Advances in cancer biology - metastasis最新文献

Background

Metastatic colorectal carcinoma (CRC) is one of the leading causes of mortality of colorectal CRC. Very few prognostic markers and factors affecting progression are studied between metastatic CRC and early CRC. Adipokines are speculated to be associated with this area of interest. In the current study leptin, leptin receptor (Ob-R), adiponectin, adiponectin R1, and adiponectin R2 expression were measured at gene levels to determine a possible association between adipokines and early/metastatic cancer to ultimately identifying a definitive diagnostic marker.

Materials and methods

Tissue samples were obtained from 62 patients with radical specimens of CRC. Genes expression was determined by Quantitative Reverse-Transcription Polymerase Chain Reaction (qRT-PCR). The association between the clinicopathological parameters and gene expression levels were analyzed by statistical analysis.

Results

Overexpression of leptin mRNA is observed in small tumors (size< 5 cms) (P<0.05).b. Leptin receptor were overexpressed in advanced tumors (1.013 ± 0.152) than early tumors (0.453 ± 0.131). c.Adiponectin expression was higher in early tumors (1.535 ± 0.406) than in advanced tumors (0.48 ± 0.148). d. Distant organ metastasis shows under-expression of adipoR1. e.Overexpression of adipoR2 is seen in small (size<5 cms) (P<0.05) tumors.

Conclusion

LEPR is better indicator of advancement of tumor than Leptin. ADIPOR1 is a better indicator in advanced CRC than ADIPOR2 and ADIPOQ.

Triple-negative breast cancer (TNBC), which accounts for approximately 15–20% of all breast cancers, defined as lack of expression of estrogen receptor, progesterone receptor and Her-2 neu receptors. TNBC has two subtypes basal like and non-basal like, the former characterised by aggressive biology with limited therapeutic options. This study explored molecular markers involved in pathogenesis of TNBC and investigated novel potential diagnostic and therapeutic targets by CGH array and transcriptome array. aCGH analysis in TNBC demonstrated genes amplified were 3888, number of pathway hits was 1554 and major pathways amplified was found to be WNT signalling pathway and Cadherin signalling pathway. Among all metastatic sites and remission, activation of WNT signalling pathway is commonly observed. TNBC exhibited 1486 copy number variations (CNVR) which is approximately 250 times higher than controls. More than 20 CNVR was observed in all chromosomes and more than 80 CNVR was observed in Chr 1 to Chr 4, Chr 7, Chr 11 and Chr X. Common CNVR associated with amplified regions in Chr 22, Chr 14, Chr 8 and Chr 2 was observed in TNBC and CNVR associated with Chr 22q11.22–23, Chr 6p21.32–33, Chr11q12.2, Chr14q32.22–23, Chr 8p11.22–23, was observed in metastatic disease. In transcriptome array analysis a total of 11,359 differentially expressed genes with fold change 2.0 were in observed in TNBC comprise of 7639 upregulated genes and 3720 downregulated genes. Further, with fold change 10, 1526 upregulated genes and 839 down regulated genes were identified. Panther pathway analysis identified the main pathways of upregulated genes were Wnt signalling pathway, Integrin signalling pathway and Cadherin signalling pathway. The main pathways of down regulated genes were Inflammation mediated by chemokine and cytokine signalling pathways. PPI network shows that COL12A1, COL6A3, FN1, MMP3, WNT5A were key upregulated genes and ITGB7, PTPRC, ITGA4, LCK and CD247 were key down regulated genes. Cytoscape analysis followed by multiple list comparator tool identified top 5 significant hub genes were FN1, MMP3, COLL11A1, COL12A1 and COL3A1. The significant pathway genes obtained by CGH array and transcriptome array when compared, exhibited 5 common genes COL4A1, FN1, COL6A3, COL5A2 and PCDH7. These genes were not overexpressed in Controls and therefore involved in pathogenesis of TNBC. Expressions of these genes were validated by studying protein expression by immunohistochemistry. FN1 and COL6A3 protein over expression predicted worse DFS in TNBC and can be considered as therapeutic targets at diagnosis to reduce the disease metastases. These findings provide new insights into the pathogenesis of TNBC and guide for selection of targets related to diagnosis, prognosis and prediction of treatment in TNBC.

Background

Manifestation of epithelial-to-mesenchymal transition (EMT) program in tumor cells is associated with the occurrence of multiple intermediate phenotypic states namely epithelial (E), mesenchymal (M) and hybrid E/M across the epithelial-mesenchymal spectrum and these states exhibit different invasive properties. Understanding the cellular and molecular mechanisms defining the E/M hybrid state of the cells during bladder tumor development may significantly aid in the identification of novel diagnostic and prognostic markers.

Materials and methods

The present study is taken up to identify hybrid E/M score based on the immunohistochemical localization and surface expressions of epithelial proteins [E-cadherin and Beta-catenin] and mesenchymal marker proteins [N-cadherin and Vimentin] on formalin fixed paraffin embedded tumor sections of the prospective series of 99 non-muscle invasive bladder cancer (NMIBC) and 87 muscle invasive bladder cancer (MIBC) patients. E/M score was then statistically examined with patients’ demographics to assess its potential in the diagnosis and prognosis of UCB patients.

Results

Among the E (E-cadherin^high, β-catenin^high), hybrid E/M (E-cadherin^low, β-catenin^low, N- cadherin^high and Vimentin^high) and M (N-cadherin^high and Vimentin^high) phenotypes, E/M phenotype was observed to be more prevalent in MIBC compared to E phenotype in NMIBC subtype. The current study reports the statistical association of tumor stage and tumor grade with the hybrid E/M state of urothelial tumor cells across both the subtypes. Hybrid E/M phenotype in MIBC patients was significantly shown to lower the overall survival time period compared to NMIBC patients. This supports the contribution of hybrid E/M state of tumor cells to the.

aggressiveness of the disease.

Conclusions

Characterizing the hybrid E/M state instead of all or none phenotype becomes an imperative to understand the dynamics of EMT and MET in the tumor pathophysiology of NMIBC and MIBC subtypes, and could contribute to better patient stratification and therapeutic strategies.

The breast cancer scenario now requires new solutions for diagnosis and follow-up. The neutrophil-to-lymphocyte ratio (NLR) has been studied as a possible biomarker for predicting prognosis in solid tumors. Due to the ease of obtaining these values from a blood count, NLR could be useful in clinical practice. Therefore, the aim of this study was to analyze the relation between NLR and pathologic complete response (PCR) in breast cancer patients undergoing neoadjuvant treatment. We performed a cross-sectional retrospective study, including ductal breast cancer patients who underwent neoadjuvant chemotherapy and surgery between 2017 and 2019 at the reference hospital institution (n = 1230). Our data were obtained from medical records and laboratory results, so the study was approved by the research ethics committee of the data-providing hospital. Inclusion and exclusion criteria resulted in a final sample of 114 patients. The area under the curve (ROC) showed no statistically significant area (AUC = 0.546) with a CI95% = 0.417–0.676. No relation between NLR and PCR was observed (p = 0.631), indicating that NLR is not a good biomarker for PCR in this population. Regarding the pattern of NLR for different molecular subtypes, no statistical relation was found (p = 0.929). Thus, our study supports the literature that suggests there is no relationship between NLR and PCR.

Endometrial cancer (EC) is the most common gynecological cancer, with rising mortality rates. Targeting non-coding RNAs (ncRNAs) to diagnose and cure endometrial cancer has shown both promise and limitations in recent studies. In comparison to normal tissues, LncRNAs are differentially expressed in ECs, and their dysregulation has been associated to tumor grade, lymph node metastasis, depth of myometrial invasion, FIGO stage and patient survival. Oncogenic lncRNAs (CCAT2, BANCR, NEAT1, MALAT1, LINP1, SRA and LSINCT5) and tumor suppressor lncRNAs (GAS5, MEG3, OIP5-AS1, FER1L4, and LINC00672) have been identified as downstream effectors or upstream modulators of important signaling pathways driving EC metastasis, including the PTEN/PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, WNT/β-catenin, and p53 signaling pathways. Short non-coding RNAs called miRNAs also effect expression of genes at the post-transcriptional level. Multiple studies have shown that miRNAs play a critical role in the regulation of EC. We present a review of ncRNA expression patterns, prognostic significance, biological function and roles in the tumor microenvironment in EC cells in EC associated pathways. We also discuss how ncRNAs can be used as biomarkers for EC diagnosis and as potential therapeutic targets for different EC subtypes based on their ncRNA signature.

Cancer immune evasion is one of the principal mechanisms leading to the progression and metastatization of the disease. Despite the migration and infiltration at the tumor site of immune cells, multiple factors can influence the composition of hot or “immune-sensitive” tumors and cold or “immune-resistant” tumors. Among the multiple mechanisms responsible for the make-up of the tumor microenvironment are the expression levels of major histocompatibility molecules (MHC) and of the antigen processing machinery, the metabolic network, hypoxia, and the secretion of pro-inflammatory molecules (e.g., cytokines, chemokines, and growth factors). Moreover, the different triggered pathways can mediate the reprogramming of activated, memory, effector, or regulatory/tolerogenic subtypes of immune cells (T, NK, dendritic cells, and macrophages). Recent studies have focused on the role of cancer metabolism in evading immune surveillance through the action of the active tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO). Immune suppression and evasion mechanisms in cancer cells are now being extensively studied with a special focus on developing immunotherapy strategies, such as the targeting of immune checkpoints (programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1), Cytotoxic T-lymphocyte antigen-4 (CTLA-4)), adoptive cell therapy or cancer vaccines. In this review, an overview of the underlying mechanisms of cancer immune evasion and the efficacy of the therapeutic targets and agents to overcome the immune escape are described.

Introduction

Approximately 30% of patients with hormone receptor-positive breast cancer show resistance to tamoxifen, which may result in local or distant recurrence. Based on previous evidence, it can be inferred that tamoxifen sensitivity is influenced by an oxidative genetic imbalance.

Objective

To evaluate the association between the genotypes of SOD2 single-nucleotide polymorphisms and the risk of recurrence in patients with luminal breast cancer treated with adjuvant tamoxifen.

Methods

This is a retrospective cohort study. Biopsy samples from tumors were used for Val16Ala-SNP real-time PCR genotyping. Other potential markers of apoptosis and proliferation were analyzed by immunohistochemistry. Survival was defined as follow-up of a minimum of 72 months and compared using Cox regression multivariate analysis adjusted for grade, clinical staging, and Bcl-2 and Ki67 markers.

Results

36% patients relapsed, 35% presented with histological grade 3, and 29% had clinical stage III. The frequencies of SOD2 were 35% Ala/Ala, 35% Val/Val, and 30% Ala/Val. Val-allele women tended to be more at risk for recurrence than others (RR = 2.14 (95% CI 0.84–5.47). Patients with the Val allele had a 15% reduction in relapse-free survival, whereas with Ala/Ala, this reduction was only 8%. The expression of Caspase-3 was low in patients with relapse (p = 0.008).

Conclusion

This study emphasizes the importance of oxidative response in cancer cells during tamoxifen treatment. The presence of the Val allele showed a strong trend, which could be considered as a hypothesis generator.

Computational methods have driven the rapid identification of tobacco microRNAs (miRNAs) from tissue-specific sequence data and witnessed success in associating miRNAs in response to stress, pollutants, viral infection and resistance, and cigarette smoking. Although tobacco exerted medicinal properties through phytochemicals, the role of its miRNAs in regulating tobacco and human genes and related functional implications is not elucidated thoroughly. In this present study, we have identified new and homologous miRNAs using a rigorous workflow of miRNA derivation and target prediction upon a comprehensive collection of tobacco expressed sequence tags and charted its putative roles in gene regulation via inter and intraspecies relationships. Current, computational approach have identified a total of 38 mature miRNAs comprising 31 tobacco-specific miRNAs from plant homologous families, and 7 new miRNA candidates. These seven new miRNAs were studied for tobacco target gene prediction in which most of them encode innate immunity, defense mechanism, plant development, F-box/Leucine rich-repeat protein and other protein kinases. Two out of these seven miRNAs have passed the updated emphasized criteria namely nta-miR403 and nta-miR8036. Interestingly, the workflow succeeded in establishing an intraspecies relationship by distinguishing the molecular targets already known in tobacco and homologous plants. Interspecies relationship between 38 tobacco miRNAs upon human transcriptome data revealed the most significant target CCDC88c (DAPLE) with perfect seed pairing of miR-156, regulating non-canonical WNT signaling pathways in cancer progression and metastasis. These findings may add to existing knowledge of impacting canonical WNT/β-catenin pathways. These decisive findings hold a strong clue for promoting tobacco miRNAs research and outlined the prediction of conserved miRNAs and their functions in inter and intraspecies relationships.

S100 proteins have emerged as key regulators in the mammary gland and have been implicated in breast cancer development and metastasis. This review provides a comprehensive overview of the roles of S100 proteins in mammary gland regulation and their impact on breast cancer progression. The mammary gland, a complex organ involved in lactation and tissue homeostasis, undergoes dynamic changes during different physiological stages. S100 proteins play crucial roles in mammary gland development, differentiation, and function, participating in cellular processes such as proliferation, migration, and apoptosis. However, dysregulation of S100 proteins can contribute to breast cancer initiation and metastasis. These proteins are involved in angiogenesis, invasion, migration, and epithelial-mesenchymal transition, promoting aggressive behavior in breast cancer cells. Understanding the intricate mechanisms by which S100 proteins exert their effects in the mammary gland and breast cancer is crucial for the development of targeted therapies and identification of diagnostic and prognostic biomarkers. Further research in this field will provide valuable insights and potential advancements in breast cancer management. This review highlights the significance of unraveling the role of S100 proteins in mammary gland regulation and their impact on breast cancer metastasis.