Inflammatory mammary carcinoma (IMC) is the most aggressive variant of invasive mammary tumours in dogs and in women. Decorin is an extracellular matrix molecule whose expression can be reduced or absent in various human cancers, which is associated with a poor prognosis. E-cadherin is a cell adhesion protein whose expression is reduced in several neoplasms. However, it is overexpressed in inflammatory breast cancers of women. EGFR is also associated with cancer development and is commonly overexpressed in aggressive neoplasms. This study aimed to characterise the expressions of Decorin, E-cadherin, and EGFR in canine inflammatory and non-inflammatory mammary carcinomas (IMC and non-IMC) and to evaluate their expression levels as prognostic indicators for survival and occurrence of metastases. Thirty-three IMC and 43 non-IMC cases were analysed retrospectively and submitted to immunohistochemical analysis. The reactions were quantified in five high-power field images from areas of the highest intensity and frequency of immunostaining (hot spots). We found significantly lower expression of Decorin and higher of E-cadherin and EGFR in canine IMCs. Patients with tumours that exhibited Decorin expression in less than 26.35% of epithelial cells had shorter survival (p = 0.0410) and a higher occurrence of distant metastases (p = 0.0115). E-cadherin is overexpressed in canine IMCs (p < 0.0001), similar to what occurs in women, reinforcing that dogs can be used as a study model for human IMC. EGFR overexpression in canine IMCs (p = 0.0322) provides evidence for potential targeted therapy with tyrosine kinase inhibitors.

Oral cancer (OC) is one of the major types of cancer and the most common cause of cancer-related mortality in Asia. In recent years, matrix stiffness in the tumor microenvironment has been found to play an important role in regulating tumor cell behavior. However, the regulatory mechanisms associated with matrix stiffness in OC cells remain unclear.

In this study, polyacrylamide gels with different stiffness were prepared to simulate low versus high matrix stiffness environments in tumor tissues by adjusting the acrylamide and cross-linker concentrations. Subsequently, the effects of different stiffness on OC cell survival, migration, invasion and invadopodia formation were explored based on cell counting kit-8 (CCK-8), Transwell and confocal microscopy. Meanwhile, the levels of markers relevant to phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), apoptosis (BAX and BCL2) as well as metastasis (Cadherin-1, CDH1; Cadherin-2, and CDH2) were calculated via western blotting and real-time quantitative PCR.

According to the results, high matrix stiffness was seen to contribute to the increased number of migrated and invaded cells as well as the enhanced viability of OC cells, along with the aggravated invadopodia formation and the up-regulation in CDH2 and BCL2 levels yet the down-regulation in CDH1 and BAX levels. Elevated PI3K/AKT phosphorylation levels were also seen in high matrix stiffness-mediated OC cells, and the intervention using LY294002 could visibly overturned the effects of high matrix stiffness on the cell migration, invasion and invadopodia formation of OC cells.

This study reveals that matrix stiffness may enhance the invasiveness and anti-apoptotic ability of OC cells by activating the PI3K/AKT pathway, which provides a new idea for exploring the microenvironmental regulation of tumor mechanics and targeted intervention strategies.

Metastasis remains a primary cause of cancer-related mortality, with its intricate mechanisms continuing to be uncovered through advancing research. Among the various regulatory processes involved, RNA modification has emerged as a critical epitranscriptomic mechanism influencing cancer metastasis. N6-methyladenosine (m6A), recognized as one of the most prevalent and functionally significant RNA modifications, plays a central role in the regulation of RNA metabolism. In this review, we explore the multifaceted role of m6A in the different stages of cancer metastasis, including epithelial-mesenchymal transition, invasion, migration, and colonization. In addition to summarizing the current state of our understanding, we offer insights into how m6A modifications modulate key oncogenic pathways, highlighting the implications of recent discoveries for therapeutic interventions. Furthermore, we critically assess the limitations of previous studies and propose areas for future research, including the potential for targeting m6A as a novel approach in anti-metastatic therapies. Our analysis provides a comprehensive understanding of the regulatory landscape of m6A in metastasis, offering directions for continued exploration in this rapidly evolving field.

Glioblastoma (GBM) is an aggressive type of brain cancer, frequently invasive, with a low survival rate and complicated treatment. Recent studies have shown the modulation of epithelial-mesenchymal transition (EMT) biomarkers in glioblastoma cells associated with tumor progression, chemoresistance, and relapse after treatment. GBM handlings are based on aggressive chemical therapies and surgical resection with poor percentage of survival, boosting the search for more specific remedies. Marine eukaryotic microalgae are rapidly advancing as a source of anticancer drugs due to their ability to produce potent secondary metabolites with biological activity. Among such microalgae, dinoflagellates, belonging to the species Amphidinium carterae, are known producers of neurotoxins and cytotoxic compounds. We tested the capability of chemical extracts from two different strains of A. carterae to modulate the EMT markers in T98G, human GBM cells. In vitro proliferation and migration studies and EMT biomarkers' abundance and modulation assays showed that the different A. carterae strains differently modulated both EMT markers and the proliferation/migration capability of GBM cells. This study sets the bases to find a marine microalgae-derived natural compound that could potentially target the epithelial-mesenchymal transition in brain-derived tumor types.

Cholangiocarcinoma (CCA) is an epithelial bile duct cancer frequently found at an advanced stage, leading to poor response to current therapies. Although gemcitabine (GEM) and cisplatin (CIS) are the current gold-standard for treating unresectable CCA, GEM resistance often occurs. To predict the response to GEM, we evaluated chromosomal aberrations using a chromosome microarray, and their association with GEM response by histoculture drug response assay. Our findings revealed principal component analysis and orthogonal partial-least square discriminant analysis cross validated score plot between response and non-response groups were different. Different signature patterns of chromosomes between response and non-response groups analyzed by heatmap analysis identified 34 regions of 15 chromosomes. An increased signal in responders and a decreased signal in non-responders were found in regions 4q32.1, 5q12.3, 10q21.3, 11p11.2, 11q14.2, 16p11.2, 17q22, 21q21.3 and 22q12.3. In contrast, a high signal in non-responders and low signal in responders were seen in regions 2q37.2, 11q14.1, 16q22.3 and 16q23.3. High signal of CDH13 and TENM4 were demonstrated in GEM non-response, while a high CWC27 signal was noted in GEM response. This signature pattern could provide the knowledge to improve a predictive biomarker for GEM response, benefitting for individual CCA patient management and chemotherapeutic selection.

Tumors evolve through the acquisition of increasingly aggressive traits associated with dysplasia. This progression is accompanied by alterations in tumor mechanical properties, especially through extracellular matrix remodeling. However, the contribution of pre-tumoral tissue mechanics to tumor aggressiveness remains poorly known in vivo. Here, we show that adherens junction tension in pre-tumoral tissues dictates subsequent tumor evolution in Drosophila. Increased cell contractility, observed in aggressive tumors before any sign of tissue overgrowth, proved sufficient to trigger dysplasia in normally hyperplastic tumors. In addition, high contractility precedes any changes in cell polarity and contributes to tumor evolution through cell death induction, which favors cell-cell junction weakening. Overall, our results highlight the need to re-evaluate the roles of tumoral cell death and identify pre-tumoral cell mechanics as an unsuspected early marker and key trigger of tumor aggressiveness.

Malignant pleural mesothelioma (PM) is a highly aggressive disease of the lung pleura associated with poor prognosis. Despite advances in improving the clinical management of this malignancy, there is no effective chemotherapy for refractory or relapsing PM. The acquisition of resistance to standard and targeted therapy in this disease is a foremost concern; therefore, a deeper understanding of the complex factors surrounding the emergence of drug resistance is deemed necessary. In this review, we will present broad insights into various cellular and molecular concepts, accounting for the recalcitrance of PM to chemotherapy, including signaling networks regulating drug tolerance, drug resistance-associated proteins, genes, and miRNAs, as well as the critical role of cancer stem cells. Identification of the biological determinants and their associated mechanisms may provide a framework for the development of appropriate treatment.

Alternative splicing (AS) plays a critical role in gene expression by generating protein diversity from single genes. This review provides an overview of the role of AS in regulating cell fate, focusing on its involvement in processes such as cell proliferation, differentiation, apoptosis, and tumorigenesis. We explore how AS influences the cell cycle, particularly its impact on key stages like G1, S, and G2/M. The review also examines AS in cell differentiation, highlighting its effects on mesenchymal stem cells and neurogenesis, and how it regulates differentiation into adipocytes, osteoblasts, and chondrocytes. Additionally, we discuss the role of AS in programmed cell death, including apoptosis and pyroptosis, and its contribution to cancer progression. Importantly, targeting aberrant splicing mechanisms presents promising therapeutic opportunities for restoring normal cellular function. By synthesizing recent findings, this review provides insights into how AS governs cellular fate and offers directions for future research into splicing regulatory networks.

Research on breast cancer stem cells (BCSCs) is crucial for improving our understanding of their roles in tumor resistance, metastasis, and relapse. This study investigated the anti-cancer effects of two isomers of hydroxycinnamic acids (HCA): para-coumaric acid (PCA) and ortho-coumaric acid (OCA) on breast cancer stem cells (BCSCs). The isolated and characterized stem cells contained CD44 + /CD24 surface markers, exhibited high levels of aldehyde dehydrogenase activity, and were able to form mammospheres. The evaluation of HCAs on stem cell proliferation, cell cycle, and apoptosis was conducted by comparing them with MCF-7, the luminal breast cancer cell line. The viability and immunoblot analyses demonstrated that HCA applications resulted in a dose-dependent decrease in the number of viable cells and inhibited phosphorylation of Extracellular regulated kinases 1/2 (ERK1/2). These findings were supported by the detection of suppressed colony formation and delayed wound-healing in HCA-exposed cells. E-cadherin expression increased in OCA-treated cells. Additionally, the arrest of G1/S phase progression and the downregulation of Cyclin D1 expression exhibited that OCA and PCA-induced cytostatic effects in BSCS cells. After treatment, the increased Annexin-V/7-AAD staining, along with elevated expression of caspase-3/7 and a decreased Bcl-2/Bax ratio, indicated apoptosis mediated by the activation of Janus kinase (JNK) and p38 Mitogen-activated kinase (p38 MAPK). In conclusion, both OCA and PCA exhibit anti-carcinogenic potential on BCSCs; However, OCA has a stronger effect and is becoming a promising candidate for further research.

Soluble vector family member 6 (SLC2A6) has been implicated in the aggressiveness and poor prognosis of various cancers, yet its specific role in hepatocellular carcinoma (HCC) remains to be fully elucidated. This study utilized multiple databases to investigate the relationship between SLC2A6 expression and clinical stage, methylation status, drug sensitivity, immune infiltration, and immune checkpoint regulation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. Furthermore, in vitro and in vivo experiments were performed to assess the impact of SLC2A6 knockout on the proliferation, migration, invasion, and underlying mechanisms in hepatocellular carcinoma (LIHC) cells. SLC2A6 expression was significantly correlated with tumor prognosis, clinical stage, and methylation levels, and was found to influence immune cell infiltration and immune checkpoint gene expression. In LIHC, SLC2A6 was associated with key biological processes, including the cell cycle, P53 signaling, and ferroptosis. Knockdown of SLC2A6 markedly suppressed the proliferation, migration, and invasion of HCC cells, with this inhibition being closely tied to the ferroptosis pathway. SLC2A6 plays a pivotal role in the regulation of pan-cancer processes, particularly in tumor prognosis and immune-related mechanisms. In LIHC, it emerges as a potential prognostic biomarker and therapeutic target for the regulation of ferroptosis, offering new insights for targeted cancer therapies.

Triple negative breast cancer is considered to be a malignancy of grave concern with limited routes of treatment due to the absence of specific breast cancer markers and ambiguity of other potential drug targets. Poor prognosis and inadequate survival rates have prompted further research into the understanding of the molecular pathophysiology and targeting of the disease. To overcome the recurrence and resistance mechanisms of the TNBC cells, various approaches have been devised, and are being continuously evaluated to enhance their efficacy and safety. Chemo-Adjuvant therapy is one such treatment modality being employed to improve the efficiency of standard chemotherapy. Combining chemo-adjuvant therapy with other upcoming approaches of cancer therapeutics such as phytoconstituents and nanotechnology has yielded promising results in the direction of improving the prognosis of TNBC. Numerous nanoformulations have been proven to substantially enhance the specificity and cellular uptake of drugs by cancer cells, thus reducing the possibility of unintended systemic side effects within cancer patients. While phytoconstituents offer a wide variety of beneficial active constituents useful in cancer therapeutics, most favorable outcomes have been observed within the scope of polyphenols, isoquinoline alkaloids and isothiocyanates. With an enhanced understanding of the molecular mechanisms of TNBC and the advent of newer targeting technologies and novel phytochemicals of medicinal importance, a new era of cancer theranostic treatments can be explored. This review hopes to instantiate the current body of research regarding the role of certain phytoconstituents and their potential nanoformulations in targeting specific TNBC pathways for treatment and diagnostic purposes.

A complex inheritance has been suggested in families with colorectal-, gastric- and prostate cancer. Therefore, we conducted a genome-wide association study (GWAS) in colorectal cancer patients, who's relatives had prostate-, and/or gastric cancer.

The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model. Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case-control study.

Candidate loci/genes on ten chromosomal regions were suggested with odds ratios between 1.71-3.62 and p-values < 5 × 10-8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of DNA from 122 colorectal cancer patients with gastric- and/or prostate cancer in their families was performed to search for candidate variants in the haplotype regions. The identified candidate variants were tested in a nested case-control study of similar colorectal cancer cases and controls. There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested.

This study demonstrated a proof of principle strategy to identify risk variants found by GWAS, and identified ten candidate loci that could be associated with colorectal, gastric- and prostate cancer.

Breast cancer (BC) is the most commonly diagnosed cancer and the predominant cause of death in women. BC is a complex disorder, and the exploration of several types of BC omic data, highlighting genes, perturbations, signaling and cellular mechanisms, is needed. We collected mutational data from 9,555 BC samples using cBioPortal. We classified 1174 BC genes (mutated ≥ 40 samples) into five tiers (BCtier_I-V) and subjected them to pathway and protein‒protein network analyses using EnrichR and STRING 11, respectively. BCtier_I possesses 12 BC genes with mutational frequencies > 5%, with only 5 genes possessing > 10% frequencies, namely, PIK3CA (35.7%), TP53 (34.3%), GATA3 (11.5%), CDH1 (11.4%) and MUC16 (11%), and the next seven BC genes are KMT2C (8.8%), TTN (8%), MAP3K1 (8%), SYNE1 (7.2%), AHNAK2 (7%), USH2A (5.5%), and RYR2 (5.4%). Our pathway analyses revealed that the five top BC pathways were the PI3K-AKT, TP53, NOTCH, HIPPO, and RAS pathways. We found that BC panels share only seven genes. These findings show that BC arises from genetic disruptions evident in BC signaling and protein networks.

The Conical 9 well dish (C9 well dish) is characterized by a decreasing cross-sectional area towards the base. This design was hypothesized to enhance embryonic development by emulating the in vivo physical environment through density modulation. Comparative analyses revealed no significant difference in nuclear maturation rates between the C9 well dish and the 5-well dish. Reactive oxygen species (ROS) generation was lower in the C9 well dish compared to the 5-well dish; however, this difference was not statistically significant. On the second day of in vitro culture, the cleavage rate in the C9 well dish was 4.66% higher, although not statistically significant, and the rates of blastocyst development were similar across both dishes. No significant differences were observed in the intracellular levels of glutathione (GSH) and ROS, as well as in the total cell number within the blastocysts between the dish types. The expression of mitogen-related factors, TGFα and IGF-1, in the blastocysts was consistent between the dishes. However, PDGFβ expression was significantly lower in the C9 well dish compared to the 35 mm petri dish. Similarly, the expression of the apoptosis factor Bax/Bcl2l2 showed no significant differences between the two dishes. Despite the marked difference in PDGFβ expression, its impact on blastocyst formation appeared negligible. The study also confirmed the feasibility of culturing a small number of oocytes per donor, collected via Ovum Pick-Up (OPU), with reduced volumes of culture medium and mineral oil, thus offering economic advantages. In conclusion, the present study indicates that the C9 well dish is effective for in vitro development of a small quantity of oocytes and embryos, presenting it as a viable alternative to traditional cell culture dishes.

To explore the underlying molecular mechanism of Notch1/cadherin 5 (CDH5) pathway in modulating in cell malignant behaviors of gastric cancer (GC).

We performed bioinformatic analyses to screen the potential target genes of Notch1 from cadherins in GC. Western blot and RT-PCR were conducted to detect CDH5 expression in GC tissues and cells. We utilized chromatin immunoprecipitation (CHIP) assays to assess the interaction of Notch1 with CDH5 gene. The effects of Notch1/CDH5 axis on the proliferation, invasion, migration and vasculogenic mimicry in GC cells were evaluated by EdU, wound healing, transwell, and tubule formation assays.

Significantly increased CDH5 expression was found in GC tissues compared with paracancerous tissues and associated to clinical stage and poor overall survival (OS) in patients with GC. Notch1 positively regulate the expression of CDH5 in GC cells. CHIP assays validated that CDH5 was a direct target of Notch1. In addition, Notch1 upregulation enhanced the proliferation, migration, invasion and vasculogenic mimicry capacity of GC cells, which could be attenuated by CDH5 silencing.

These results indicated Notch1 upregulation enhanced GC malignant behaviors by triggering CDH5, suggesting that targeting Notch1/CDH5 axis could be a potential therapeutic strategy for GC progression.

The establishment and utilization of preclinical animal models constitute a pivotal aspect across all facets of cancer research, indispensably contributing to the comprehension of disease initiation and progression mechanisms, as well as facilitating the development of innovative anti-cancer therapeutic approaches. These models have emerged as crucial bridges between basic and clinical research, offering multifaceted support to clinical investigations. This study initially focuses on the importance and benefits of establishing preclinical animal models, discussing the different types of preclinical animal models and recent advancements in cancer research. It then delves into cancer treatment, studying the characteristics of different stages of tumor development and the development of anti-cancer drugs. By integrating tumor hallmarks and preclinical research, we elaborate on the path of anti-cancer drug development and provide guidance on personalized cancer therapy strategies, including synthetic lethality approaches and novel drugs widely adopted in the field. Ultimately, we summarize a strategic framework for selecting preclinical safety experiments, tailored to experimental modalities and preclinical animal species, and present an outlook on the prospects and challenges associated with preclinical animal models. These models undoubtedly offer new avenues for cancer research, encompassing drug development and personalized anti-cancer protocols. Nevertheless, the road ahead continues to be lengthy and fraught with obstacles. Hence, we encourage researchers to persist in harnessing advanced technologies to refine preclinical animal models, thereby empowering these emerging paradigms to positively impact cancer patient outcomes.

Protein post-translational modification (PTM) is a covalent process that occurs in proteins during or after translation through the addition or removal of one or more functional groups, and has a profound effect on protein function. Glycosylation is one of the most common PTMs, in which polysaccharides are transferred to specific amino acid residues in proteins by glycosyltransferases. A growing body of evidence suggests that glycosylation is essential for the unfolding of various functional activities in organisms, such as playing a key role in the regulation of protein function, cell adhesion and immune escape. Aberrant glycosylation is also closely associated with the development of various diseases. Abnormal glycosylation patterns are closely linked to the emergence of various health conditions, including cancer, inflammation, autoimmune disorders, and several other diseases. However, the underlying composition and structure of the glycosylated residues have not been determined. It is imperative to fully understand the internal structure and differential expression of glycosylation, and to incorporate advanced detection technologies to keep the knowledge advancing. Investigations on the clinical applications of glycosylation focused on sensitive and promising biomarkers, development of more effective small molecule targeted drugs and emerging vaccines. These studies provide a new area for novel therapeutic strategies based on glycosylation.

The transforming growth factor beta (TGF-β) signaling plays a critical role in immune evasion and tumor progression. However, its modulatory influences on prognosis, tumor microenvironment (TME), and therapeutic efficacy remain unknown in colorectal cancer (CRC). We summarized TGF-β-related genes and comprehensively estimated their expression pattern in 2142 CRC samples from 9 datasets. Two distinct cluster patterns were divided and biological characteristics of each pattern were further analyzed. Then, to quantify the TGF-β cluster pattern of individual CRC patient, we generated the TGF-β score (TGFBscore) model based on TGF-β cluster pattern-relevant differentially expressed genes (DEGs). Subsequently, we conducted correlation analysis for TGFBscore and clinical prognosis, consensus molecular subtypes (CMSs), TME characteristics, liver metastasis, drug response, and immunotherapeutic efficacy in CRC. We illustrated transcriptional and genetic alterations of TGF-β-relevant genes, which were closely linked with carcinogenic pathways. We identified two different TGF-β cluster patterns, characterized by a high and a low TGFBscore. The TGFBscore-high group was significantly linked with worse patient survival, epithelial-mesenchymal transition (EMT) activation, liver metastasis tendency, and the infiltration of immunosuppressive cells (regulatory T cells [Tregs], M2 macrophages, cancer-associated fibroblasts [CAFs], and myeloid-derived suppressor cells [MDSCs]), while the TGFBscore-low group was linked with a survival advantage, epithelial phenotype, early CRC staging, and the infiltration of immune-activated cells (B cell, CD4 T cell, natural killer T [NKT] cell, and T helper 1 [Th1] cell). In terms of predicting drug response, TGFBscore negatively correlated (sensitive to TGFBscore-high group) with drugs targeting PI3K/mTOR, JNK and p38, RTK signaling pathways, and positively correlated (sensitive to TGFBscore-low group) with drugs targeting EGFR signaling pathway. Also, TGFBscore could predict the efficacy of different anti-tumor therapies. TGFBscore-low patients might benefit more from anti-PDL1 immunotherapy, adjuvant chemotherapy (ACT), and ERBB targeted therapy, whereas TGFBscore-high patients might benefit more from antiangiogenic targeted therapy. Our study constructed a novel TGF-β scoring model that could predict prognosis, liver metastasis tendency, and TME characteristics for CRC patients. More importantly, this work emphasizes the potential clinical utility of TGFBscore in evaluating the efficacy of chemotherapy, targeted therapy, and immunotherapy, guiding individualized precision treatment in CRC.

Background/Objectives. Novel diagnostic and therapeutic approaches are needed to improve the clinical management of nonfunctioning pituitary neuroendocrine tumors (NF-PitNETs). Here, the expression of two proteins controlling the epithelial-mesenchymal transition (EMT)-an underlying NF-PitNET pathogenic mechanism-were analyzed as prognostic markers: E-cadherin (E-Cad) and KLHL14. Methods. The immunohistochemistry characterization of KLHL14 and E-Cad subcellular expression in surgical specimens of 12 NF-PitNET patients, with low and high invasiveness grades (respectively, Ki67+ < and ≥3%) was carried out. Results. The analysis of healthy vs. NF-PitNET tissues demonstrated an increased protein expression and nuclear translocation of KLHL14. Moreover, both E-Cad and KLHL14 shifted from a cytoplasmic (C) form in a low invasive NF-PitNET to a nuclear (N) localization in a high invasive NF-PitNET. A significant correlation was found between E-Cad/KLHL14 co-localization in the cytoplasm (p = 0.01) and nucleus (p = 0.01) and with NF-PitNET invasiveness grade. Conclusions. Nuclear buildup of both E-Cad and KLHL14 detected in high invasive NF-PitNET patients highlights a novel intracellular mechanism governing the tumor propensity to local invasion (Ki67+ ≥ 3%). The prolonged progression-free survival trend documented in patients with lower KLHL14 expression further supported such a hypothesis even if a larger cohort of NF-PitNET patients have to be analyzed to definitively recognize a key prognostic role for KLHL14.

Numerous studies have investigated the association between CDH1 polymorphisms and gastric cancer (GC) risk. However, the results have been inconsistent and controversial. To further determine whether CDH1 polymorphisms increase the risk of GC, we conducted a meta-analysis by pooling the data.

Relevant case-control studies were collected from PubMed, Embase, Web of Science and Cochrane databases up to January 7, 2024. Subsequently, odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of correlations. A sensitivity analysis was performed to evaluate the robustness and reliability of these included studies.

A total of 25 articles including 44 studies, were included in this meta-analysis, including 26 studies on rs16260, 6 studies on rs3743674, 7 studies on rs5030625, and 5 studies on rs1801552. The pooled results showed that rs16260 was remarkably associated with an increased GC risk of GC among Caucasians. Moreover, the rs5030625 variation dramatically enhanced GC predisposition in the Asian population. However, no evident correlations between CDH1 rs3743674 and rs1801552 polymorphisms and GC risk were observed.

Our findings suggested that CDH1 gene polymorphisms were significantly correlated with GC risk, especially in rs16260 and rs5030625 polymorphisms.

Colorectal cancer is a leading cause of cancer-related mortality worldwide. Traditionally, colorectal cancer has been recognized as a disease caused by genetic mutations. However, recent studies have revealed the significant role of epigenetic alterations in the progression of colorectal cancer. Epithelial-mesenchymal transition, a critical step in cancer cell metastasis, has been found to be closely associated with the tumor microenvironment and immune factors, thereby playing a crucial role in many kinds of biological behaviors of cancers. In this review, we explored the impact of N6-methyladenosine and post-translational modifications (like methylation, acetylation, ubiquitination, SUMOylation, glycosylation, etc.) on the process of epithelial-mesenchymal transition in colorectal cancer and the epigenetic regulation for the transcription factors and pathways correlated to epithelial-mesenchymal transition. Furthermore, we emphasized that the complex regulation of epithelial-mesenchymal transition by epigenetics can provide new strategies for overcoming drug resistance and improving treatment outcomes. This review aims to provide important scientific evidence for the prevention and treatment of colorectal cancer based on epigenetic modifications.

Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection (HBV, HCV), exposure to aflatoxin B1, metabolic syndrome, and obesity (as an independent factor). Directly or indirectly, they induce chromosomal aberrations, mutations, and epigenetic changes in specific genes involved in intracellular signaling pathways, responsible for synthesis of growth factors, cell proliferation, differentiation, survival, the metastasis process (including the epithelial-mesenchymal transition and the expression of adhesion molecules), and angiogenesis. All these disrupted molecular mechanisms contribute to hepatocarcinogenesis. Furthermore, equally important is the interaction between tumor cells and the components of the tumor microenvironment: inflammatory cells and macrophages-predominantly with a pro-tumoral role-hepatic stellate cells, tumor-associated fibroblasts, cancer stem cells, extracellular vesicles, and the extracellular matrix. In this paper, we reviewed the molecular biology of hepatocellular carcinoma and the intricate mechanisms involved in hepatocarcinogenesis, and we highlighted how certain signaling pathways can be pharmacologically influenced at various levels with specific molecules. Additionally, we mentioned several examples of recent clinical trials and briefly described the current treatment protocol according to the NCCN guidelines.

Epithelial-mesenchymal transition (EMT) is a process during which epithelial cells lose epithelial characteristics and gain mesenchymal features. Here, we used several cell models to study migratory activity and redistribution of cell-cell adhesion proteins in cells in different EMT states: EGF-induced EMT of epithelial IAR-20 cells; IAR-6-1 cells with a hybrid epithelial-mesenchymal phenotype; and their more mesenchymal derivatives, IAR-6-1-DNE cells lacking adherens junctions. In migrating cells, the cell-cell adhesion protein α-catenin accumulated at the leading edges along with ArpC2/p34 and α-actinin. Suppression of α-catenin shifted cell morphology from fibroblast-like to discoid and attenuated cell migration. Expression of exogenous α-catenin in MDA-MB-468 cells devoid of α-catenin drastically increased their migratory capabilities. The Y654 phosphorylated form of β-catenin was detected at integrin adhesion complexes (IACs). Co-immunoprecipitation studies indicated that α-catenin and pY654-β-catenin were associated with IAC proteins: vinculin, zyxin, and α-actinin. Taken together, these data suggest that in cells undergoing EMT, catenins not participating in assembly of adherens junctions may affect cell migration.

PW06 [(E)-3-(9-ethyl-9H-carbazol-3-yl)-1-(2,5-dimethoxyphenyl) prop-2-en-1-one], a kind of the carbazole derivative containing chalcone moiety, induced cell apoptosis in human pancreatic carcinoma in vitro. There is no investigation to show that PW06 inhibits cancer cell metastasis in human pancreatic carcinoma in vitro. Herein, PW06 (0.1-0.8 μM) significantly exists in the antimetastatic activities of human pancreatic carcinoma MIA PaCa-2 cells in vitro. Wound healing assay shows PW06 at 0.2 μM suppressed cell mobility by 7.45 and 16.55% at 6 and 24 hours of treatments. PW06 at 0.1 and 0.2 μM reduced cell mobility by 14.72 and 21.8% for 48 hours of treatment. Transwell chamber assay indicated PW06 (0.1-0.2 μM) suppressed the cell migration (decreased 26.67-35.42%) and invasion (decreased 48.51-68.66%). Atomic force microscopy assay shows PW06 (0.2 μM) significantly changed the shape of cell morphology. The gelatin zymography assay indicates PW06 decreased MMP2's and MMP9's activities at 48 hours of treatment. Western blotting assay further confirms PW06 reduced levels of MMP2 and MMP9 and increased protein expressions of EGFR, SOS1, and Ras. PW06 also increased the p-JNK, p-ERK, and p-p38. PW06 increased the expression of PI3K, PTEN, Akt, GSK3α/β, and E-cadherin. Nevertheless, results also show PW06 decreased p-Akt, mTOR, NF-κB, p-GSK3β, β-catenin, Snail, N-cadherin, and vimentin in MIA PaCa-2 cells. The confocal laser microscopy examination shows PW06 increased E-cadherin but decreased vimentin in MIA PaCa-2 cells. Together, our findings strongly suggest that PW06 inhibited the p-Akt/mTOR/NF-κB/MMPs pathways, increased E-cadherin, and decreased N-cadherin/vimentin, suppressing the migration and invasion in MIA PaCa-2 cells in vitro.

To investigate DNA methylation of specific gene promoters in endometrial hyperplasia compared to normal endometrial tissue.

To search for epigenetic events, methylation-specific multiplex ligation-dependent probe amplification was employed to compare the methylation status of 64 tissue samples with atypical endometrial hyperplasia, 60 tissue samples with endometrial hyperplasia without atypia, and 40 control tissue samples with normal endometrium.

Differences in DNA methylation among the groups were found in PTEN, CDH13, and MSH6 promoters (PTEN: atypical hyperplasia 32%, benign hyperplasia 6.8%, normal endometrium 10%; P=0.004; CDH13: atypical hyperplasia, 50%; benign hyperplasia, 43%; normal endometrium 8.1%; P=0.003; MSH6 atypical hyperplasia 84%, benign hyperplasia, 62%; normal endometrium, 52%; P=0.008.) Higher rates of CDH13 promoter methylation were identified in the groups with both forms of endometrial hyperplasia when compared to the control group (atypical hyperplasia, P=0.003, benign hyperplasia, P=0.0002). A higher rate of DNA methylation of the PTEN and MSH6 promoters was observed in samples with atypical endometrial hyperplasia than in samples with benign endometrial hyperplasia (PTEN: P=0.02; MSH6: P=0.01) and samples with normal endometrial tissue (PTEN, P=0.04; MSH6, P=0.006).

DNA methylation of CDH13, PTEN, and MSH6 appear to be involved in the development of endometrial hyperplasia.

Obesity is strongly associated with occurrence, metastasis, and resistance to therapy in breast cancers, which also exhibit high adipose content in the tumor microenvironment. Adipose tissue-derived mesenchymal stromal cells (ASCs) are recruited to breast cancer by many mechanisms, including hypoxia, and contribute to metastatic transition of the cancer. Breast cancers are characterized by regions of hypoxia, which can be temporally unstable owing to a mismatch between oxygen supply and consumption. Using a high-sensitivity nanopatterned stromal invasion assay, we found that ASCs could promote stromal invasion of not only breast cancer cell lines but also MCF10A1, a cell line derived from untransformed breast epithelium. RNA sequencing of MCF10A1 cells conditioned with medium from ASCs revealed upregulation of genes associated with increased cell migration, chemotaxis, and metastasis. Furthermore, we found that fluctuating or oscillating hypoxia could induce senescence in ASCs, which could result in an increased invasive potential in the treated MCF10A1 cells. These findings highlight the complex interplay within the breast cancer microenvironment, hypoxia, and the role of ASCs in transforming even non-cancerous breast epithelium toward an invasive phenotype, providing insights into early metastatic events.

Metazoan development relies on the formation and remodeling of cell-cell contacts. Dynamic reorganization of adhesion receptors and the actomyosin cell cortex in space and time plays a central role in cell-cell contact formation and maturation. Nevertheless, how this process is mechanistically achieved when new contacts are formed remains unclear. Here, by building a biomimetic assay composed of progenitor cells adhering to supported lipid bilayers functionalized with E-cadherin ectodomains, we show that cortical F-actin flows, driven by the depletion of myosin-2 at the cell contact center, mediate the dynamic reorganization of adhesion receptors and cell cortex at the contact. E-cadherin-dependent downregulation of the small GTPase RhoA at the forming contact leads to both a depletion of myosin-2 and a decrease of F-actin at the contact center. At the contact rim, in contrast, myosin-2 becomes enriched by the retraction of bleb-like protrusions, resulting in a cortical tension gradient from the contact rim to its center. This tension gradient, in turn, triggers centrifugal F-actin flows, leading to further accumulation of F-actin at the contact rim and the progressive redistribution of E-cadherin from the contact center to the rim. Eventually, this combination of actomyosin downregulation and flows at the contact determines the characteristic molecular organization, with E-cadherin and F-actin accumulating at the contact rim, where they are needed to mechanically link the contractile cortices of the adhering cells.

The atypical cadherin FAT1 function either as a pro or antitumorigenic in tumors of different tissue origins. Our group previously demonstrated the protumorigenic nature of FAT1 signaling in glioblastoma (GBM). In this study, we investigated how FAT1 influences the expression of clustered oncomiRs (miR-221-3p/miR-222-3p) and their downstream effects in GBM. Through several experiments involving the measurement of specific gene/microRNA expression, gene knockdowns, protein and cellular assays, we have demonstrated a novel oncogenic signaling pathway mediated by FAT1 in glioma. These results have been verified using antimiRs and miR-mimic assays. Initially, in glioma-derived cell lines (U87MG and LN229), we observed FAT1 as a novel up-regulator of the transcription factor NFκB-RelA. RelA then promotes the expression of the clustered-oncomiRs, miR-221-3p/miR-222-3p, which in turn suppresses the expression of the tumor suppressor gene (TSG), PDCD10 (Programmed cell death protein10). The suppression of PDCD10, and other known TSG targets (PTEN/PUMA), by miR-221-3p/miR-222-3p, leads to increased clonogenicity, migration, and invasion of glioma cells. Consistent with our in-vitro findings, we observed a positive expression correlation of FAT1 and miR-221-3p, and an inverse correlation of FAT1 and the miR-targets (PDCD10/PTEN/PUMA), in GBM tissue-samples. These findings were also supported by publicly available GBM databases (The Cancer Genome Atlas [TCGA] and The Repository of Molecular Brain Neoplasia Data [Rembrandt]). Patients with tumors displaying high levels of FAT1 and miR-221-3p expression (50% and 65% respectively) experienced shorter overall survival. Similar results were observed in the TCGA-GBM database. Thus, our findings show a novel FAT1/RelA/miR-221/miR-222 oncogenic-effector pathway that downregulates the TSG, PDCD10, in GBM, which could be targeted therapeutically in a specific manner.

Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. In this disease, E-cadherin-defective cells are detected invading the adjacent stroma since very early stages. Although E-cadherin loss is well established as a triggering event, other determinants of the invasive process persist largely unknown. Herein, we develop an experimental strategy that comprises in vitro extrusion assays using E-cadherin mutants associated to HDGC, as well as mathematical models epitomising epithelial dynamics and its interaction with the extracellular matrix (ECM). In vitro, we verify that E-cadherin dysfunctional cells detach from the epithelial monolayer and extrude basally into the ECM. Through phase-field modelling we demonstrate that, aside from loss of cell-cell adhesion, increased ECM attachment further raises basal extrusion efficiency. Importantly, by combining phase-field and vertex model simulations, we show that the cylindrical structure of gastric glands strongly promotes the cell's invasive ability. Moreover, we validate our findings using a dissipative particle dynamics simulation of epithelial extrusion. Overall, we provide the first evidence that cancer cell invasion is the outcome of defective cell-cell linkages, abnormal interplay with the ECM, and a favourable 3D tissue structure.

The Cadherin gene family holds immense significance in maintaining the integrity and functionality of stomach tissues, playing crucial roles in cell-cell adhesion, cell migration and differentiation. Dysregulation of cadherin expression and function has been closely associated with various gastric diseases, particularly gastric cancer (GC). Understanding the regulation and clinical implications of cadherin genes in GC is essential to improve our knowledge and to identify new potential prognostic markers and therapeutic targets.

In this study, we provide an overview on the role of cadherin family genes in GC using bioinformatics analysis. We analyzed the expression, mutational status, and prognostic value of these genes based on available public datasets. Our methodology involved data mining, differential expression analysis, functional enrichment analysis, and survival analysis to explore the association between cadherin gene expression and clinical outcomes in GC patients. Additionally, we investigated the relationship between cadherin expression and immune cell infiltration to gain insights into the tumor microenvironment's role in GC progression.

Our bioinformatics analysis revealed significant differential expression of 16 cadherin genes in GC samples compared to normal tissues. Approximately up to 52% of the analyzed cancer samples exhibited genomic alterations in these cadherins, indicating their potential relevance in GC development. Functional enrichment analysis demonstrated that these differentially expressed cadherins were closely associated with critical cellular processes, including cell adhesion and immune-modulation. Remarkably, lower expression levels of most cadherin genes were linked to improved prognosis in GC patients, suggesting their potential importance as valuable prognostic biomarkers.

The findings deriving from our comprehensive study provide important insights into the dysregulation of cadherin genes in GC and their impact on gene expression, molecular pathways, and prognosis. The associations with clinical outcomes and immune cell infiltration highlight the potential role of cadherin genes as prognostic biomarkers and therapeutic targets in GC.

Classical cadherins are calcium-dependent cell-cell adhesion proteins that play key roles in the formation and maintenance of tissues. Deficiencies in cadherin adhesion are hallmarks of numerous cancers. In this article, we review recent biophysical studies on the regulation of cadherin structure and adhesion. We begin by reviewing distinct cadherin binding conformations, their biophysical properties, and their response to mechanical stimuli. We then describe biophysical guidelines for engineering Abs that can regulate adhesion by either stabilizing or destabilizing cadherin interactions. Finally, we review molecular mechanisms by which cytoplasmic proteins regulate the conformation of cadherin extracellular regions from the inside out.

(1) Background: Metformin, an anti-diabetic drug, seems to protect against aggressive acquisition in colorectal cancers (CRCs). However, its mechanisms are still really unknown, raising questions about the possibility of its positive impact on non-diabetic patients with CRC. (2) Methods: An in vitro study based on human colon cancer cell lines and an ex vivo study with different colon cancer stages with proteomic and transcriptomic analyses were initiated. (3) Results: Metformin seems to protect from colon cancer invasive acquisition, irrespective of glucose concentration. (4) Conclusions: Metformin could be used as an adjuvant treatment to surgery for both diabetic and non-diabetic patients in order to prevent the acquisition of aggressiveness and, ultimately, recurrences.

Liver cancer is a global health challenge as it is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is often found in liver cells, where it is associated with high morbidity and mortality rates. Recent studies have shown that extracellular vesicles (EVs) secreted by HCC cells play a critical role in HCC progression and metastasis. EVs contain proteins, nucleic acids, lipids, and metabolites as cargos. EVs derived from HCC cells can transfer oncogenic factors to surrounding cells leading to increased tumor growth, cell invasion, and angiogenesis. In this review, we summarize the roles that EVs play and the specific effects of their cargos on HCC progression and metastasis and identify potential therapeutic targets for HCC treatment.

Cellular signaling pathways involved in the maintenance of the equilibrium between cell proliferation and apoptosis have emerged as rational targets that can be exploited in the prevention and treatment of cancer. Epigallocatechin-3-gallate (EGCG) is the most abundant phenolic compound found in green tea. It has been shown to regulate multiple crucial cellular signaling pathways, including those mediated by EGFR, JAK-STAT, MAPKs, NF-κB, PI3K-AKT-mTOR, and others. Deregulation of the abovementioned pathways is involved in the pathophysiology of cancer. It has been demonstrated that EGCG may exert anti-proliferative, anti-inflammatory, and apoptosis-inducing effects or induce epigenetic changes. Furthermore, preclinical and clinical studies suggest that EGCG may be used in the treatment of numerous disorders, including cancer. This review aims to summarize the existing knowledge regarding the biological properties of EGCG, especially in the context of cancer treatment and prophylaxis.

Glycans are an essential part of cells, playing a fundamental role in many pathophysiological processes such as cell differentiation, adhesion, motility, signal transduction, host-pathogen interactions, tumour cell invasion, and metastasis development. These glycans are also able to exert control over the changes in tumour immunogenicity, interfering with tumour-editing events and leading to immune-resistant cancer cells. The incomplete synthesis of O-glycans or the formation of truncated glycans such as the Tn-antigen (Thomsen nouveau; GalNAcα- Ser/Thr), its sialylated version the STn-antigen (sialyl-Tn; Neu5Acα2-6GalNAcα-Ser/Thr) and the elongated T-antigen (Thomsen-Friedenreich; Galβ1-3GalNAcα-Ser/Thr) has been shown to be associated with tumour progression and metastatic state in many human cancers. Prognosis in various human cancers is significantly poor when they dedifferentiate or metastasise. Recent studies in glycobiology have shown truncated O-glycans to be a hallmark of cancer cells, and when expressed, increase the oncogenicity by promoting dedifferentiation, risk of metastasis by impaired adhesion (mediated by selectins and integrins), and resistance to immunological killing by NK cells. Insight into these truncated glycans provides a complimentary and attractive route for cancer antigen discovery. The recent emergence of immunotherapies against cancers is predicted to harness the potential of using such agents against cancer-associated truncated glycans. In this review, we explore the role of truncated O-glycans in cancer progression and metastasis along with some recent studies on the role of O-glycans in endocrine cancers affecting the thyroid and adrenal gland.

Human malignancies arise predominantly in tissues of epithelial origin, where the stepwise transformation from healthy epithelium to premalignant dysplasia to invasive neoplasia involves sequential dysregulation of biological networks that govern essential functions of epithelial homeostasis. Cutaneous squamous cell carcinoma (cSCC) is a prototype epithelial malignancy, often with a high tumour mutational burden. A plethora of risk genes, dominated by UV-induced sun damage, drive disease progression in conjunction with stromal interactions and local immunomodulation, enabling continuous tumour growth. Recent studies have identified subpopulations of SCC cells that specifically interact with the tumour microenvironment. These advances, along with increased knowledge of the impact of germline genetics and somatic mutations on cSCC development, have led to a greater appreciation of the complexity of skin cancer pathogenesis and have enabled progress in neoadjuvant immunotherapy, which has improved pathological complete response rates. Although measures for the prevention and therapeutic management of cSCC are associated with clinical benefit, the prognosis remains poor for advanced disease. Elucidating how the genetic mechanisms that drive cSCC interact with the tumour microenvironment is a current focus in efforts to understand, prevent and treat cSCC.

Invasive lobular carcinoma (ILC) sometimes presents with unique clinical, pathologic, and radiographic features. In this case report, we describe a patient with ILC, whose initial presentation consisted with symptoms secondary to bone-marrow dissemination. In addition, the breast primary was revealed only by magnetic resonance imaging (MRI) followed by real-time virtual sonography (RVS).

A 51-year-old woman presented to our outpatient clinic with dyspnea on exertion. She had severe anemia (hemoglobin, 5.3 g/dL) and thrombocytopenia (platelet count, 31 × 10³/mL). Bone-marrow biopsy was performed to evaluate hematopoietic function. The pathologic diagnosis was bone-marrow carcinomatosis due to metastatic breast cancer. Initial mammography followed by ultrasonography (US) failed to detect the primary tumor. On MRI, a non-mass-enhancement lesion was observed. While second-look US also did not detect the lesion, it was clearly visualized with RVS. We were finally able to biopsy the breast lesion. The pathologic diagnosis was ILC positive for both estrogen receptor and progesterone receptor, with 1 + immunohistochemical staining for human epidermal growth factor receptor 2. This case of ILC was characterized by bone-marrow metastasis. Due to decreased cell adhesion, the risk of bone-marrow metastasis is higher in ILC than in invasive ductal carcinoma, the most prevalent type of breast cancer. Biopsy of the primary lesion, which was initially only detected with MRI, was successfully performed with clear visualization during RVS, which is based on the fusion of MRI and US images.

In this case report and literature review, we describe the unique clinical characteristics of ILC and a strategy for identifying primary lesions that are initially only visualized with MRI.