p65 subunit., Materials and Methods: This interventional follow-up study enrolled 40 participants of both sexes aged 28-78 years, with a median age of 56 years, where unstimulated saliva was collected before denture placement, immediately after the denture placement, and 24 h, 7 days, and 30 days after the denture placement. The most prominent ROS overproduction was reported on the seventh day (p < 0.05), followed by a significant fall in antioxidative defense., Results: The NF-κB p65 subunit, whose expression pattern was highest in the same time period on the seventh day, serves as a signaling molecule for redox imbalance due to ROS production. Over the next 30 days, its levels remained moderately increased compared to the basal value, which may influence pro-inflammatory pathways and the integrity of oral tissue components. These alterations may be induced by the dentures, which can produce high pressures on the supporting tissues or by the synthetic materials used for producing the dentures., Conclusion: Our research may help to clarify the potential pathways by which oxidative stress and redox-sensitive inflammatory mediators, as well as mechanical and chemical irritants, may serve as risk factors for premalignant lesions in the mouth. Further research on this topic is required to understand the molecular mechanisms behind the relationship between inflammation and oral premalignant lesions caused by mechanical and chemical irritation., (© 2024 The Author(s). Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

The intratumoral microbiome (TM) refers to the microorganisms in the tumor tissues, including bacteria, fungi, viruses, and so on, and is distinct from the gut microbiome and circulating microbiota. TM is strongly associated with tumorigenesis, progression, metastasis, and response to therapy. This paper highlights the current status of TM. Tract sources, adjacent normal tissue, circulatory system, and concomitant tumor co-metastasis are the main origin of TM. The advanced techniques in TM analysis are comprehensively summarized. Besides, TM is involved in tumor progression through several mechanisms, including DNA damage, activation of oncogenic signaling pathways (phosphoinositide 3-kinase [PI3K], signal transducer and activator of transcription [STAT], WNT/β-catenin, and extracellular regulated protein kinases [ERK]), influence of cytokines and induce inflammatory responses, and interaction with the tumor microenvironment (anti-tumor immunity, pro-tumor immunity, and microbial-derived metabolites). Moreover, promising directions of TM in tumor therapy include immunotherapy, chemotherapy, radiotherapy, the application of probiotics/prebiotics/synbiotics, fecal microbiome transplantation, engineered microbiota, phage therapy, and oncolytic virus therapy. The inherent challenges of clinical application are also summarized. This review provides a comprehensive landscape for analyzing TM, especially the TM-related mechanisms and TM-based treatment in cancer., (© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat‐sen University Cancer Center.)

Abstract Gastric cancer is a heterogenous disease with different phenotypes, genotypes, and clinical outcomes, including sensitivity to treatments and prognoses. Recent medical advances have enabled the classification of this heterogenous disease into several groups and the consequent analysis of their clinicopathological characteristics. Gastric cancer associated with Epstein–Barr virus (EBV) and microsatellite‐unstable tumors are considered to be the two major subtypes as they are clearly defined by well‐established methodologies, such as in situ hybridization and polymerase chain reaction‐based analyses, respectively. However, discrepancies in the histological diagnosis of gastric neoplasms remain problematic, and international harmonization should be performed to improve our understanding of gastric carcinogenesis. We re‐evaluated Japanese cases of early gastric cancer according to the current World Health Organization (WHO) criteria and classified them into genomic subtypes based on microsatellite instability (MSI) and EBV positivity to determine the initial genetic events in gastric carcinogenesis. A total of 113 Japanese early gastric cancers (including low‐ and high‐grade dysplasias) treated with endoscopic resection over 5 years were archived in our hospital. A histological re‐evaluation according to the WHO criteria revealed 54 adenocarcinomas, which were divided into 6 EBV‐positive (11.1%), 7 MSI‐high (MSI‐H, 13.0%), and 41 microsatellite stable cases (75.9%). MSI‐H adenocarcinoma was confirmed by an immunohistochemistry assay of mismatch repair proteins. Programmed death‐ligand 1 immunostaining with two antibodies (E1L3N and SP263) was positive in tumor cells of one MSI‐H adenocarcinoma case (1/7, 14.3%). The proportion of stained cells was higher with clone SP263 than with E1L3N. Histologically, EBV‐positive carcinomas were poorly differentiated (83.8%), and MSI‐H cancers were frequent in well to moderately differentiated adenocarcinoma (85.7%), indicating that the EBV‐positive subtype presented with high‐grade morphology even when an early lesion. Our study indicates that the WHO criteria are useful for subdividing Japanese early gastric cancers, and this subdivision may be useful for comparative analysis of precursor lesions and early carcinoma.

Abstract There is now sufficient evidence to indicate that aging is associated with the emergence of a clonogenic and neoplastic‐prone tissue landscape, which fuels early stages of cancer development and helps explaining the rise in cancer incidence and mortality in older individuals. Dietary interventions are among the most effective approaches to delay aging and age‐related diseases, including cancer. Reduced caloric intake has been, historically, the most intensely investigated strategy. Recent findings point to a critical role of a long fasting interval in mediating some of the beneficial effects of caloric restriction. Time‐restricted feeding, intermittent fasting, and fasting mimicking diets are being proposed for their potential to prolong healthy life span and to delay late‐onset diseases such as neoplasia. Evidence will be discussed suggesting that the effects of these dietary regimens are mediated, at least in part, through retardation of age‐related functional changes at cell and tissue level, including a delay in the emergence of the neoplastic‐prone tissue microenvironment.

Abstract Bacteria identified in the oral cavity are highly complicated. They include approximately 1000 species with a diverse variety of commensal microbes that play crucial roles in the health status of individuals. Epidemiological studies related to molecular pathology have revealed that there is a close relationship between oral microbiota and tumor occurrence. Oral microbiota has attracted considerable attention for its role in in‐situ or distant tumor progression. Anaerobic oral bacteria with potential pathogenic abilities, especially Fusobacterium nucleatum and Porphyromonas gingivalis, are well studied and have close relationships with various types of carcinomas. Some aerobic bacteria such as Parvimonas are also linked to tumorigenesis. Moreover, human papillomavirus, oral fungi, and parasites are closely associated with oropharyngeal carcinoma. Microbial dysbiosis, colonization, and translocation of oral microbiota are necessary for implementation of carcinogenic functions. Various underlying mechanisms of oral microbiota‐induced carcinogenesis have been reported including excessive inflammatory reaction, immunosuppression of host, promotion of malignant transformation, antiapoptotic activity, and secretion of carcinogens. In this review, we have systemically described the impact of oral microbial abnormalities on carcinogenesis and the future directions in this field for bringing in new ideas for effective prevention of tumors.

Abstract Tumors result from genetic and epigenetic alterations that change cellular survival and differentiation probabilities, promoting clonal dominance. Subsequent genetic and selection processes in tumors allow cells to lose their tissue fidelity and migrate to other parts of the body, turning tumors into cancer. However, the relationship between genetic damage and cancer is not linear, showing remarkable and sometimes seemingly counterintuitive patterns for different tissues and across animal taxa. In the present paper, we attempt to integrate our understanding of somatic evolution and cancer as a product of three major orthogonal processes: occurrence of somatic mutations, evolution of species‐specific life‐history traits, and physiological aging. Patterns of cancer risk have been shaped by selective pressures experienced by animal populations over millions of years, influencing and influenced by selection acting on traits ranging from mutation rate to reproductive strategies to longevity. We discuss how evolution of species shapes their cancer profiles alongside and in connection with other evolving life‐history traits and how this process explains the patterns of cancer incidence we observe in humans and other animals.

Abstract The multistep transition from a normal to a malignant cellular phenotype is often termed “somatic evolution” caused by accumulating random mutations. Here, we propose an alternative model in which the initial genetic state of a cancer cell is the result of mutations that occurred throughout the lifetime of the host. However, these mutations are not carcinogenic because normal cells in multicellular organism cannot ordinarily evolve. That is, proliferation and death of normal cells are controlled by local tissue constraints typically governed by nongenomic information dynamics in the cell membrane. As a result, the cells of a multicellular organism have a fitness that is identical to the host, which is then the unit of natural selection. Somatic evolution of a cell can occur only when its fate becomes independent of host constraints. Now, survival, proliferation, and death of individual cells are dependent on Darwinian dynamics. This cellular transition from host‐defined fitness to self‐defined fitness may, consistent with the conventional view of carcinogenesis, result from mutations that render the cell insensitive to host controls. However, an identical state will result when surrounding tissue cannot exert control because of injury, inflammation, aging, or infection. Here, all surviving cells within the site of tissue damage default to self‐defined fitness functions allowing them to evolve so that the mutations accumulated over the lifetime of the host now serve as the genetic heritage of an evolutionary unit of selection. Furthermore, tissue injury generates a new ecology cytokines and growth factors that might promote proliferation in cells with prior receptor mutations. This model integrates genetic and nongenetic dynamics into cancer development and is consistent with both clinical observations and prior experiments that divided carcinogenesis to initiation, promotion, and progression steps.

Global efforts have been undertaken to define the genome‐wide distribution of epigenetic markers in cancerous tissues, which provide an invaluable opportunity to understand cancer biology and identify predictive signatures. Several studies have focused on the gene expression patterns of squamous carcinoma to identify tumor subtypes and find prognostic and therapeutic targets because squamous carcinoma genomes showed high instability. However, the number of reliable reports referring prognostic significance of genes and their role in squamous carcinoma is still quite limited. Krüppel‐like factor 7 (KLF7) is a transcription factor that is widely expressed in numerous human tissues at low levels. Members of the KLF family have established roles in tumor cell fate, stress response, cell survival and the tumor‐initiating properties of cancer stem‐like cells. Hence to investigate whether KFL7 expression from cancer tissue holds promise as a prognostic and/or therapeutic target, we analyzed gene expression profiles from squamous carcinoma and surgical margin tissues in The Cancer Genome Atlas. We identified significant up‐regulation of KLF7 in squamous carcinoma, which was confirmed by immunohistochemical staining. Elevated KLF7 expression was associated with poor squamous carcinoma prognosis before and after correcting for confounding factors by multivariate Cox regression analysis. Several pathways, such as Neurotrophin and GnRH pathways, were activated in KLF7‐up‐regulated squamous carcinoma samples through Gene Set Enrichment Analysis. In conclusion, we consolidate the potential role(s) of KLF7 in squamous carcinoma carcinogenesis from The Cancer Genome Atlas surgical margin tissue, offering insights into expression signatures that are potentially useful for prognosis modalities.

Abstract Gastric cancer (GC) is the second leading cause of cancer‐related death worldwide. Studies have shown that miR‐922 facilitates the development of various diseases and tumors. However, the role of miR‐922 in GC and related molecular mechanisms are still unrevealed. Current study indicated that miR‐922 was overexpressed in GC tissues and cells. The survival rate of patients in high miR‐922 expression group is significantly lower than that in low miR‐922 expression group. In addition, overexpression of miR‐922 observably restrained the apoptosis of SGC7901 cells and promoted SGC7901 cell proliferation, migration, and invasion. TargetScan predicted that suppressors of cytokine signaling 1 (SOCS1) was a potential target of miR‐922. miR‐922 upregulation profoundly inhibited the expression of SOCS1. Furthermore, the mRNA level of SOCS1 in GC tissues was significantly lower than that in adjacent tissues, indicating that miR‐922 promoted the proliferation, invasion, and migration, and inhibited apoptosis of SGC7901 cells by downregulating the level of SOCS1. In conclusion, miR‐922 may have potential for diagnosis of GC.

Abstract Ameloblastic carcinoma (AC) is defined as a rare primary epithelial odontogenic malignant neoplasm and the malignant counterpart of benign epithelial odontogenic tumor of ameloblastoma (AB) by the WHO classification. AC develops pulmonary metastasis in about one third of the patients and reveals a poor prognosis. However, the mechanisms of AC oncogenesis remain unclear. In this report, we aimed to clarify the mechanisms of malignant transformation of AB or AC carcinogenesis. The relatively important genes in the malignant transformation of AB were screened by DNA microarray analysis, and the expression and localization of related proteins were examined by immunohistochemistry using samples of AB and secondary AC. Two genes of hypoxia‐inducible factor 1 alpha subunit (HIF1A) and zinc finger E‐box‐binding homeobox 1 (ZEB1) were significantly and relatively upregulated in AC than in AB. Both genes were closely related in hypoxia and epithelial‐mesenchymal transition (EMT). In addition, expressions of HIF‐1α and ZEB1 proteins were significantly stronger in AC than in AB. In the cell assays using ameloblastoma cell line, AM‐1, hypoxia condition upregulated the expression of transforming growth factor‐β (TGF‐β) and induced EMT. Furthermore, the hypoxia‐induced morphological change and cell migration ability were inhibited by an antiallergic medicine tranilast. Finally, we concluded that hypoxia‐induced HIF‐1α and ZEB1 were critical for the malignant transformation of AB via TGF‐β‐dependent EMT. Then, both HIF‐1α and ZEB1 could be potential biomarkers to predict the malignant transformation of AB.

Lung cancer is a major cause of morbidity and mortality. The specific pulmonary structure to directly connect with ambient air makes it more susceptible to damage from airborne toxins. External oxidative stimuli and endogenous reactive oxygen species (ROS) play a crucial role in promoting lung carcinogenesis and development. The biological properties of higher ROS levels in tumor cells than in normal cells make them more sensitive and vulnerable to ROS injury. Therefore, the strategy of targeting ROS has been proposed for cancer therapy for decades. However, it is embarrassing that countless attempts at ROS-based therapies have had very limited success, and no FDA approval in the anticancer list was mechanistically based on ROS manipulation. Even compared with the untargetable proteins, such as transcription factors, ROS are more difficult to be targeted due to their chemical properties. Thus, the pleiotropic roles of ROS provide therapeutic potential for anticancer drug discovery, while a better dissection of the mechanistic action and signaling pathways is a prerequisite for future breakthroughs. This review discusses the critical roles of ROS in cancer carcinogenesis, ROS-inspired signaling pathways, and ROS-based treatment, exemplified by lung cancer. In particular, an eight considerations rule is proposed for ROS-targeting strategies and drug design and development., (© 2024 Wiley Periodicals LLC.)

Omics, bioinformatics, molecular docking, and experimental validation were used to elucidate the hepatoprotective effects, mechanisms, and active compounds of Shandougen (SDG) based on the biolabel-led research pattern. Integrated omics were used to explore the biolabels of SDG intervention in liver tissue. Subsequently, bioinformatics and molecular docking were applied to topologically analyze its therapeutic effects, mechanisms, and active compounds based on biolabels. Finally, an animal model was used to verify the biolabel analysis results. Omics, bioinformatics, and molecular docking revealed that SDG may exert therapeutic effects on liver diseases in the multicompound and multitarget synergistic modes, especially liver cirrhosis. In the validation experiment, SDG and its active compounds (betulinic acid and gallic acid) significantly improved the liver histopathological damage in the CCl 4 -induced liver cirrhosis model. Meanwhile, they also produced significant inhibitory effects on the focal adhesion pathway (integrin alpha-1, myosin regulatory light chain 2, laminin subunit gamma-1, etc.) and alleviated the associated pathological processes: focal adhesion (focal adhesion kinase 1)-extracellular matrix (collagen alpha-1(IV) chain, collagen alpha-1(VI) chain, and collagen alpha-2(VI) chain) dysfunction, carcinogenesis (alpha-fetoprotein, NH 3 , and acetylcholinesterase), inflammation (tumor necrosis factor alpha, interleukin-1 [IL-1], IL-6, and IL-10), and oxidative stress (reactive oxygen species, malonaldehyde, and superoxide dismutase). This study provides new evidence and insights for the hepatoprotective effects, mechanisms, and active compounds of SDG., (© 2024 John Wiley & Sons, Ltd.)

Abstract Background Lung cancer has emerged as a global public health problem and is the most common cause of cancer deaths by absolute cases globally. Besides tobacco, smoke infectious diseases such as human papillomavirus (HPV) might be involved in the pathogenesis of lung cancer. However, data are inconsistent due to differences in study design and HPV detection methods. Aim A systematic meta‐analysis was performed to examine the presence of HPV‐infection with lung cancer. Methods and Results All studies in all languages were considered for the search concepts “lung cancer” and “HPV” if data specific to HPV prevalence in lung cancer tissue were given. This included Journal articles as well as abstracts and conference reports. As detection method, only HPV PCR results from fresh frozen and paraffin‐embedded tissue were included. Five bibliographic databases and three registers of clinical trials including MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov were searched through February 2020. A total 4298 publications were identified, and 78 publications were selected, resulting in 9385 included lung cancer patients. A meta‐analysis of 15 case‐control studies with n = 2504 patients showed a weighted overall prevalence difference of 22% (95% CI: 12%‐33%; P

Abstract Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra‐crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention. We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non‐Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somatic CTNNB1 mutations are common drivers of LS‐associated CRCs, if affecting both alleles of the gene. Further, we simulated the effect of different mutations on the entire crypt, distinguishing non‐transforming and transforming mutations. As an example, we analyzed the spread of mutations in the genes APC and CTNNB1, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation's potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread. The in silico experiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency‐inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.

Abstract Gut microbiota have close interactions with the host. It can affect cancer progression and the outcomes of cancer therapy, including chemotherapy, immunotherapy, and radiotherapy. Therefore, approaches toward the modulation of gut microbiota will enhance cancer prevention and treatment. Modern drug delivery systems (DDS) are emerging as rational and promising tools for microbiota intervention. These delivery systems have compensated for the obstacles associated with traditional treatments. In this review, the essential roles of gut microbiota in carcinogenesis, cancer progression, and various cancer therapies are first introduced. Next, advances in DDS that are aimed at enhancing the efficacy of cancer therapy by modulating or engineering gut microbiota are highlighted. Finally, the challenges and opportunities associated with the application of DDS targeting gut microbiota for cancer prevention and treatment are briefly discussed.

Cervical cancer is one of the leading causes of cancer death in women worldwide, and its tumorigenesis can be influenced by the microenvironment. The anti‐inflammatory protein annexin A1 (ANXA1) has been reported to be associated with cancer progression and metastasis, suggesting that it plays a role in regulating tumour cell proliferation. Here, we examined the effect of the N‐terminal peptide Ac2‐26 of ANXA1 on the HaCaT cell line (normal) and HeLa cell line (cervical cancer) co‐cultured with endothelium cell‐conditioned medium (HMC). Treatment with Ac2‐26 decreased proliferation and increased motility of cervical cancer cells, but did not affect cellular morphology or viability. Combined HMC stimulus and Ac2‐26 treatment resulted in an increase in apoptotic HeLa cells, upregulated expression of MMP2, and downregulated expression of COX2, EP3 and EP4. In conclusion, Ac2‐26 treatment may modulate cellular and molecular mechanisms underlying cervical carcinogenesis.

Next‐generation sequencing provides an opportunity to detect viral species from RNA‐seq data of human tissues, but existing computational approaches do not perform optimally on clinical samples. We developed a bioinformatic method called VirTect for detecting viruses in neoplastic human tissues using RNA‐seq data. Here, we used VirTect to analyze RNA‐seq data from 363 head and neck squamous cell carcinoma (HNSCC) patients and identified 22 human papillomavirus (HPV)‐induced HNSCCs. These predictions were validated by manual review of pathology reports on histopathologic specimens. VirTect showed better performance in recall and accuracy compared to the two existing prediction methods, VirusFinder and VirusSeq, in identifying viral sequences from RNA‐seq data. The majority of HPV carcinogenesis studies thus far have been performed on cervical cancer and generalized to HNSCC. Our results suggest that carcinogenesis of HPV‐induced HNSCC and other cases of HNSCC involve different genes, so understanding the underlying molecular mechanisms will have a significant impact on therapeutic approaches and outcomes. In summary, RNA‐seq together with VirTect can be an effective solution for the detection of viruses from tumor samples and can facilitate the clinicopathologic characterization of various types of cancers with broad applications for oncology.

The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide‐spectrum molecular studies that delve into the impact of T2DM‐related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2DM. We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes‐related metabolic and signaling processes. Proteomic approaches highlighted several cancer‐related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD/YAP‐TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high‐glucose conditions. In conclusion, T2DM associates with deregulation of cancer‐related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD/YAP‐TAZ complex as a potential driver.

Abstract Most solid cancers are characterized by chromosomal instability (CIN)—an elevated rate of large‐scale chromosomal aberrations and ploidy changes. Chromosomal instability may arise through mutations in a range of genomic integrity loci and is commonly associated with fast disease progression, poor prognosis, and multidrug resistance. However, the evolutionary forces promoting CIN‐inducing alleles (hereafter, CIN mutators) during carcinogenesis remain poorly understood. Here, we develop a stochastic, individual‐based model of indirect selection experienced by CIN mutators via genomic associations with fitness‐affecting mutations. Because mutations associated with CIN affect large swaths of the genome and have the potential to simultaneously comprise many individual loci, we show that indirect selection on CIN mutators is critically influenced by genome organization. In particular, we find strong support for a key role played by the spatial clustering of loci with either beneficial or deleterious mutational effects. Genomic clustering of selected loci allows CIN mutators to generate favorable chromosomal changes that facilitate their rapid expansion within a neoplasm and, in turn, accelerate carcinogenesis. We then examine the distribution of oncogenic and tumor‐suppressing loci in the human genome and find both to be potentially more clustered along the chromosome than expected, leading us to speculate that human genome may be susceptible to CIN hitchhiking. More quantitative data on fitness effects of individual mutations will be necessary, though, to assess the true levels of clustering in the human genome and the effectiveness of indirect selection for CIN. Finally, we use our model to examine how therapeutic strategies that increase the deleterious burden of genetically unstable cells by raising either the rate of CIN or the cost of deleterious mutations affect CIN evolution. We find that both can inhibit CIN hitchhiking and delay carcinogenesis in some circumstances, yet, in line with earlier work, we find the latter to be considerably more effective.

Circular RNA is an important regulator for non-small cell lung cancer (NSCLC). Circ&#95;0000735 has been found to be significantly overexpressed in NSCLC tissues. Therefore, its role and mechanism in NSCLC progression need to be further explored. The expression levels of circ&#95;0000735, miR-345-5p and A disintegrin and metalloprotease 19 (ADAM19) were determined using quantitative real-time PCR. EdU staining, wound healing and transwell assays were utilized to detect cell proliferation and metastasis. The protein levels of metastasis markers, exosome markers and ADAM19 were determined using western blot. Animal experiments were performed to confirm the role of circ&#95;0000735 in NSCLC tumorigenesis. The exosomes from cells and serum were identified using transmission electron microscopy and nanoparticle tracking analysis. We found that circ&#95;0000735 was upregulated in NSCLC, and its knockdown repressed NSCLC cell proliferation and metastasis. In terms of mechanism, circ&#95;0000735 targeted miR-345-5p to regulate ADAM19. MiR-345-5p inhibitor reversed the suppressive effect of circ&#95;0000735 knockdown on NSCLC progression, and ADAM19 overexpression abolished the inhibition effect of miR-345-5p on NSCLC progression. Also, animal experiments showed that silencing of circ&#95;0000735 reduced NSCLC tumorigenesis. In addition, exosomes mediated the intercellular transmission of circ&#95;0000735, and serum exosomal circ&#95;0000735 might be an important indicator for the diagnosis of NSCLC. In conclusion, circ&#95;0000735 facilitated NSCLC progression via miR-345-5p/ADAM19 pathway, and serum exosomal circ&#95;0000735 might be a potential biomarker for NSCLC diagnosis., (© 2024 Wiley Periodicals LLC.)

Cadmium (Cd) is a multitarget, carcinogenic, nonessential environmental pollutant. Due to its toxic effects at very low concentrations, lengthy biological half-life, and low excretion rate, exposure to Cd carries a concern. Prolonged exposure to Cd causes severe injury to the nervous system of both humans and animals. Nevertheless, the precise mechanisms responsible for the neurotoxic effects of Cd have yet to be fully elucidated. The accurate chemical mechanism potentially entails the destruction of metal-ion homeostasis, inducing oxidative stress, apoptosis, and autophagy. Here we review the evidence of the neurotoxic effects of Cd and corresponding strategies to protect against Cd-induced central nervous system injury., (© 2024 Wiley Periodicals LLC.)

Background: RACK1 has been identified as a multifunctional cytosolic protein, and plays a pivotal role in multiple biological responses involved in several kinds of tumors, while its effect in cervical cancer has not been well elucidated yet. The study aimed to investigate the role of RACK1 in cervical cancer occurrence and progression., Methods: The expression of RACK1 in cervical specimens was measured by immunohistochemical staining and Western blot assay. Transgenic mice were used to detect the role of RACK1 in modulating tumorigenesis in vivo. Cervical carcinoma cell lines were used to explore the underlying mechanisms of RACK1 on the behaviors of tumor cells in vitro., Results: We found that RACK1 expression was upregulated in cancer tissues compared with adjacent tissues, and its expression was gradually increased from cervictis, and cervical intraepithelial neoplasis (CIN) to carcinoma. Genetic overexpression of RACK1 facilitated tumor formation and growth in nude mice. Mechanism studies disclosed that RACK1 over-expression prolonged the G 0 /G 1 phase by up-regulating the expression of cyclinD1, down-regulating p21 and p27 probably by modulating the phosphorylation of AKT., Conclusions: Taken together, we concluded that RACK1 stimulates tumorigenesis and progression of cervical cancer via modulating the proliferation of tumor cells, implying that targeting RACK1 may serve as a promising method for cervical cancer therapy., (© 2024 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Hepatocellular carcinoma (HCC) is among the world's worst malignancies. Nuclear division cycle 1 (NDC1) is an essential membrane-integral nucleoporin, found in this study to be significantly increased in primary HCC. A multivariate analysis revealed that higher NDC1 expression was linked to worse outcome in HCC patients. Mouse xenograft tumors overexpressing NDC1 grew rapidly, and HCC cells overexpressing NDC1 showed enhanced proliferation, invasion, and migration in vitro. In contrast, knocking down NDC1 had the opposite effects in vitro. Furthermore, co-immunoprecipitation and liquid chromatograph mass spectrometer analyses revealed that NDC1 activated PI3K/AKT signaling by interacting with BCAP31. In summary, NDC1 and BCAP31 cooperate to promote the PI3K/AKT pathway, which is essential for HCC carcinogenesis. This suggests that NDC1 is predictive of prognosis in HCC., (© 2024 Wiley Periodicals LLC.)

Abstract Background Medulloblastomas (MBs) are a heterogeneous group of childhood brain tumors with four consensus subgroups, namely MBSHH, MBWNT, MBGroup 3, and MBGroup 4, representing the second most common type of pediatric brain cancer after high‐grade gliomas. They suffer from a high prevalence of genetic predisposition with up to 20% of MBSHH caused by germline mutations in only six genes. However, the spectrum of germline mutations in MBSHH remains incomplete. Methods Comprehensive Next‐Generation Sequencing panels of both tumor and patient blood samples were performed as molecular genetic characterization. The panels cover genes that are known to predispose to cancer. Results Here, we report on a patient with a pathogenic germline PTEN variant resulting in an early stop codon p.(Glu7Argfs*4) (ClinVar ID: 480383). The patient developed macrocephaly and MBSHH, but reached remission with current treatment protocols. Conclusions We propose that pathogenic PTEN variants may predispose to medulloblastoma, and show that remission was reached with current treatment protocols. The PTEN gene should be included in the genetic testing provided to patients who develop medulloblastoma at an early age. We recommend brain magnetic resonance imaging upon an unexpected acceleration of growth of head circumference for pediatric patients harboring pathogenic germline PTEN variants.

Abstract Background Research in the field of relation between microbes and colorectal carcinogenesis has gained increasing interest in past years. Recently, link between microbial biofilm and carcinogenesis in colon was demonstrated by several authors indicating that biofilm not only is a key player in carcinogenesis, but also may contribute to the understanding of side-specific colon cancer—right sided colon cancer versus left sided. In this article, we briefly highlight the major findings of the research of biofilm and carcinogenesis and demonstrate our findings of colonic cancer tissue and colonic polyp examined for biofilm. Case presentation Colonic cancer tissue from a patient with a right-sided colon cancer, and an adenoma tubular polyp were examined for biofilm formation by flourescens in situ hybridization. In cancer tissue we found biofilm formation on the surface epithelium but surprisingly also deep into the crypts. No biofilms were found in tubular polyp tissue. Conclusions To our knowledge, this is the first-time biofilm formation deep into colonic crypts are demonstrated in a patient with right-sided colon cancer. This may indicate that bacterial biofilm may have a key role in carcinogenesis.