Early Stages Of Tumorigenesis Research Articles

Validation of gene polymorphisms (rs2682818 and rs2043556) in has-miR-618 and has-miR-605 with the breast cancer susceptibility

BackgroundBreast cancer (BC) is one of the most frequent types of cancer and the second leading cause of cancer-affiliate death among ladies. BC is a heterogeneous sickness that is impacted by environment and genetic elements. Diagnosis in the early stages impacts treatment and patient survival rate. miRNA can play a vital role in BC's early stages of tumorigenesis. Single nucleotide polymorphism (SNP) can cause changes in miRNA expression and function, which are related to the risk of several cancers. AimThe goal of this examination is to assess the affiliation among two has-miR-605 (rs2043556A > G) and has-miR-618 (rs2682818 C > A) gene polymorphisms with the risk of BC in the Iranian ladies. MethodsOur case-control examination assessed two hundred whole blood samples of one hundred ladies with BC and one hundred healthy ladies. Hence, to assess the connection between the presence of SNP miRNA genes and the risk of BC, genotyping was done by the usage of the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, then the usage of the Chi-square test of SPSS software statistically analyzed the acquired result. ResultsOur findings confirmed a statistically substantial distinction within the genotype frequency of the has-miR-618 gene polymorphism among the groups (P = 0.043), whereas no statistically substantial distinction inside the genotype frequency of the has-miR-605 gene polymorphism among the control and case (P = 0.183). In addition, the allelic frequency of two polymorphisms, (rs2043556 A > G) G allele (OR = 2.163, CI 95 % = 1.56–2.988, P = 0.022) and (rs2682818 C > A) A allele (OR = 3.997, CI 95 % = 1.584–10.081, P = 0.002) substantially enhance the risk of BC. ConclusionThe results show that the G allele of rs2043556 and the A allele of rs2682818 increase the risk of BC in the women population of East Azerbaijan province.

Targeting the Tumor Epigenetic Regulator SETDB1 for Tumor Therapy.

Epigenetic alterations are implicated in the early stages of tumorigenesis and are widely recognized as a ubiquitous phenomenon in cancer development. Aberrant epigenetic modifications can alter the expression of target genes, induce heterochromatin formation, and gradually drive normal cells towards immortalized tumor cells with significant consequences. SETDB1 (SET domain bifurcated histone lysine methyltransferase 1), a typical histone me-thyltransferase, promotes the formation of heterochromatin and inhibits the transcription of genes by modifying the methylation of lysine 9 of histone 3. SETDB1 is usually highly ex-pressed in tumors with high copy numbers, accompanied by poor prognosis and low patient survival rates, which is a typical case of abnormal epigenetic modification. We discuss the mechanism of SETDB1 in a variety of cancers and review the epigenetic inhibitors that have been reported in recent years, along with their anti-tumor effects. In addition, we summarize the role of SETDB1 in a variety of diseases and cell functions.

Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies.

The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.

Abstract 5635: TPM4 overexpression promotes colon epithelial cell tumorigenesis in vitro and correlates with human colon tumor progression in vivo

Abstract Because colon cancer still exerts a heavy burden on human health, we are interested in identifying very early events in colon epithelial cell tumorigenesis in order to develop strategies to treat and possibly prevent colon carcinogenesis. We hypothesize that aberrant expression of genes involved in crypt-luminal colon epithelial cell migration, needed for proliferative, undifferentiated stem cells at the crypt bottom to mature into growth arrested, mature effector cells near the lumen, may disrupt normal differentiation and initiate events that can trigger the transition from a normal to premalignant state in colon epithelial cells. Forced upregulation of tropomyosin 4 (TPM4), an actin-binding protein that exerts many effects on contractility and migration, prevents certain aspects of Caco2 maturation induced by contact inhibition of growth, including increased expression of the digestive enzyme sucrose isomaltase and glutathione S-transferase alpha 1. Furthermore, TPM4.2-overexpressing cells exhibit numerous morphological abnormalities. Compared to untransfected Caco2 cells and empty-vector stable transfectant controls, TPM4.2-overexpressing Caco2 cell clones elaborate aberrant thin membrane protrusions and expanded membrane ruffles. Particularly striking are defective maintenance of dome structures at middle (day 14) and late (day 21) time points of induced differentiation in TPM4.2-overeexpressing clones. We further hypothesize that TPM4 is overexpressed in human colon tumors, particularly at early stages of tumorigenesis. In order to test this hypothesis, we examined TPM4 RNA expression in datasets obtained from human colon tissue at premalignant as well as tumorigenic stages. TPM4 trends toward overexpression in premalignant, relative to normal, human colon tissue (uninvolved mucosa from patients with familial adenomatous polyposis, or FAP) and is significantly overexpressed in adenocarcinoma tissue relative to normal controls. Interestingly, TPM4 overexpression may be more pronounced at earlier, rather than later, stages of adenocarcinoma. Our results suggest that aberrant TPM4 overexpression in colon epithelial cells can promote adoption of a tumorigenic state. Certain aspects of Caco2 cell maturation are disrupted by forced TPM4 overexpression during induced differentiation, and TPM4 overexpression correlates with early stages of colon tumorigenesis. Misregulation of TPM4 gene expression may therefore represent a critical molecular event that can block normal differentiation and induce early events in colon epithelial cell tumorigenesis. TPM4 expression level may therefore prove to be a useful biomarker that can, along with other diagnostics, help to determine tumorigenic progression in human colon tissue and to develop novel strategies to prevent colon cancer and treat it at early stages. Citation Format: Giulio Ferrero, Barbara Pardini, Alessio Naccarati, Michael Papetti. TPM4 overexpression promotes colon epithelial cell tumorigenesis in vitro and correlates with human colon tumor progression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5635.

Abstract 1445: Emergence of frameshift mutations during tumorigenesis in VCMsh2 mouse model of Lynch syndrome

Abstract Monoallelic germline mutations in MMR genes (e.g., MLH1, MSH2, MSH6, and PMS2) predispose individuals to Lynch syndrome (LS) with microsatellite instability (MSI) throughout the genome. Mutations at coding mononucleotide repeats (MNR) usually result in frameshift mutations (FSMs). Recurrent FSMs are thought to play a central role in the increased risk of different types of cancer. Neoantigens produced by FSMs have been shown to elicit immune responses, which is the basis for frameshift neoantigen-based vaccines. To develop a prophylactic vaccine and prevention strategy for this high-risk population, we assessed FSMs during tumorigenesis from histologically normal mucosa and fecal DNA of a LS mouse model using targeted sequencing and a panel of FSMs in MNR regions. Msh2LoxP/LoxP;Villin-Cre mice (VCMsh2) started developing detectable tumors at 7-8 months and median survival was 11.5 months with 100% penetrance. Interestingly, FSMs were detectable not only in tumors and mucosa at 7-8 months, but also in young mice (1 month), embryos and pups although FSMs detected and variant allele frequency (VAF) were very low, indicating that FSMs accumulated over time, and FSMs alone may be not sufficient for tumorigenesis since tumors emerge at older age. To determine whether Msh2 was absent in embryos and pups, immunohistochemical (IHC) analysis was performed. Msh2 was lost in almost all intestine epithelial cells in 2-month-old mice but still present in young pups and embryos with very few cells absent of Msh2, indicating that emerging FSMs in these young pups may be due to decreased Msh2 expression because of delayed Cre function. To determine whether low Msh2 expression could lead to the emergence of FSMs, intestine mucosa from 8-, 10-, and 12-month-old Msh2LoxP/+;Villin-Cre heterozygous mice was sequenced. FSMs were detectable with low VAF, although they didn’t develop tumors. IHC staining revealed that Msh2 was absent in only a few intestine epithelial cells in these heterozygous mice, suggesting that loss of heterozygosity was a late event and rare at 12 months. To determine whether MSI emerged in young VCMsh2 pups and heterozygous mice due to haploinsufficiency of Msh2, MSI was assessed using seven markers and fragment size analysis. One marker (mBat67) showed instability in the intestinal mucosa of heterozygous mice and three showed instability in fecal DNA of one month old VCMsh2 mice. Interestingly, mucosal and fecal samples from a time course study in VCMsh2 mice showed progressive increase in MSI with a good correlation between MSI and FSMs during the tumorigenesis process. In summary, FSMs emerged at an early stage of tumorigenesis in VCMsh2 mice, which correlated with MSI status. Our data indicates that FSMs and MSI status can be used to monitor the tumor development of LS colorectal cancer. Funded by the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I Citation Format: Yurong Song, Lei Wei, Shaneen S. Baxter, Brandon Somerville, Holli Loomans-Kropp, Chelsea Sanders, Ryan N. Baugher, Stephanie D. Mellott, Todd B. Young, Heidi E. Lawhorn, Teri M. Plona, Qiang Hu, Song Liu, Alan Hutson, Simone Difilippantonio, Ligia Pinto, Steven M. Lipkin, Matthias Kloor, Shizuko Sei, Robert H. Shoemaker. Emergence of frameshift mutations during tumorigenesis in VCMsh2 mouse model of Lynch syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1445.

B-360 Usefulness of the Ratios of CYFRA21-1 and p53 Autoantibody Immune Complexes to Their Free Antigens in Lung Cancer

Abstract Background Autoantibodies against specific cancer-associated antigens are produced in the early stages of tumorigenesis. In lung cancer, the possibility of autoantibodies as diagnostic biomarkers has been proposed. This study was to evaluate the usefulness of novel DNA-guided sandwich immunoassay detecting CYFRA21-1 and p53 autoantibody immune complexes and their free antigens in diagnosis of lung cancer. Methods In total, 100 patients with lung cancer and 119 healthy controls were analyzed with 9G testTM Lung/Cancer (Biometrix Technology, South Korea) measuring plasma autoantibody immune complexes (CYFRA21-1 with anti-CYFRA21-1 autoantibody immune complex (CIC), p53 with anti-p53 autoantibody immune complex (PIC)) and their free antigens (CYFRA 21-1 and p53). The ratios of CIC to CYFRA21-1 (CIC/CYFRA21-1) and PIC to p53 (PIC/p53), and the multiplication of the two ratios, named as LC index were calculated. Results The levels of CIC and PIC were significantly increased in lung cancer compared with those in healthy control (P = 0.0062 and P = 0.0026, respectively), while free antigens didn’t distinguish between lung cancer and healthy control. The ratios CIC/CYFRA21-1 and PIC/p53 were significantly higher in lung cancer than those in healthy control (all, P < 0.0001). Diagnostic performances expressed as area under the curve (AUC) were higher in the ratios of autoantibody immune complexes to each free antigen (PIC/p53 and CIC/CYFRA21-1) than autoantibody immune complexes (PIC and CIC) (AUC; 0.887, 0.847 vs 0.618, 0.608, respectively). The most excellent diagnostic performance was proven with LC index at diagnostic cut-off 3.60, which showed 81% sensitivity and 95% specificity with 0.945 AUC (P < 0.001). It was more sensitive to early lung cancer than to advanced lung cancer (sensitivity 87.5% vs 72.7%). Conclusion The ratios of CIC to CYFRA21-1 and PIC to p53 are useful biomarkers in lung cancer diagnosis and the combination of the ratios, LC index could be complementary tool for lung cancer screening with radiological tests.

Elevated expression levels of COX-2, IL-8 and VEGF in colon adenocarcinoma.

There is growing evidence of a connection between inflammation and tumor development and NF-κB is an important transcription factor in the inflammation pathway. Genetic approaches have proven the role of NF-κB responsive genes in tumorigenesis. The NF-κB responsive genes products such as IL-8, VEGF and COX-2 are the key components of angiogenesis. MMP-2 and MMP-9 are playing important roles in the disruption of the extracellular matrix that may contribute to the metastasis of tumor cells. This study aimed to investigate gene expression levels of COX-2, IL-8, VEGF, MMP-2 and MMP-9 in colon tumors. A total of 34 fresh colon carcinoma specimens and paired normal adjacent tissues (NAT) were collected during the surgery and RNA isolations were carried out from specimens. Synthesis of cDNA was carried out from these RNAs with oligo dT18 primers. The transcribed cDNA was used for PCR amplification reactions for the investigated genes with β-actin being the internal reference via the semi-quantitative RT-PCR method. A statistically significant difference was observed for COX-2, IL-8 and VEGF which were all upregulated in colon tumors compared with adjacent normal tissues (p<0.05). However, MMP-2 and MMP-9 expression levels did not change between tumor and normal tissues (p>0.05). Upregulated expression levels of COX-2, IL-8 and VEGF might occur in the early stages of tumorigenesis and detection of these mRNA levels may be beneficial for early diagnosis and management of colon tumors.

Abstract A085: A luminal intermediate cell state maintains long-term prostate homeostasis and contributes to tumorigenesis

Abstract Cellular heterogeneity poses tremendous challenges for developing cell-targeted therapies and biomarkers of clinically significant prostate cancer. The origins of this heterogeneity within the cellular complexities of normal adult and aging tissue remain unknown leaving important cellular states and transcriptional programs that allow the expansion of malignant clones in early cancer unidentified. These unresolved questions hamper the development of novel therapies designed to block the deregulated proliferation of prostate epithelial cells. To define cell states that contribute to early cancer development, we performed in vivo lineage tracing with multicolor reporters, whole organ mapping and single cell transcriptomics of normal and malignant prostate from genetically-engineered mouse models. We show here that the long-term luminal homeostasis is maintained by multiple clones with various fitness levels. Long-term clonal expansions are enabled by a luminal transcriptional state harboring basal markers (Luminal Intermediate, LumI) and controlled by Wnt/p63 signaling. Moreover, LumI cells greatly expand during early stages of tumorigenesis in several mouse models of prostate cancer. Specific genetic ablation of p63 from luminal cells in vivo decreases clonal activity in homeostasis and reduces the formation of aggressive clones in prostate tumor models. Finally, the LumI cells and Wnt signaling appear to significantly increase in human aging prostate and prostate cancer samples, highlighting the importance of this hybrid cell state for human pathologies with potential translational impact. Our models reveal a continuity of this cell state from normal homeostasis to aging and early cancer with specific alterations at each stage. Understanding how the luminal intermediate cell state is regulated in homeostasis and deregulated in hyperproliferative contexts is crucial for the development of prognostic markers and new therapeutic interventions for prostate diseases. Citation Format: Fu Luo, Lara F. Tshering, Karis Tutuska, Mariola Szenk, Diana Rubel, James G. Rail, Savanah Russ, Jingxuan Liu, Alice Nemajerova, Gábor Balázsi, Flaminia Talos. A luminal intermediate cell state maintains long-term prostate homeostasis and contributes to tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A085.

Deterministic evolution and stringent selection during preneoplasia

The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.

MiR‑4732‑5p promotes ovarian cancer mobility by targeting MCUR1.

MicroRNAs (miRNAs/miRs) play critical roles in tumor progression. However, the role of miR-4732 and its underlying molecular mechanism in ovarian cancer (OC) remain unclear. In the present study, the high expression of miR-4732 was confirmed to be associated with the mortality of patients with OC following surgery, according to The Cancer Genome Atlas Ovarian Cancer database (TCGA-OV). Additionally, the expression of miR-4732 was positively associated with an increased tendency to exhibit an early TNM stage (IIA, IIB and IIC) of OC, indicating its promotional role in the early stages of tumorigenesis. By performing in vitro gain-of-function experiments, the transient transfection of IGROV1 cells with miR-4732-5p mimics enhanced cell viability according to Cell Counting Kit-8 assay, and cell migration and invasion in Transwell assays. However, though the application of loss-of-function experiments, the transient transfection of IGROV1 cells with miR-4732-5p inhibitors hindered cell viability, cell migration and invasion in vitro. Mitochondrial calcium uniporter regulator 1 (MCUR1) was validated as a downstream direct target of miR-4732-5p through bioinformatics analysis, western blotting and luciferase assays. Therefore, the results of the present study provide evidence that miR-4732-5p may promote OC cell mobility through the direct targeting of the tumor suppressor, MCUR1.

Dioscin modulates macrophages polarization and MDSCs differentiation to inhibit tumorigenesis of colitis-associated colorectal cancer.

It has been reported that colitis is one of risk factors in colorectal cancer (CRC). Intervention of intestinal inflammation and in the early stage of tumorigenesis is of great significance to control the incidence and mortality of CRC. In recent years, natural active products of traditional Chinese medicine have been confirmed that they had made great progress in disease prevention. Here, we showed that Dioscin, a natural active product of Dioscorea nipponica Makino, inhibited initiation and tumorigenesis of AOM/DSS-induced colitis-associated colon cancer (CAC), including alleviating colonic inflammation, improving intestinal barrier function and decreasing tumor burden. In addition, we also explored the immunoregulatory effect of Dioscin on mice. The results showed that Dioscin modulated M1/M2 macrophages phenotype in spleen and decreased monocytic myeloid-derived suppressor cells (M-MDSCs) population in blood and spleen of mice. The in vitro assay demonstrated that Dioscin promoted M1 as well as inhibited M2 macrophages phenotype in LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model. Based on the plasticity of MDSCs and its ability to differentiate into M1/M2 macrophages, we here found that Dioscin increased M1- and decreased M2-like phenotype during the process of MDSCs differentiation in vitro, suggesting Dioscin promoted MDSCs differentiate into M1 as well as inhibited its differentiation into M2 macrophages. Taken together, our study indicated that Dioscin had the inhibitory effect on the initial of tumorigenesis at early stage of CAC via the ant-inflammatory effect, which provided a natural active candidate for effective prevention of CAC.

Promoter methylation levels of RASSF1 and ATIC genes are associated with lung cancer in Iranian patients.

Epigenetic alterations like methylation of tumor suppressor genes or oncogenes, in respiratory epithelium have been associated with lung cancer. Hypermethylation of genes promoter is an epigenetic event, and is responsible to tumor suppressor genes inactivation as well as oncogenes activation. This study aimed to assess the role of methylation status in promoter of RASSF1 and ATIC genes their potential implication in the pathogenesis of lung tumor in Iranian patients. In this study, we collected 100 tissue samples (50lung cancer tissues and 50 adjacent non-cancerous lung tissues) from Iranian lung cancer patients. The genomic DNA was extracted, and methylation status of both RASSF1 andATIC genes was investigated by methylation-sensitive high-resolution melting (MS-HRM) assay technique and Real-Time PCR. Cancer Genome Atlas (TCGA) dataset wasalso analyzed for further validation of the gene's methylation. Methylation of RASSF1 gene promoter was significantly higher in lung tumor tissues. However, promoter methylation levels of ATIC gene was significantly lower in lung tumor tissues. These results were additionally confirmed by TCGA analysis. Promoter methylation of both RASSF1 and ATIC genes was significantly associated with lymph node metastasis, and clinical stage of lung cancer. Thereceiver operating characteristic (ROC) curve analysis indicated a high accuracy of promoter methylation in these genes as a diagnostic biomarker for lung cancer. Methylation levels of both RASSF1 and ATIC genes promoters were associated with lung cancer pathogenesis in Iranian population, and may be a suitable biomarker for diagnosis and prognosis of lung cancer in early stage of tumorigenesis.

UCP2 Upregulation Increases Fra-1 Expression and S-phase Cell Population without Decreasing Apoptosis during Skin Cell Transformation

Upregulation of uncoupling protein 2 (UCP2) is considered a prosurvival mechanism for cancer cells. This prosurvival function is thought to be mediated by UCP2’s uncoupling activity which reduces the production of superoxide in the mitochondria. However, exactly how highly expressed UCP2 regulates cell proliferation, cell cycle, and cell death during the early stage of tumorigenesis has not been studied thoroughly. For this purpose, we generated UCP2 stably overexpressed JB6 Cl-41 cells (a skin cell transformation model) and performed studies to answer the above questions. Our results demonstrated that UCP2 overexpression enhanced cell proliferation, activation of the oncoprotein Fra-1, anchorage-independent growth, 3D spheroids growth, and glucose uptake during skin cell transformation. Next, our results demonstrated that UCP2 overexpression resulted in marked decreases in the proportion of the cells in the G1 phase and an increase of cells in the S phase of the cell cycle, which was accompanied by increased expression of Cyclin E and Cdk2. Lastly, UCP2 overexpression did not enhance or suppress apoptosis during skin cell transformation, as indicated by Annexin V and active caspase 3/7 staining. Taken together, these data suggest that UCP2 upregulation mainly enhances the Fra-1 oncogenic pathway which drives cell proliferation, without inhibiting apoptosis during skin cell transformation.

Immunoediting instructs tumor metabolic reprogramming to support immune evasion

Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that Tcell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the Tcell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating Tcells and forming the suppressive tumor microenvironment.

The role of toll-like receptors (TLRs) and their therapeutic applications in endometrial cancer.

Endometrial cancer (EC) is developed nations' most prevalent form of gynecologic cancer. Patients are frequently diagnosed with EC when the tumor is still limited to the uterus. Patients without tumor metastasis have a 5-year survival rate ranging from 80 to 90%; however, almost 16.8% of EC patients develop a metastatic form of the tumor. In the early stages of tumorigenesis, the immune system is able to identify aberrant cells as non-self, therefore providing the optimal pro-inflammatory microenvironment for the elimination of cancer cells. Although, chronic inflammation can be a crucial aspect of tumor development. Toll-like receptors (TLRs), as the main pattern recognition receptors (PRRs) in innate immunity, may stimulate an inflammatory response and provide cell survival in the tumor microenvironment (TME). TLRs are vital immunomodulators that may significantly impact the development of gynecologic malignancies. Therefore, TLR inhibitors are being researched for their possible benefits in treating gynecologic cancers. The aim of this study is to review the current knowledge in this field and provide some insight into the therapeutic potential of TLR inhibitors in EC.

Distinct mutational features across preinvasive and invasive subtypes identified through comprehensive profiling of surgically resected lung adenocarcinoma

AbstractLung adenocarcinoma (LUAD) is a heterogeneous disease. Our study aimed to understand the unique molecular features of preinvasive to invasive LUAD subtypes. We retrospectively analyzed the clinical, histopathological, and molecular data of 3,254 Chinese patients with preinvasive lesions (n = 252), minimally invasive adenocarcinomas (n = 479), and invasive LUAD (n = 2,523). Molecular data were elucidated using a targeted 68-gene next-generation sequencing panel. Our findings revealed four preinvasive lesion-predominant gene mutations, including MAP2K1 insertion-deletions (indels), BRAF non-V600E kinase mutations, and exon 20 insertions (20ins) in both EGFR and ERBB2, which we referred to as mutations enriched in AIS (MEA). The detection rate of MEA in invasive tumors was relatively lower. MAP2K1 missense mutations, which were likely passenger mutations, co-occurred with oncogenic driver mutations, while small indels were mutually exclusive from other genes regardless of the invasion level. BRAF non-V600E kinase-mutant invasive adenocarcinomas (IAC) had significantly higher mutation rates in tumor suppressor genes but lower frequency of co-occurring oncogenic driver mutations than non-kinase-mutant IAC, suggesting the potential oncogenic activity of BRAF non-V600E kinase mutations albeit weaker than BRAF V600E. Moreover, similar to the extremely low frequency of MAP2K1 indels in IAC, BRAF non-V600E kinase domain mutations co-occurring with TSC1 mutations were exclusively found in preinvasive lesions. Compared with EGFR L858R and exon 19 deletion, patients with preinvasive lesions harboring 20ins in either EGFR or ERBB2 were significantly younger, while those with IAC had similar age. Furthermore, our study demonstrated distinct mutational features for subtypes of oncogene mutations favored by different invasion patterns in adenocarcinomas. In conclusion, our data demonstrate distinct mutational features between preinvasive lesions and invasive tumors with MEA, suggesting the involvement of MEA in the early stages of tumorigenesis. Further pre-clinical studies are required to establish the role of these genes in the malignant transformation of LUAD.

Autophagy at the intersection of aging, senescence, and cancer.

Autophagy is an evolutionarily conserved cellular process in which macromolecules undergo lysosomal degradation. It fulfills essential roles in quality controlling cellular constituents and in energy homeostasis. Basal autophagy is also widely accepted to provide a protective role in aging and aging‐related disorders, and its decline with age might precipitate the onset of a variety of diseases. In this review, we discuss the role of basal autophagy in maintaining homeostasis, in part through the maintenance of stem cell populations and the prevention of cellular senescence. We also consider how stress‐induced senescence, for example, during oncogene activation and in premalignant disease, might rely on autophagy, and the possibility that the age‐associated decline in autophagy might promote tumour development through a variety of mechanisms. Ultimately, evidence suggests that autophagy is required for malignant cancer progression in a number of settings. Thus, autophagy appears to be tumour‐suppressive during the early stages of tumorigenesis and tumour‐promoting at later stages.

Tumor-Associated Inflammation: The Tumor-Promoting Immunity in the Early Stages of Tumorigenesis.

Tumorigenesis is a multistage progressive oncogenic process caused by alterations in the structure and expression level of multiple genes. Normal cells are continuously endowed with new capabilities in this evolution, leading to subsequent tumor formation. Immune cells are the most important components of inflammation, which is closely associated with tumorigenesis. There is a broad consensus in cancer research that inflammation and immune response facilitate tumor progression, infiltration, and metastasis via different mechanisms; however, their protumor effects are equally important in tumorigenesis at earlier stages. Previous studies have demonstrated that during the early stages of tumorigenesis, certain immune cells can promote the formation and proliferation of premalignant cells by inducing DNA damage and repair inhibition, releasing trophic/supporting signals, promoting immune escape, and activating inflammasomes, as well as enhance the characteristics of cancer stem cells. In this review, we focus on the potential mechanisms by which immune cells can promote tumor initiation and promotion in the early stages of tumorigenesis; furthermore, we discuss the interaction of the inflammatory environment and protumor immune cells with premalignant cells and cancer stem cells, as well as the possibility of early intervention in tumor formation by targeting these cellular mechanisms.

Dichotomous role of autophagy in cancer.

Autophagy is an evolutionary conserved catabolic process that plays physiological and pathological roles in a cell. Its effect on cellular metabolism, the proteome, and the number and quality of organelles, diversely holds the potential to alter cellular functions. It acts paradoxically in cancer as a tumor inhibitor as well as a tumor promoter. In the early stage of tumorigenesis, it prevents tumor initiation by the so-called "quality control mechanism" and suppresses cancer progression. For late-staged tumors that are exposed to stress, it acts as a vibrant process of degradation and recycling that promotes cancer by facilitating metastasis. Despite this dichotomy, the crucial role of autophagy is evident in cancer, and associated with mammalian targets of rapamycin (mTOR), p53, and Ras-derived major cancer networks. Irrespective of the controversy regarding autophagic manipulation, promotion and suppression of autophagy act as potential therapeutic targets in cancer treatment and may provide various anticancer therapies.

Transcriptome of sessile serrated adenoma/polyps is associated with MSI-high colorectal cancer and decreased expression of CDX2.

The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor-normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability-high (MSI-H) CRC (p < 10-5 ). Transcriptome analysis of five MSI-related genes (MSH2, MSH6, MLH1, PMS1, and PMS2) and five CRC-related genes (BRAF, KRAS, APC, TP53, and CDX2) showed that CDX2 expression was most severely decreased in SSA/P. Immunohistochemical staining confirmed that CDX2 protein was reduced compared with the surrounding mucosa. Direct sequencing of the BRAF gene showed that the BRAF V600E mutation was detected in only nine of 36 cases. In a mouse model, BRAF, APC, or CDX2 deficiency indicated that the gene expression pattern with loss of CDX2 is more similar to our SSA/Ps compared with those induced by BRAF or APC mutation. Transcriptome analysis of SSA/Ps showed characteristic gene expression with a strong resemblance to MSI-H CRC. Downregulation of CDX2 expression is an essential molecular mechanism involved in the initial stage of SSA/P tumorigenesis. (UMIN000027365).