Advances in cancer biology - metastasis最新文献

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.

Cancer is the most challenging global health issue despite advancement in new drug development and biological understanding of oncology. Metastasis is the hallmark of cancer development resulting in huge death and it remained poorly understood. Various research articles published to control cancer and metastasis using lipidic nanocarriers so far. However, safety and high patient compliance are the prime concern. Medication is always of major concern for a clinician before prescribing any dosage form or drug. The high toxicity profile of anticancer drugs led to increased financial burden of treatment, mortality and complex consequences. Therefore, conventional dosage forms failed to culminate various issues related to therapeutic efficacy and drug related toxicity. Then, many researchers tried the novel drug delivery systems for effective and safe targeting of anticancer drugs. Exosomes, vesicular systems, and erythrocytes have been explored to treat cancer. It was imperative to compile major findings from these researches carried out so far. In the review, we highlighted application of exosomes, liposomes, and erythrocytes to control metastasis and cancer. Moreover, we have addressed various critical attributes of liposomes while formulation design for improved therapeutic efficacy and mechanistic perspective for drug targeting using the described vesicular carriers. Finally, we compiled major findings of clinical data published in clinical research plate-form. This review highlighted the major findings associated with nanovesicles based tumor targeting in which anticancer drugs are encapsulated in suitable vesicular systems and reach to site specific delivery of drugs.

Environmental chemicals are a persistent and pervasive part of everyday life. A subset of environmental chemicals are xenoestrogens, compounds that bind to the estrogen receptor (ER) and drive estrogen-related processes. One such chemical, benzophenone-3 (BP3), is a common chemical in sunscreen. It is a potent UV protectant but also is quickly absorbed through the skin. While it has been approved by the FDA, there is a renewed interest in the safety of BP3, particularly in relation to breast cancer. The focus of this study was to examine the impact that BP3 has on triple negative breast cancer (TNBC) through alterations to cells in the immune microenvironment. In this study, we exposed female mice to one of two doses of BP3 before injecting them with a TNBC cell line. Several immune endpoints were examined both in the primary tissues and from in vitro studies of T cell behavior. Our studies revealed that in the lung tumor microenvironment, exposure to BP3 not only increased the number of metastases, but also the total area of tumor coverage. We also found that BP3 caused alterations in immune populations in a tissue-dependent manner, particularly in T cells. Taken together, our data suggest that while BP3 may not directly affect the proliferation of TNBC, growth and metastasis of TNBC-derived tumors can be altered by BP3 exposures via the alterations in the immune populations of the tumor microenvironment.

Cancer is still a global challenge for healthcare professional and scientists due to complicated pathological pathways, inefficient early diagnosis, and limited safe delivery system at economic treatment cost. Despite these, other factors (life style, environmental problem, socio-economic issues, patient related complications, expensive therapy, and genetic history of oncogene) played significant role to spread and complicate treatment. However, various novel carriers have been explored and reported for effective and efficient drug delivery using polymers and lipid. Among them, vesicular systems are considered as the most biocompatible and safe for delivery of hydrophilic and lipophilic drug candidates. Therefore, the present review addressed various forms of nanovesicular systems with their benefits, progressive development stages, and mechanistic insights for drug targeting (active and passive), specific cancer wise nanovesicles, exosomes, and commercial products with potential clinical applications. The review primarily highlighted the major findings of nanovesicles employed to control solid tumor when a chemotherapeutic drug was used in specific vesicles based nanocarriers. Notably, miscellaneous exosomes, blood cells-based drug delivery (neutrophils and leukocytes), pH-responsive nanovesicles improved drug therapy by targeting tumor tissues and high drug access in the site of action. Finally, co-administration of chemotherapeutic drugs (combination therapy) further revealed convincing therapeutic outcomes as compared to standalone.

Background

Tumor-associated macrophages (TAMs) express cytokines and chemokines that can suppress antitumor immunity and promote tumor progression. The immunomodulatory and antitumor function of β-defensin 2 is still unclear, despite the evidence of infection response. We previously reported that β-defensin 2 modulates immunomodulatory and their antitumor function of macrophages in breast cancer. We investigate the association between β-defensin 2 and TAMs and determined the role in tumor-promoting attributes of TAMs reversal of phenotype in tumor regression.

Methods

Swiss albino mice and C127i breast cancer cell line was used in this study. C127i conditioned media was prepared and generated macrophage-derived TAMs to study antitumor function. Flow cytometry was performed for phenotype identification of macrophages and TAMs. MTT assay was performed to estimate cytotoxicity and dose optimization of β-defensin 2. Oxidative stress was analyzed by H₂O₂ and NO estimation, and qPCR was performed for iNOS, cytokines and chemokines expression.

Results

PEC harvested macrophages were characterized by flow-cytometry using F4/80, CD11c antibodies with 98% pure population of macrophages and cultured in C127i conditioned media for 7 days. TAMs markers were estimated, and it was found that 98% expression of F4/80, CD-206, and CD-115 expression compared to macrophages. Purified 100 ng/ml of β-defensin 2 was used to stimulate the TAMs population was viable, which was confirmed by cell viability assay. ROS levels decreased in TAMs treated with β-defensin 2 compared to control group. Interleukins (ILs)-6, 10, and 3, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β and chemokine ligand (CXCL)-1, 5 and 15, chemokine ligand (CCL)-24 and 5 decreased drastically compared to control.

Conclusion

This is the first report of β-defensin 2 on TAMs to elucidate the immunomodulatory and anti-tumor function. It was found that the cytokines, chemokines, and reactive oxygen species (ROS) expression pliably changed which facilitates tumor regression. β-defensin 2 must be targets as adjuvant for future cancer immunotherapeutic agent.

Mesothelin (MSLN), a tumor-associated antigen, is upregulated in various malignancies, including gastric cancer (GC). In addition, MSLN is found in the blood-stream of affected individuals, where it is referred to as soluble MSLN-related protein (SMRP). This study aims to investigate the role of MSLN in GC and evaluate its potential as a plasma biomarker for diagnosis and prognosis. Toward that end, GC tissues were obtained, upon signed consent, from affected individuals undergoing surgery or endoscopy (n = 82). Quantitative RT-PCR and immunohistochemistry were performed to determine MSLN expression. Simultaneously, The Cancer Genome Atlas (TCGA) database was mined to evaluate global status of MSLN gene expression in gastric cancer. Next, in vitro cell-culture studies were conducted to evaluate MSLN-driven proliferation properties. Using ELISA, sera from 55 GC-affected individuals were tested for MSLN level. Additionally, plasma mesothelin levels were compared in 6 cases before and after surgery. Upregulated MSLN expression was found in GC tissues, compared to adjacent normal tissues (p < 0.001). Cell culture studies with a MSLN-overexpressing stable GC line showed increased cell proliferation and invasion with ectopic MSLN. Additionally, gene-set-enrichment-analysis (GSEA) revealed an association of MSLN with the genes involved in the epithelial-mesenchymal transition and G2/M checkpoint. GC-affected cases showed higher serum MSLN levels, compared to healthy controls, with rapid decrease post-surgery. We found that MSLN upregulation correlates with poor clinical outcome and promotes growth advantage to GC cells in vitro. With further experimental evidences, we propose that MSLN could potentially be used as a plasma biomarker for diagnosis of GC.

The potential role for microRNA (miRNA) in the metastatic process that occurs in head and neck squamous cell carcinoma (HNSCC) was examined. miRNA was extracted from surgically excised tumor samples from 41 HNSCC cancer patients diagnosed with distant metastasis (DM) and from 53 patients who displayed no evidence of disease (NED) for a minimum of two years a minimum of two years after treatment with post-operative radiotherapy (PORT). A comparative two-way ANOVA of miRNA expression between DM and NED specimens identified 28 differentially expressed miRNAs with a false discovery rate (FDR) < 0.2 and fold change > 1.5. Two miRNA, miR-551a and miR-551b-3p, which share the same seed sequence, were associated with the DM group and with poor survival. Cell proliferation, migration, and invasion assays using the HN5 and UMSCC-17B HNSCC cell lines were performed after transfecting mimics or inhibitors of these miRNA uncovered an oncogenic role for miR-551a and miR-551b-3p. Furthermore, it was determined that miR-551a and miR-551b-3p directly target GLIPR2 mRNA, a negative regulator of autophagy. Overexpression of GLIPR2 reduced proliferation, migration and invasion of HNSCC cells. In addition, overexpression of miR-551a and miR-551b-3p increased radioresistance while GLIPR2 overexpression increased the radiosensitivity of HNSCC cell lines. These results propose that the miR-551a, miR-551b-3p and GLIPR2 axis plays an important role in tumor growth, invasion and metastasis, at least in part by modulating autophagy and that the proliferative and pro-survival roles of miR-551a and miR-551b-3p may represent potential therapeutic targets by inhibiting autophagy through the regulation of GLIPR2 expression in HNSCC.

Breast Cancer arises to be the most diagnosed cancer type in recent decades. It ranks to be the most vulnerable among women in terms of incidence and mortality. In 2020, 2.3 million women were diagnosed with breast cancer, and 6.85 lacs of death were reported globally. Here, we will focus mainly on TNBC, the most complicated breast cancer subtype. Therefore, novel treatment modalities are urgently required. Treatments like chemotherapy and radiotherapy limit the efficacy of therapeutic outcomes. Thus, new specific ideas are coming up to find a way out. For triple-negative breast cancer (TNBC), which is currently the most complex and challenging breast cancer subtype to treat, chemotherapy is still the standard of care. There has been a lot of study into novel treatments for people with TNBC because of its poor prognosis and the high chance of clinical recurrence. Chimeric antigen receptor (CAR) T cell-based immunotherapy directs the patient's immune system to recognize and eradicate tumor cells that express tumor-associated antigens (TAAs). It opens up a new area of research. Chimeric Antigen Receptor (CAR-T) cell therapy is an immunotherapy type derived from adoptive T cell relocation. CAR-T cells are well equipped with specific antibodies to identify antigens in self-tumor cells, thus bringing out cytotoxic outcomes. CARs are the modified receptors with improved specificity and responsiveness to intensify the recognition of cancer cells. The therapeutic effects of CAR-T cell treatment, including breast cancer, have not lived up to expectations in solid tumors despite recent triumphs in treating hematologic malignancies. In this review, we will discuss some recent developments in the field of breast cancer-specific immunotherapy using CAR-T.