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Simple Summary: Small cell lung cancer (SCLC) is a deadly cancer that is treated by chemo- and radiotherapy, which work by damaging DNA. However, most SCLC patients will develop resistance to these treatments, resulting in a poor outlook with few effective treatment options available. This review summarizes our understanding of the causes of treatment resistance and the treatments which have been studied to overcome resistance. While there is still much to be understood, new methods being developed may improve our ability to study this disease and find effective treatments. Background: Small cell lung cancer (SCLC) is a lethal form of lung cancer with few treatment options and a high rate of relapse. While SCLC is initially sensitive to first-line DNA-damaging chemo- and radiotherapy, relapse disease is almost universally therapy-resistant. As a result, there has been interest in understanding the mechanisms of therapeutic resistance in this disease. Conclusions: Progress has been made in elucidating these mechanisms, particularly as they relate to the DNA damage response and SCLC differentiation and transformation, leading to many clinical trials investigating new therapies and combinations. Yet there remain many gaps in our understanding, such as the effect of epigenetics or the tumor microenvironment on treatment response, and no single mechanism has been found to be ubiquitous, suggesting a significant heterogeneity in the mechanisms of acquired resistance. Nevertheless, the advancement of techniques in the laboratory and the clinic will improve our ability to study this disease, especially in patient populations, and identify methods to surmount therapeutic resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Histopathological and molecular factors could play a role in determining LNM in colon cancer. Extended lymphadenectomies in right-sided patients have been associated with complications. We demonstrated that histopathological and molecular analysis can be useful in predicting LNM and therefore identify high risk patients which could potentially benefit from D3 lymphadenectomy/CME. Background: Lymphadenectomy plays a central role in the treatment of localized colon cancer. While in left colon cancer the D3 lymphadenectomy/CME is considered the standard of care, lymphatic stations to be removed in right colon cancer are still a matter of discussion. The individuation of LNM risk factors could help in choosing the lymphadenectomy in right-sided tumors. This study aims to analyze the correlation of histopathological and molecular characteristics with lymph node metastasis, both in right- and left-sided colon cancer, and their impact on survival; Methods: We conducted a single-center observational retrospective study. The following data were collected and analyzed for each patient: demographics, histopathological and molecular data, and intraoperative and perioperative data. Statistical analyses were performed, including descriptive statistics, multivariate logistic regression and survival analysis; Results: An association between tumor size (pT, p < 0.001), grading (p = 0.013), budding (p < 0.001), LVI (79,4% p < 0.001) and LNM was observed. A multivariate analysis identified pT4 (OR 5.45, p < 0.001) and LVI+ (OR 10.7, p < 0.001) as significant predictors of LNM. Right-sided patients presented a worse OS when associated with LNM, while no significant difference was observed in N0 patients; Conclusions: histological and molecular analysis can help identify high risk patients, which could benefit from extended lymphadenectomies. These patients could be ideal candidates for the D3 lymphadenectomy/CME. [ABSTRACT FROM AUTHOR]

Bladder cancer (BCa) is the fourth most common cancer in men and one of the most common urinary tract cancers, especially in developed countries. The aim of this paper is to comprehensively analyze the biology of bladder cancer, including its epidemiology, etiology, histological types, risk factors, clinical symptoms, and diagnostic methods. The paper presents the dominant histological types of bladder cancer, such as transitional cell carcinoma (TCC), which accounts for 90–95% of cases, squamous cell carcinoma (SCC), and adenocarcinoma, which is much rarer. Risk factors, such as smoking, occupational exposure to chemicals, schistosomiasis, and genetic factors, which significantly affect the pathogenesis of bladder cancer, are also discussed. The paper focuses on modern diagnostic methods, including blue light cystoscopy (BLC) and computed tomography urography (CTU), which show increased sensitivity and specificity in detecting early neoplastic changes. The importance of TNM classification and the role of neoadjuvant chemotherapy in improving patient prognosis are also discussed. Based on a review of the scientific literature, the paper emphasizes the need for early diagnosis and an individualized therapeutic approach, which may contribute to improving the survival and quality of life of patients with bladder cancer. The potential for prevention, including quitting smoking and limiting exposure to harmful chemicals, has also been demonstrated to significantly reduce the risk of disease. Patient education and monitoring high-risk groups are key to reducing the incidence of bladder cancer. [ABSTRACT FROM AUTHOR]

This article describes how the transcriptional alterations of the innate immune system divide dysplasias into aggressive forms that, despite the treatment, relapse quickly and more easily, and others where the progression is slow and more treatable. It elaborates on how the immune system can change the extracellular matrix, favoring neoplastic progression, and how infections can enhance disease progression by increasing epithelial damage due to the loss of surface immunoglobulin and amplifying the inflammatory response. We investigated whether these dysregulated genes were linked to disease progression, delay, or recovery. These transcriptional alterations were observed using the RNA-based next-generation sequencing (NGS) panel Oncomine Immune Response Research Assay (OIRRA) to measure the expression of genes associated with lymphocyte regulation, cytokine signaling, lymphocyte markers, and checkpoint pathways. During the analysis, it became apparent that certain alterations divide dysplasia into two categories: progressive or not. In the future, these biological alterations are the first step to provide new treatment modalities with different classes of drugs currently in use in a systemic or local approach, including classical chemotherapy drugs such as cisplatin and fluorouracile, older drugs like fenretinide, and new checkpoint inhibitor drugs such as nivolumab and pembrolizumab, as well as newer options like T cell therapy (CAR-T). Following these observed alterations, it is possible to differentiate which dysplasias progress or not or relapse quickly. This information could, in the future, be the basis for determining a close follow-up, minimizing surgical interventions, planning a correct and personalized treatment protocol for each patient and, after specific clinical trials, tailoring new drug treatments. [ABSTRACT FROM AUTHOR]

5-fluorouracil (5-FU), a chemotherapeutic agent against oral squamous cell carcinoma (OSCC), is limited by poor pharmacokinetics and toxicity. The pH-sensitive zeolite imidazolate framework-8 (ZIF-8) may increase the selectivity and length of 5-FU released into the acidic tumor microenvironment. This study examined the in vitro 5-FU absorption and release profiles of ZIF-8, and then progressed to cytotoxicity assays using the OSCC primary cell line SCC7. The 5-FU loading capacity of ZIF-8 was calculated with UV-vis spectroscopy (λ = 260 nm). 5-FU release was quantified by submerging 5-FU@ZIF-8 in pH 7.4 and 5.5 acetate buffer over 48 h. For the cytotoxicity assays, 5-FU, ZIF-8, and 5-FU@ZIF-8 were added to SCC7 cultures at 25, 50, and 100 μg/mL. Cell viability was assessed through toluidine blue staining and further quantified through transcriptomic RNA sequencing. ZIF-8 stabilized at a maximum absorption of 2.71 ± 0.22 mg 5-FU, and released 0.66 mg more 5-FU at pH 5.5 than 7.4 for at least 72 h. The cytotoxicity assays showed that 5-FU@ZIF-8 had a synergistic inhibitory effect at 50 μg/mL. The RNA sequencing analysis further revealed the molecular targets of 5-FU@ZIF-8 in SCC7. 5-FU@ZIF-8 may release 5-FU based on the pH of the surrounding microenvironments and synergistically inhibit OSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Spatial transcriptomics is a technique of measuring gene expression with spatial resolution on a tissue slide, which is especially useful in cancer research. This scoping study reviews 41 articles published by the end of 2023 to examine current trends for employed methods, applications, and data analysis approaches for spatial transcriptomics, identifying challenges and practical uses of this technique in studying cancer. The research shows that cancer is a major focus in spatial transcriptomics studies, with certain tools and methods being particularly popular among scientists. However, many studies do not fully explain their data processing methods, making it hard to reproduce their results. Emphasis on transparent sharing of analysis scripts and tailored single-cell analysis methods for ST is recommended to enhance study reproducibility and reliability in the domain. This work may stand as a spatial transcriptomics developmental snapshot and reference to contemporary neoplasm biology research conducted through this technique. Spatial transcriptomics (ST) examines gene expression within its spatial context on tissue, linking morphology and function. Advances in ST resolution and throughput have led to an increase in scientific interest, notably in cancer research. This scoping study reviews the challenges and practical applications of ST, summarizing current methods, trends, and data analysis techniques for ST in neoplasm research. We analyzed 41 articles published by the end of 2023 alongside public data repositories. The findings indicate cancer biology is an important focus of ST research, with a rising number of studies each year. Visium (10x Genomics, Pleasanton, CA, USA) is the leading ST platform, and SCTransform from Seurat R library is the preferred method for data normalization and integration. Many studies incorporate additional data types like single-cell sequencing and immunohistochemistry. Common ST applications include discovering the composition and function of tumor tissues in the context of their heterogeneity, characterizing the tumor microenvironment, or identifying interactions between cells, including spatial patterns of expression and co-occurrence. However, nearly half of the studies lacked comprehensive data processing protocols, hindering their reproducibility. By recommending greater transparency in sharing analysis methods and adapting single-cell analysis techniques with caution, this review aims to improve the reproducibility and reliability of future studies in cancer research. [ABSTRACT FROM AUTHOR]

Cytosine methylation contributes to the regulation of gene expression and normal hematopoiesis in mammals. It is catalyzed by the family of DNA methyltransferases that include DNMT1, DNMT3A, and DNMT3B. Peripheral T–cell lymphomas (PTCLs) represent aggressive mature T–cell malignancies exhibiting a broad spectrum of clinical features with poor prognosis and inadequately understood molecular pathobiology. To better understand the molecular landscape and identify candidate genes involved in disease maintenance, we profiled DNA methylation and gene expression of PTCLs. We found that the methylation patterns in PTCLs are deregulated and heterogeneous but share 767 hypo- and 567 hypermethylated differentially methylated regions (DMRs) along with 231 genes up- and 91 genes downregulated in all samples, suggesting a potential association with tumor development. We further identified 39 hypomethylated promoters associated with increased gene expression in the majority of PTCLs. This putative oncogenic signature included the TRIP13 (thyroid hormone receptor interactor 13) gene whose genetic and pharmacologic inactivation inhibited the proliferation of T–cell lines by inducing G2-M arrest and apoptosis. Our data thus show that human PTCLs have a significant number of recurrent methylation alterations that may affect the expression of genes critical for proliferation whose targeting might be beneficial in anti-lymphoma treatments. [ABSTRACT FROM AUTHOR]

Immune evasion is a key phenomenon in understanding tumor recurrence, metastasis, and other critical steps in tumor progression. The tumor microenvironment (TME) is in constant flux due to the tumor's ability to release signals that affect it, while immune cells within it can impact cancer cell behavior. Cancer cells undergo several changes, which can change the enrichment of different immune cells and modulate the activity of existing immune cells in the tumor microenvironment. Cancer cells can evade immune surveillance by downregulating antigen presentation or expressing immune checkpoint molecules. High levels of tumor-infiltrating lymphocytes (TILs) correlate with better outcomes, and robust immune responses can control tumor growth. On the contrary, increased enrichment of Tregs, myeloid-derived suppressor cells, and M2-like anti-inflammatory macrophages can hinder effective immune surveillance and predict poor prognosis. Overall, understanding these immune evasion mechanisms guides therapeutic strategies. Researchers aim to modulate the TME to enhance immune surveillance and improve patient outcomes. In this review article, we strive to summarize the composition of the tumor immune microenvironment, factors affecting the tumor immune microenvironment (TIME), and different therapeutic modalities targeting the immune cells. This review is a first-hand reference to understand the basics of immune surveillance and immune evasion. [ABSTRACT FROM AUTHOR]

Simple Summary: With advanced bioinformatic and sequencing technologies, many non-coding RNAs have been found to harbor non-canonical open reading frames (ncORFs). Some studies suggest that many ncORF-encoded microproteins or micropeptides possess important roles in cancer biology, yet the functional roles of these ncORF-encoded peptides are mostly unknown. The purpose of this review is to provide a comprehensive overview of existing knowledge on ncORF-encoded microproteins in cancer biology and highlight their roles as potential prognostic and therapeutic targets in cancer. Cancer develops from abnormal cell growth in the body, causing significant mortalities every year. To date, potent therapeutic approaches have been developed to eradicate tumor cells, but intolerable toxicity and drug resistance can occur in treated patients, limiting the efficiency of existing treatment strategies. Therefore, searching for novel genes critical for cancer progression and therapeutic response is urgently needed for successful cancer therapy. Recent advances in bioinformatics and proteomic techniques have allowed the identification of a novel category of peptides encoded by non-canonical open reading frames (ncORFs) from historically non-coding genomic regions. Surprisingly, many ncORFs express functional microproteins that play a vital role in human cancers. In this review, we provide a comprehensive description of different ncORF types with coding capacity and technological methods in discovering ncORFs among human genomes. We also summarize the carcinogenic role of ncORFs such as pTINCR and HOXB-AS3 in regulating hallmarks of cancer, as well as the roles of ncORFs such as HOXB-AS3 and CIP2A-BP in cancer diagnosis and prognosis. We also discuss how ncORFs such as AKT-174aa and DDUP are involved in anti-cancer drug response and the underestimated potential of ncORFs as therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemotherapy (NACT) is a pivotal treatment for breast cancer (BC). However, the success of NACT is uncertain and dependent on BC subtype. A valuable tool to identify biomarkers of the response to chemotherapy is metabolomics. We used plasma from BC patients together with clinical data to verify whether certain metabolites present before NACT can predict the responsiveness of the patient. Liquid chromatography–mass spectrometry and untargeted metabolomic analysis were performed. A statistical model was used to predict the response to NACT for samples separated into two sets: training and validation. The results showed 95.4%/93.3% sensitivity, 94.6%/94.7% accuracy, and 91.6%/100.0% specificity for each set, respectively. The compounds correctly classified 94.9% of resistant and 93.7% of sensitive females. The identified metabolites can be considered together with clinical data, allowing for the development of precision medicine strategies that lead to better treatment choices. Background: Neoadjuvant chemotherapy (NACT) has arisen as a treatment option for breast cancer (BC). However, the response to NACT is still unpredictable and dependent on cancer subtype. Metabolomics is a tool for predicting biomarkers and chemotherapy response. We used plasma to verify metabolomic alterations in BC before NACT, relating to clinical data. Methods: Liquid chromatography coupled to mass spectrometry (LC-MS) was performed on pre-NACT plasma from patients with BC (n = 75). After data filtering, an SVM model for classification was built and validated with 75%/25% of the data, respectively. Results: The model composed of 19 identified metabolites effectively predicted NACT response for training/validation sets with high sensitivity (95.4%/93.3%), specificity (91.6%/100.0%), and accuracy (94.6%/94.7%). In both sets, the panel correctly classified 95% of resistant and 94% of sensitive females. Most compounds identified by the model were lipids and amino acids and revealed pathway alterations related to chemoresistance. Conclusion: We developed a model for predicting patient response to NACT. These metabolite panels allow clinical gain by building precision medicine strategies based on tumor stratification. [ABSTRACT FROM AUTHOR]

Biomarkers, including proteins, nucleic acids, antibodies, and peptides, are essential for identifying diseases such as cancer and differentiating between healthy and abnormal cells in patients. To date, studies have shown that cancer stem cells have DNA repair mechanisms that deter the effects of medicinal treatment. Experiments with cell cultures and chemotherapy treatments of these cultures have revealed the presence of small cells, with a small amount of cytoplasm that can be intensively stained with azure eosin, called microcells. Microcells develop during sporosis from a damaged tumor macrocell. After anticancer therapy in tumor cells, a defective macrocell may produce one or more microcells. This study aims to characterize microcell morphology in melanoma cell lines. In this investigation, we characterized the population of cancer cell microcells after applying paclitaxel treatment to a Sk-Mel-28 melanoma cell line using immunocytochemical cell marker detection and fluorescent microscopy. Paclitaxel-treated cancer cells show stronger expression of stem-associated ALDH2, SOX2, and Nanog markers than untreated cells. The proliferation of nuclear antigens in cells and the synthesis of RNA in microcells indicate cell self-defense, promoting resistance to applied therapy. These findings improve our understanding of microcell behavior in melanoma, potentially informing future strategies to counteract drug resistance in cancer treatment. [ABSTRACT FROM AUTHOR]

Pain is one of the most common symptoms in patients with cancer. Pain not only negatively affects the quality of life of patients with cancer, but it has also been associated with reduced survival. Pain management is therefore a critical component of cancer care. Prescription opioids remain the first-line approach for the management of moderate-to-severe pain associated with cancer. However, there has been increasing interest in understanding whether these analgesics could impact cancer progression. Furthermore, epidemiological data link a possible association between prescription opioid usage and cancer development. Until more robust evidence is available, patients with cancer with moderate-to-severe pain may receive opioids to decrease suffering. However, future studies should be conducted to evaluate the role of opioids and opioid receptors in specific cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain cancers, which can start in the brain or spread there from other parts of the body, are difficult to treat and often lead to severe health issues and death. Radiotherapy (RT) is a main treatment that helps control symptoms and can sometimes cure the disease, but many brain cancers resist it, especially those that start in the brain. Combining immunotherapy with RT has shown promise for treating cancers that spread to the brain, but has limited success with gliomas, the most common primary brain cancer. This review looks at why brain tumors resist RT, new strategies to overcome this, and the role of the tumor's environment. We highlight key findings from recent research and identify new treatment opportunities to improve outcomes and survival rates for brain cancer patients. Malignant central nervous system (CNS) cancers include a group of heterogeneous dis-eases characterized by a relative resistance to treatments and distinguished as either primary tumors arising in the CNS or secondary tumors that spread from other organs into the brain. Despite therapeutic efforts, they often cause significant mortality and morbidity across all ages. Radiotherapy (RT) remains the main treatment for brain cancers, improving associated symptoms, improving tumor control, and inducing a cure in some. However, the ultimate goal of cancer treatment, to improve a patient's survival, remains elusive for many CNS cancers, especially primary tumors. Over the years, there have thus been many preclinical studies and clinical trials designed to identify and overcome mechanisms of resistance to improve outcomes after RT and other therapies. For example, immunotherapy delivered concurrent with RT, especially hypo-fractionated stereotactic RT, is synergistic and has revolutionized the clinical management and outcome of some brain tumors, in particular brain metastases (secondary brain tumors). However, its impact on gliomas, the most common primary malignant CNS tumors, remains limited. In this review, we provide an overview of radioresistance mechanisms, the emerging strategies to overcome radioresistance, the role of the tumor microenviroment (TME), and the selection of the most significant results of radiation–immuno–oncological investigations. We also identify novel therapeutic opportunities in primary and secondary brain tumors with the purpose of elucidating current knowledge and stimulating further research to improve tumor control and patients' survival. [ABSTRACT FROM AUTHOR]

Several chronic inflammatory diseases have been linked to high-salt (HS) diets. Chronic inflammation is an established causative hallmark of cancer. However, a direct role of HS diets in tumorigenesis is yet to be defined. Previous orthotopic murine breast tumor studies have shown that short-term HS diets caused inhibition of tumor growth through the activation of cytotoxic adaptive immune responses. However, there have been experimental challenges in developing a viable chronic HS-diet-based murine tumor model. To address this, we have developed a novel chronic HS diet tumor model through the sequential passaging of tumor cells in mice under HS dietary conditions. Two orthotopic murine triple-negative breast cancer models, 4T1 tumor cells injected into BALB/c mice and Py230 tumor cells injected into C57Bl/6 mice, were utilized in our study. For the HS diet cohort, prior to orthotopic injection with tumor cells, the mice were kept on a 4% NaCl diet for 2 weeks. For the regular salt (RS) diet cohort, the mice were kept on a 1% NaCl diet. Following syngeneic cancer cell injection, tumors were allowed to grow for 28 days, following which they were collected to isolate immune cell-depleted cancer cells (passage 1, P1). The tumor cells from P1 were reinjected into the next set of non-tumor-bearing mice. This procedure was repeated for three cycles (P2–P4). In P1, compared to the RS diet cohort, we observed reduced tumor kinetics in both murine tumor models on the HS diet. In contrast, by P4, there was significantly higher tumor progression in the HS diet cohort over the RS diet cohort. Flow cytometry analysis demonstrated an 8-fold increase in tumor-initiating stem cells (TISCs) from P1 to P4 of the HS diet cohort, while there were no significant change in TISC frequency with sequential passaging in the RS diet cohort. Molecular studies showed enhanced expression of TGFβR2 and CD80 on TISCs isolated from the P4 HS diet cohort. In vitro studies demonstrated that TGFβ stimulation of these TISCs increased the cellular expression of CD80 molecules. Further, the chronic HS diet selectively induced the glycolytic metabolic phenotype over the mitochondrial oxidative phosphorylation phenotype in TISCs, which is needed for the production of metabolites during tumor cell differentiation and proliferation. The infiltrating CD8 and CD4 T-lymphocytes in P4 tumors demonstrated increased expression of the immune checkpoint inhibitor (ICI) CTLA4, a known binding partner of CD80, to cause immune exhaustion and pro-tumorigenic effects. Interestingly, anti-TGFβ monoclonal antibodies (mAbs) played a synergistic role in further enhancing the anti-tumor effect of anti-CTLA4 mAb. In summary, our findings demonstrated that chronic HS diet increased the frequency of TISCs in tumors leading to blunting of cytotoxic adaptive immune responses causing tumor proliferation. Furthermore, a combination of anti-TGFβ with current ICI-based immunotherapies could exert more favorable anti-cancer clinical outcomes. [ABSTRACT FROM AUTHOR]

The analysis of small RNA sequencing data across a range of biofluids is a significant research area, given the diversity of RNA types that hold potential diagnostic, prognostic, and predictive value. The intricate task of segregating the complex mixture of small RNAs from both human and other species, including bacteria, fungi, and viruses, poses one of the most formidable challenges in the analysis of small RNA sequencing data, currently lacking satisfactory solutions. This study introduces sRNAflow, a user-friendly bioinformatic tool with a web interface designed for the analysis of small RNAs obtained from biological fluids. Tailored to the unique requirements of such samples, the proposed pipeline addresses various challenges, including filtering potential RNAs from reagents and environment, classifying small RNA types, managing small RNA annotation overlap, conducting differential expression assays, analysing isomiRs, and presenting an approach to identify the sources of small RNAs within samples. sRNAflow also encompasses an alternative alignment-free analysis of RNA-seq data, featuring clustering and initial RNA source identification using BLAST. This comprehensive approach facilitates meaningful comparisons of results between different analytical methods. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of pleural effusion is a common debilitating occurrence during metastasized breast cancer. Malignant cells in pleural effusions originating from the primary tumor suggest the spread of the disease and can serve as a model for metastatic breast cancer. Hence, we established three-dimensional organoid lines from four patients with malignant pleural effusion. Patient-derived organoids were characterized by flow cytometry for individual target antigen expression profiles. Adapter CAR-T cells (AdCAR-T) and biotinylated monoclonal antibodies were evaluated to specifically target patient-derived organoids and assess responses in a personalized fashion. This study demonstrates the feasibility of precision immunotherapy utilizing AdCAR-T to target patient-individualized antigen patterns. A frequent symptom of metastasized breast cancer (BC) includes the development of malignant pleural effusion (MPE), which contains malignant cells derived from the primary tumor site. The poor prognosis of MPE in metastasized BC indicates the necessity for dependable precision oncology and the importance of models representing the heterogenous nature of metastatic BC. In this study, we cultured MPE-derived metastatic tumor cells from four advanced BC patients using organoid technology. We assessed the expression of tumor-associated antigens on MPE-derived organoid lines by flow cytometry (FC). Based on an individual antigen expression pattern, patient-derived organoids were treated with adapter CAR-T cells (AdCAR-T) and biotinylated monoclonal antibodies targeting CD276, HER2, EGFR, TROP2, or EpCAM. Co-culture assays revealed specific organoid lysis by AdCAR-T depending on individual antigen expression patterns. Our results demonstrate that MPE-derived organoids can serve as a reliable tool for assessing the efficacy of AdCAR-T on metastatic BC in a patient-individualized manner. This approach could potentially be applied in a preclinical setting to instruct therapy decisions. Further, our study demonstrates the feasibility of precision immunotherapy utilizing AdCAR-T to target patient-individualized antigen patterns. [ABSTRACT FROM AUTHOR]

A high level of homocysteine (Hcy) is associated with oxidative/ER stress, apoptosis, and impairment of angiogenesis, whereas hydrogen sulfide (H2S) has been found to reverse this condition. Recent studies have shown that cancer cells need to produce a high level of endogenous H2S to maintain cell proliferation, growth, viability, and migration. However, any novel mechanism that targets this balance of Hcy and H2S production has yet to be discovered or exploited. Cells require homocysteine metabolism via the methionine cycle for nucleotide synthesis, methylation, and reductive metabolism, and this pathway supports the high proliferative rate of cancer cells. Although the methionine cycle favors cancer cells for their survival and growth, this metabolism produces a massive amount of toxic Hcy that somehow cancer cells handle very well. Recently, research showed specific pathways important for balancing the antioxidative defense through H2S production in cancer cells. This review discusses the relationship between Hcy metabolism and the antiapoptotic, antioxidative, anti-inflammatory, and angiogenic effects of H2S in different cancer types. It also summarizes the historical understanding of targeting antioxidative defense systems, angiogenesis, and other protective mechanisms of cancer cells and the role of H2S production in the genesis, progression, and metastasis of cancer. This review defines a nexus of diet and precision medicine in targeting the delicate antioxidative system of cancer and explores possible future therapeutics that could exploit the Hcy and H2S balance. [ABSTRACT FROM AUTHOR]

Simple Summary: A frequent disabling symptom during metastasized breast cancer is the development of ascites and pleural effusion, which is associated with poor outcomes. Malignant cells in ascites and pleural effusions derived from the primary tumor site indicate the spreading of cancer and can serve as a model for metastatic breast cancer. Therefore, we cultured metastatic cells from six patients with ascites or pleural effusion in a three-dimensional fashion to obtain organoids. The organoids recapitulated the characteristics of metastatic samples, as shown by immunohistochemistry and mutation analysis. Drug assays of organoids were performed to assess individual responses in a personalized manner. Overall, metastatic organoid cultures derived from malignant pleural effusion and malignant ascites demonstrated in vivo-like phenotypes and drug responses. Hence, these metastatic organoids can serve as an accurate model for the investigation of breast cancer progression and therapy predictions. The poor outcome of metastasized breast cancer (BC) stresses the need for reliable personalized oncology and the significance of models recapitulating the heterogeneous nature of BC. Here, we cultured metastatic tumor cells derived from advanced BC patients with malignant ascites (MA) or malignant pleural effusion (MPE) using organoid technology. We identified the characteristics of tumor organoids by applying immunohistochemistry and mutation analysis. Tumor organoids preserved their expression patterns and hotspot mutations when compared to their original metastatic counterpart and are consequently a well-suited in vitro model for metastasized BC. We treated the tumor organoids to implement a reliable application for drug screenings of metastasized cells. Drug assays revealed that responses are not always in accord with expression patterns, pathway activation, and hotspot mutations. The discrepancy between characterization and functional testing underlines the relevance of linking IHC stainings and mutational analysis of metastasized BC with in vitro drug assays. Our metastatic BC organoids recapitulate the characteristics of their original sample derived from MA and MPE and serve as an invaluable tool that can be utilized in a preclinical setting for guiding therapy decisions. [ABSTRACT FROM AUTHOR]

Simple Summary: Discovered in 1964, Epstein-Barr virus was the first human cancer-causing virus identified. Cancer cells reprogram metabolic pathways to augment their ability to support abnormal rates of proliferation and promote spread through metastatic invasion. Over the course of an infection, EBV drastically alters the metabolic landscape within its host cell, leading to a variety of downstream effects such as contributing to uncontrolled and upregulated cell growth—a hallmark of cancer. In this review, we will provide a comprehensive overview of research hitherto conducted on the means and impact of various metabolic changes that EBV induces, as well as discuss existing and potential treatment options targeting vulnerabilities in EBV-transformed metabolism. The metabolism of cancer cells and Epstein–Barr virus (EBV) infected cells have remarkable similarities. Cancer cells frequently reprogram metabolic pathways to augment their ability to support abnormal rates of proliferation and promote intra-organismal spread through metastatic invasion. On the other hand, EBV is also capable of manipulating host cell metabolism to enable sustained growth and division during latency as well as intra- and inter-individual transmission during lytic replication. It comes as no surprise that EBV, the first oncogenic virus to be described in humans, is a key driver for a significant fraction of human malignancies in the world (~1% of all cancers), both in terms of new diagnoses and attributable deaths each year. Understanding the contributions of metabolic pathways that underpin transformation and virus replication will be important for delineating new therapeutic targets and designing nutritional interventions to reduce disease burden. In this review, we summarise research hitherto conducted on the means and impact of various metabolic changes induced by EBV and discuss existing and potential treatment options targeting metabolic vulnerabilities in EBV-associated diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: UTX/KDM6A is a histone H3K27 demethylase and plays an important role in mammalian development and human diseases such as urothelial cancer. We identified a region encompassing exons 12–17 of UTX that undergoes extensive splicing events. As a result, a nuclear localization sequence located in exon 14 is missing in a considerable portion of UTX transcripts in different cell lines and tissues from normal bladder epithelia and bladder cancer cases. Mass spectrometry analysis showed a role of this region in binding to the epigenetic PR-DUB and MiDAC complexes. UTX was also more extensively bound to chromatin when the alternative splicing region was presented. Our study showed that the alternative splicing of UTX transcripts plays an important role in its functions. The UTX/KDM6A histone H3K27 demethylase plays an important role in development and is frequently mutated in cancers such as urothelial cancer. Despite many studies on UTX proteins, variations in mRNA splicing have been overlooked. Using Nanopore sequencing, we present a comprehensive analysis of UTX/KDM6A splicing events in human cell lines and in tissue samples from bladder cancer cases and normal epithelia. We found that the central region of UTX mRNAs encoded by exons 12 to 17 undergoes extensive alternative splicing. Up to half of all stable mRNAs (8–48% in bladder tissues and 18–58% in cell lines) are represented by the UTX canonical isoform lacking exon 14 encoding a nuclear localization sequence, and hence exon 14-containing UTX isoforms exclusively localize to the nucleus, unlike the cytonuclear localization of the canonical isoform. Chromatin association was also higher for exon-14-containing isoforms compared to the canonical UTX. Using quantitative mass spectrometry, we found that all UTX isoforms integrated into the MLL3 and MLL4, PR-DUB and MiDAC complexes. Interestingly, one of the novel UTX isoforms, which lacks exons 14 and 16, fails to interact with PR-DUB and MiDAC complex members. In conclusion, UTX mRNAs undergo extensive alternative splicing, which controls the subcellular localization of UTX and its interactions with other chromatin regulatory complexes. [ABSTRACT FROM AUTHOR]

Simple Summary: Methyl-CpG binding protein 2 (MeCP2) is a nuclear protein that is mainly studied for its role as an epigenetic regulator of gene transcription. Gene mutations affecting the function or expression level of this epigenetic regulator, particularly in the brain, have been associated with a variety of human neurological and neurodevelopmental disorders. However, recent studies suggest that MeCP2, while being an epigenetic reader, also plays a role in the development and/or progression of several types of human cancer. This review provides a general overview of current research into the proposed molecular pathways involving MeCP2 as an emerging oncogene in human cancers and/or cancer cell lines, and highlights potential therapeutic targets in cancer biology. Epigenetic mechanisms are gene regulatory processes that control gene expression and cellular identity. Epigenetic factors include the "writers", "readers", and "erasers" of epigenetic modifications such as DNA methylation. Accordingly, the nuclear protein Methyl-CpG-Binding Protein 2 (MeCP2) is a reader of DNA methylation with key roles in cellular identity and function. Research studies have linked altered DNA methylation, deregulation of MeCP2 levels, or MECP2 gene mutations to different types of human disease. Due to the high expression level of MeCP2 in the brain, many studies have focused on its role in neurological and neurodevelopmental disorders. However, it is becoming increasingly apparent that MeCP2 also participates in the tumorigenesis of different types of human cancer, with potential oncogenic properties. It is well documented that aberrant epigenetic regulation such as altered DNA methylation may lead to cancer and the process of tumorigenesis. However, direct involvement of MeCP2 with that of human cancer was not fully investigated until lately. In recent years, a multitude of research studies from independent groups have explored the molecular mechanisms involving MeCP2 in a vast array of human cancers that focus on the oncogenic characteristics of MeCP2. Here, we provide an overview of the proposed role of MeCP2 as an emerging oncogene in different types of human cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is an aggressive as well as the most dangerous form of breast cancer. Due to the lack of biomarkers that can be targeted by specific molecular therapeutics, treatment is usually limited to chemotherapy and surgery where applicable. Oncolytic viruses are biologicals that have been engineered in many cases to express different genes that can aid in the recruitment of immune cells to trigger antitumor immune responses in addition to the direct lysis of infected cancerous cells. In this review, the basic biology of TNBC is described, as are the many OVs and their different strategies to attempt to treat TNBC in vitro, in vivo, and in human trials. Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. TNBC diagnoses account for approximately one-fifth of all breast cancer cases globally. The lack of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER-2, CD340) results in a lack of available molecular-based therapeutics. This increases the difficulty of treatment and leaves more traditional as well as toxic therapies as the only available standards of care in many cases. Recurrence is an additional serious problem, contributing substantially to its higher mortality rate as compared to other breast cancers. Tumor heterogeneity also poses a large obstacle to treatment approaches. No driver of tumor development has been identified for TNBC, and large variations in mutational burden between tumors have been described previously. Here, we describe the biology of six different subtypes of TNBC, based on differential gene expression. Subtype differences can have a large impact on metastatic potential and resistance to treatment. Emerging antibody-based therapeutics, such as immune checkpoint inhibitors, have available targets for small subsets of TNBC patients, leading to partial responses and relatively low overall efficacy. Immuno-oncolytic viruses (OVs) have recently become significant in the pursuit of effective treatments for TNBC. OVs generally share the ability to ignore the heterogeneous nature of TNBC cells and allow infection throughout a treated tumor. Recent genetic engineering has allowed for the enhancement of efficacy against certain tumor types while avoiding the most common side effects in non-cancerous tissues. In this review, TNBC is described in order to address the challenges it presents to potential treatments. The OVs currently described preclinically and in various stages of clinical trials are also summarized, as are their strategies to enhance therapeutic potential. [ABSTRACT FROM AUTHOR]

Eph receptor tyrosine kinases play critical functions during development, in the formation of tissue and organ borders, and the vascular and neural systems. Uniquely among tyrosine kinases, their activities are controlled by binding to membrane-bound ligands, called ephrins. Ephs and ephrins generally have a low expression in adults, functioning mainly in tissue homeostasis and plasticity, but are often overexpressed in cancers, where they are especially associated with undifferentiated or progenitor cells, and with tumour development, vasculature, and invasion. Mutations in Eph receptors also occur in various tumour types and are suspected to promote tumourigenesis. Ephs and ephrins have the capacity to operate as both tumour promoters and tumour suppressors, depending on the circumstances. They have been demonstrated to impact tumour cell proliferation, migration, and invasion in vitro, as well as tumour development, angiogenesis, and metastases in vivo, making them potential therapeutic targets. However, successful development of therapies will require detailed understanding of the opposing roles of Ephs in various cancers. In this review, we discuss the variations in Eph expression and functions in a variety of malignancies. We also describe the multiple strategies that are currently available to target them in tumours, including preclinical and clinical development. [ABSTRACT FROM AUTHOR]

Simple Summary: Early stage primary cancer, where the tumour has not yet spread from its site of origin, is commonly curable through surgery alone. Conversely, metastatic cancer, where the tumour has disseminated to distant sites, is almost invariably lethal and is the main cause of cancer death. Given that primary cancer is often curable, it is likely that the ability to metastasise is acquired late in the development of cancer. To investigate if specific cancer gene mutations or pathways are subject to selection at different time points during the life-history of cancer, we compared genomic data from primary and metastatic cancer and timed the acquisition of genomic alterations. The results presented here support the view that certain events are selected for late in the evolution of cancer. However, we observed no difference in the type or timing of events between primary and metastatic cancer. Taken together, our results suggest that the ability to metastasise is not acquired through evolution solely at a genomic level. Cancer metastasis is the lethal developmental step in cancer, responsible for the majority of cancer deaths. To metastasise, cancer cells must acquire the ability to disseminate systemically and to escape an activated immune response. Here, we endeavoured to investigate if metastatic dissemination reflects acquisition of genomic traits that are selected for. We acquired mutation and copy number data from 8332 tumours representing 19 cancer types acquired from The Cancer Genome Atlas and the Hartwig Medical Foundation. A total of 827,344 non-synonymous mutations across 8332 tumour samples representing 19 cancer types were timed as early or late relative to copy number alterations, and potential driver events were annotated. We found that metastatic cancers had a significantly higher proportion of clonal mutations and a general enrichment of early mutations in p53 and RTK/KRAS pathways. However, while individual pathways demonstrated a clear time-separated preference for specific events, the relative timing did not vary between primary and metastatic cancers. These results indicate that the selective pressure that drives cancer development does not change dramatically between primary and metastatic cancer on a genomic level, and is mainly focused on alterations that increase proliferation. [ABSTRACT FROM AUTHOR]

Cancers are worldwide health concerns, whether they are sporadic or hereditary. The fundamental mechanism that causes somatic or oncogenic mutations and ultimately aids cancer development is still unknown. However, mammalian cells with protein-only somatic inheritance may also contribute to cancerous malignancies. Emerging data from a recent study show that prion-like proteins and prions (PrPC) are crucial entities that have a functional role in developing neurological disorders and cancer. Furthermore, excessive PrPC expression profiling has also been detected in non-neuronal tissues, such as the lymphoid cells, kidney, GIT, lung, muscle, and mammary glands. PrPC expression is strongly linked with the proliferation and metastasis of pancreatic, prostate, colorectal, and breast malignancies. Similarly, experimental investigation presented that the PrPC expression, including the prion protein-coding gene (PRNP) and p53 ag are directly associated with tumorigenicity and metastasis (tumor suppressor gene). The ERK2 (extracellular signal-regulated kinase) pathway also confers a robust metastatic capability for PrPC-induced epithelial to mesenchymal transition. Additionally, prions could alter the epigenetic regulation of genes and overactive the mitogen-activated protein kinase (MAPK) signaling pathway, which promotes the development of cancer in humans. Protein overexpression or suppression caused by a prion and prion-like proteins has also been linked to oncogenesis and metastasis. Meanwhile, additional studies have discovered resistance to therapeutic targets, highlighting the significance of protein expression levels as potential diagnostic indicators and therapeutic targets. [ABSTRACT FROM AUTHOR]

Recently, FGFR inhibitors have been highlighted as promising targeted drugs due to the high prevalence of FGFR1 amplification in cancer patients. Although various potential biomarkers for FGFR inhibitors have been suggested, their functional effects have been shown to be limited due to the complexity of the cancer signaling network and the heterogenous genomic conditions of patients. To overcome such limitations, we have reconstructed a lung cancer network model by integrating a cell line genomic database and analyzing the model in order to understand the underlying mechanism of heterogeneous drug responses. Here, we identify novel genomic context-specific candidates that can increase the efficacy of FGFR inhibitors. Furthermore, we suggest optimal targets that can induce more effective therapeutic responses than that of FGFR inhibitors in each of the FGFR-resistant lung cancer cells through computational simulations at a system level. Our findings provide new insights into the regulatory mechanism of differential responses to FGFR inhibitors for optimal therapeutic strategies in lung cancer. [ABSTRACT FROM AUTHOR]

Cancer is a worldwide leading cause of death, and it is projected that newly diagnosed cases globally will reach 27.5 million each year by 2040. Cancers (malignant tumors), unlike benign tumors are characterized by structural and functional dedifferentiation (anaplasia), breaching of the basement membrane, spreading to adjacent tissues (invasiveness), and the capability to spread to distant sites (metastasis). In the cancer biology research field, understanding and characterizing cancer metastasis as well as features of cell death (apoptosis) is considered a technically challenging subject of study and clinically is very critical and necessary. Therefore, in addition to the cytochemical methods traditionally used, novel biophysical and bioelectrochemical techniques (e.g., cyclic voltammetry and electrochemical impedance spectroscopy), atomic force microscopy, and electron microscopic methods are increasingly being deployed to better understand these processes. Implementing those methods at the preclinical level enables the rapid screening of new anticancer drugs with understanding of their central mechanism for cancer therapy. In this review, principles and basic concepts of new techniques suggested for metastasis, and apoptosis examinations for research purposes are introduced, along with examples of each technique. From our recommendations, the privilege of combining the bio-electrochemical and biosensing techniques with the conventional cytochemical methods either for research or for biomedical diagnosis should be emphasized. [ABSTRACT FROM AUTHOR]

DNA methylation is an epigenetic mark that living beings have used in different environments. The MTases family catalyzes DNA methylation. This process is conserved from archaea to eukaryotes, from fertilization to every stage of development, and from the early stages of cancer to metastasis. The family of DNMTs has been classified into DNMT1, DNMT2, and DNMT3. Each DNMT has been duplicated or deleted, having consequences on DNMT structure and cellular function, resulting in a conserved evolutionary reaction of DNA methylation. DNMTs are conserved in the five kingdoms of life: bacteria, protists, fungi, plants, and animals. The importance of DNMTs in whether methylate or not has a historical adaptation that in mammals has been discovered in complex regulatory mechanisms to develop another padlock to genomic insurance stability. The regulatory mechanisms that control DNMTs expression are involved in a diversity of cell phenotypes and are associated with pathologies transcription deregulation. This work focused on DNA methyltransferases, their biology, functions, and new inhibitory mechanisms reported. We also discuss different approaches to inhibit DNMTs, the use of non-coding RNAs and nucleoside chemical compounds in recent studies, and their importance in biological, clinical, and industry research. [ABSTRACT FROM AUTHOR]

Heat Shock Factor 1 (HSF1), a transcription factor frequently overexpressed in cancer, is activated by proteotoxic agents and participates in the regulation of cellular stress response. To investigate how HSF1 level affects the response to proteotoxic stress, we integrated data from functional genomics analyses performed in MCF7 breast adenocarcinoma cells. Although the general transcriptional response to heat shock was impaired due to HSF1 deficiency (mainly chaperone expression was inhibited), a set of genes was identified, including ATF3 and certain FOS and JUN family members, whose stress-induced activation was stronger and persisted longer than in cells with normal HSF1 levels. These genes were direct HSF1 targets, suggesting a dual (activatory/suppressory) role for HSF1. Moreover, we found that heat shock-induced inflammatory response could be stronger in HSF1-deficient cells. Analyses of The Cancer Genome Atlas data indicated that higher ATF3, FOS, and FOSB expression levels correlated with low HSF1 levels in estrogen receptor-positive breast cancer, reflecting higher heat shock-induced expression of these genes in HSF1-deficient MCF7 cells observed in vitro. However, differences between the analyzed cancer types were noted in the regulation of HSF1-dependent genes, indicating the presence of cell-type-specific mechanisms. Nevertheless, our data indicate the existence of the heat shock-induced network of transcription factors (associated with the activation of TNFα signaling) which includes HSF1. Independent of its chaperone-mediated cytoprotective function, HSF1 may be involved in the regulation of this network but prevents its overactivation in some cells during stress. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has transformed breast cancer treatment. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. In our current communication, using breast tumor models, we demonstrated that a low salt diet could reduce irAE development following ICI therapy. Importantly, a low salt diet did not change the anti-tumor efficiency. Our current study provides a basis for future clinical trials to verify the role of a low salt diet in long-term immunotherapeutic efficiency in breast cancer patients. Immune checkpoint inhibitor (ICI) therapy has revolutionized the breast cancer treatment landscape. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. Previous studies in our laboratory and others have demonstrated that a high-salt (HS) diet induces inflammatory activation of CD4+T cells leading to anti-tumor responses. In our current communication, we analyzed the impact of dietary salt modification on therapeutic and systemic outcomes in breast-tumor-bearing mice following anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody (mAb) based ICI therapy. As HS diet and anti-CTLA4 mAb both exert pro-inflammatory activation of CD4+T cells, we hypothesized that a combination of these would lead to enhanced irAE response, while low-salt (LS) diet through blunting peripheral inflammatory action of CD4+T cells would reduce irAE response. We utilized an orthotopic murine breast tumor model by injecting Py230 murine breast cancer cells into syngeneic C57Bl/6 mice. In an LS diet cohort, anti-CTLA4 mAb treatment significantly reduced tumor progression (day 35, 339 ± 121 mm3), as compared to isotype mAb (639 ± 163 mm3, p < 0.05). In an HS diet cohort, treatment with anti-CTLA4 reduced the survival rate (day 80, 2/15) compared to respective normal/regular salt (NS) diet cohort (8/15, p < 0.05). Further, HS plus anti-CTLA4 mAb caused an increased expression of inflammatory cytokines (IFNγ and IL-1β) in lung infiltrating and peripheral circulating CD4+T cells. This inflammatory activation of CD4+T cells in the HS plus anti-CTLA4 cohort was associated with the upregulation of inflammasome complex activity. However, an LS diet did not induce any significant irAE response in breast-tumor-bearing mice upon treatment with anti-CTLA4 mAb, thus suggesting the role of high-salt diet in irAE response. Importantly, CD4-specific knock out of osmosensitive transcription factor NFAT5 using CD4cre/creNFAT5flox/flox transgenic mice caused a downregulation of high-salt-mediated inflammatory activation of CD4+T cells and irAE response. Taken together, our data suggest that LS diet inhibits the anti-CTLA4 mAb-induced irAE response while retaining its anti-tumor efficacy. [ABSTRACT FROM AUTHOR]

SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here, we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28, including growth retardation and reduced G1 to S phase progression. Most strikingly, SMER28 treatment led to a complete arrest of receptor tyrosine kinase signaling, and, consequently, growth factor-induced cell scattering and dorsal ruffle formation. This coincided with a dramatic reduction in phosphorylation patterns of PI3K downstream effectors. Consistently, SMER28 directly inhibited PI3Kδ and to a lesser extent p110γ. The biological relevance of our observations was underscored by SMER28 interfering with InlB-mediated host cell entry of Listeria monocytogenes, which requires signaling through the prominent receptor tyrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative Salmonella Typhimurium was not inhibited. Lastly, in B cell lymphoma cells, which predominantly depend on tonic signaling through PI3Kδ, apoptosis upon SMER28 treatment is profound in comparison to non-hematopoietic cells. This indicates SMER28 as a possible drug candidate for the treatment of diseases that derive from aberrant PI3Kδ activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Oligometastatic disease is an intermediate state of metastatic dissemination with a limited number of metastatic sites and extent of disease. Tumor cells need multiple capabilities in order to migrate, survive and evolve to macroscopic metastases. These capabilities are acquired by evolutionary mechanisms and are associated with several clinical factors and biomarkers. Better understanding of these properties and biomarkers may help to select patients that can benefit from local ablative therapies, which have shown to be a promising approach in recent clinical evidence. Over the last years, the oligometastatic disease state has gained more and more interest, and randomized trials are now suggesting an added value of stereotactic radiotherapy on all macroscopic disease in oligometastatic patients; but what barriers could impede widespread disease in some patients? In this review, we first discuss the concept of oligometastatic disease and some examples of clinical evidence. We then explore the route to dissemination: the hurdles a tumoral clone has to overtake before it can produce efficient and widespread dissemination. The spectrum theory argues that the range of metastatic patterns encountered in the clinic is the consequence of gradually obtained metastatic abilities of the tumor cells. Tumor clones can obtain these capabilities by Darwinian evolution, hence early in their genetic progression tumors might produce only a limited number of metastases. We illustrate selective dissemination by discussing organ tropism, the preference of different cancer (sub)types to metastasize to certain organs. Finally we discuss biomarkers that may help to distinguish the oligometastatic state. [ABSTRACT FROM AUTHOR]

Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum. Here, we review research defining the molecular basis and development of cSCC that aims to provide new insights into pathogenesis and drive the development of novel, cost and morbidity saving therapies. [ABSTRACT FROM AUTHOR]

The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. 'The Hallmarks of Cancer' illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients' outcomes.

The p53 field was born from a marriage of the techniques of cancer virus research and immunology. Over the past 40 years, it has followed the path of cancer research. Now cancer treatments are turning to immunotherapy, and there are many hints of the role of the p53 protein in both the regulation of the innate immune system and as an antigen in adaptive immune responses. The p53 gene and protein are part of the innate immune system, and play an important role in infectious diseases, senescence, aging, and the surveillance of repetitive DNA and RNAs. The mutant form of the p53 protein in cancers elicits both a B-cell antibody response (a tumor antigen) and a CD-8 killer T-cell response (a tumor-specific transplantation antigen). The future will take the p53-immune response field of research into cancer immunotherapy, autoimmunity, inflammatory responses, neuro-degeneration, aging, and life span, and the regulation of epigenetic stability and tissue regeneration. The next 40 years will bring the p53 gene and its proteins out of a cancer focus and into an organismic and environmental focus [ABSTRACT FROM AUTHOR]

A frequent symptom of metastasized breast cancer (BC) includes the development of malignant pleural effusion (MPE), which contains malignant cells derived from the primary tumor site. The poor prognosis of MPE in metastasized BC indicates the necessity for dependable precision oncology and the importance of models representing the heterogenous nature of metastatic BC. In this study, we cultured MPE-derived metastatic tumor cells from four advanced BC patients using organoid technology. We assessed the expression of tumor-associated antigens on MPE-derived organoid lines by flow cytometry (FC). Based on an individual antigen expression pattern, patient-derived organoids were treated with adapter CAR-T cells (AdCAR-T) and biotinylated monoclonal antibodies targeting CD276, HER2, EGFR, TROP2, or EpCAM. Co-culture assays revealed specific organoid lysis by AdCAR-T depending on individual antigen expression patterns. Our results demonstrate that MPE-derived organoids can serve as a reliable tool for assessing the efficacy of AdCAR-T on metastatic BC in a patient-individualized manner. This approach could potentially be applied in a preclinical setting to instruct therapy decisions. Further, our study demonstrates the feasibility of precision immunotherapy utilizing AdCAR-T to target patient-individualized antigen patterns.

Establishing how a series of potentially important genes might relate to each other is relevant to understand the origin and evolution of illnesses, such as cancer. High-throughput biological experiments have played a critical role in providing information in this regard. A special challenge, however, is that of trying to conciliate information from separate microarray experiments to build a potential genetic signaling path. This work proposes a two-step analysis pipeline, based on optimization, to approach meta-analysis aiming to build a proxy for a genetic signaling path. [ABSTRACT FROM AUTHOR]

One-third of all cancer categories in clinics have a high incidence of neoplasm metastasis. Neoplasm metastasis is one of the leading causes of cancer deaths. However, the prevailing therapeutic approach to this pathogenic process is presently unsatisfactory. Paradoxically to our efforts and expectations, except for some antibodies, no obvious improvements and therapeutic benefits in currently used drugs have been achieved until now. Therapeutic benefits in late-stage or elderly cancer patients are especially poor and useless. One of the reasons for this, we would guess, is the lack of therapeutic targets specifically related to neoplasm metastasis. In order to enhance the therapeutic efficacy, the development of antimetastatic drugs transcending from current drug-screening pathways is urgently needed. Antimetastatic drugs targeting aberrantly sialylated in tumors have evolved for about a quarter of a century and might be a future therapeutic option other than the currently utilized antimetastatic drugs, such as antivascular and MMP inhibitors. Since neoplasm tissues often manifest high levels of sialic acids and sialyl antigens or glycoligands, some types of sialic acid analogue, such as N-glycolylneuraminic acid (Nau5Gc), occurred in most tumor tissues which is normally absent in most humans. Consequently, more attention is needed to work with new therapeutic approaches to target these changes. This review addresses and discusses the latest six types of therapeutic approaches targeting sialic acids in metastatic tissues. [ABSTRACT FROM AUTHOR]