Implications For Cancer Progression Research Articles

The methionine cycle and its cancer implications.

The essential amino acid methionine is a crucial regulator of sulfur metabolism in a variety of interconnected biochemical pathways. The methionine cycle is intricately linked to the folate cycle, forming the one-carbon metabolism, a crucial regulator of S-adenosylmethionine, SAM. Recent work highlights methionine's critical role in tumor growth and progression, maintaining polyamine synthesis, and playing a crucial role in the regulation of SAM both in altered chromatin states, depending on p53 status, as well as facilitating m6A methylation of NR4A2 mRNA, hence regulating proliferation in esophageal carcinoma. Accordingly, Celecoxib, a specific NR4A2 inhibitor, is a potentially powerful inhibitor of tumor growth at least in this specific model. Additionally, formaldehyde, from endogenous or exogenous sources, can directly regulate both SAM steady-state-levels and the one-carbon metabolism, with relevant implication in cancer progression. These recent scientific advancements have provided a deeper understanding of the molecular mechanisms involved in cancer development, and its potential therapeutic regulation.

Generation of Hydrogen Peroxide in Cancer Cells: Advancing Therapeutic Approaches for Cancer Treatment.

Cancer cells show altered antioxidant defense systems, dysregulated redox signaling, and increased generation of reactive oxygen species (ROS). Targeting cancer cells through ROS-mediated mechanisms has emerged as a significant therapeutic strategy due to its implications in cancer progression, survival, and resistance. Extensive research has focused on selective generation of H2O2 in cancer cells for selective cancer cell killing by employing various strategies such as metal-based prodrugs, photodynamic therapy, enzyme-based systems, nano-particle mediated approaches, chemical modulators, and combination therapies. Many of these H2O2-amplifying approaches have demonstrated promising anticancer effects and selectivity in preclinical investigations. They selectively induce cytotoxicity in cancer cells while sparing normal cells, sensitize resistant cells, and modulate the tumor microenvironment. However, challenges remain in achieving selectivity, addressing tumor heterogeneity, ensuring efficient delivery, and managing safety and toxicity. To address those issues, H2O2-generating agents have been combined with other treatments leading to optimized combination therapies. This review focuses on various chemical agents/approaches that kill cancer cells via H2O2-mediated mechanisms. Different categories of compounds that selectively generate H2O2 in cancer cells are summarized, their underlying mechanisms and function are elucidated, preclinical and clinical studies as well as recent advancements are discussed, and their prospects as targeted therapeutic agents and their therapeutic utility in combination with other treatments are explored. By understanding the potential of these compounds, researchers can pave the way for the development of effective and personalized cancer treatments.

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer.

Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER-) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.

Expression of the Folate Receptor Proteins FOLR1 and FOLR2 in Correlation With Clinicopathological Variables of Gastric Cancer.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, owing to its aggressive nature and poor prognosis. The role of folate receptors, particularly folate receptor 1 (FOLR1) and folate receptor 2 (FOLR2), in cancer has been increasingly recognized due to their overexpression in various malignancies including gastric cancer, and its potential implications in cancer progression, treatment resistance and as therapeutic targets. To evaluate the expression patterns of FOLR1 and FOLR2 in GC patients' tissue and blood specimens and to correlate these patterns with clinicopathological variables. A total of 58 gastric cancer patients were enrolled at the Regional Cancer Centre (RCC) from March 2017 to March 2020. Immunohistochemical analysis was performed to examine the expression of FOLR1 and FOLR2 in formalin-fixed paraffin-embedded (FFPE) tissue samples. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to analyze FOLR1 and FOLR2 expression in blood samples. Statistical analyses were conducted using chi-square tests, independent T-tests, and Kaplan-Meier survival analysis. FOLR1 and FOLR2 were overexpressed in 82.76% and 70.69% of gastric cancer tissues, respectively. High expression levels of FOLR1 were significantly associated with the diffuse type of gastric cancer (p<0.005). qRT-PCR showed significant overexpression of FOLR1 in gastric cancer blood samples compared to control samples, with a median fold change of approximately 14.18 times. Conversely, FOLR2 was significantly underexpressed in gastric cancer samples, with a fold change of 0.30. However, no significant correlation was found between FOLR2 expression and the clinicopathological features. The overall survival analysis did not show a significant difference in survival rates based on the expression levels of FOLR1 and FOLR2. This study highlights the differential expression patterns of FOLR1 and FOLR2 in gastric cancer and underscores the complexity of their roles in cancer biology. While FOLR1 shows potential as a biomarker for gastric cancer due to its overexpression, further studies are needed to fully elucidate the therapeutic and prognostic implications of folate receptors in gastric cancer.

Upregulation of GOLPH3 mediated by Bisphenol a promotes colorectal cancer proliferation and migration: evidence based on integrated analysis.

The interaction between environmental endocrine-disrupting chemicals, such as Bisphenol A (BPA), and their influence on cancer progression, particularly regarding the GOLPH3 gene in colorectal cancer, remains unclear. We performed an integrated analysis of transcriptional profiling, clinical data, and bioinformatics analyses utilizing data from the Comparative Toxicogenomics Database and The Cancer Genome Atlas. The study employed ClueGO, Gene Set Enrichment Analysis, and Gene Set Variation Analysis for functional enrichment analysis, alongside experimental assays to examine the effects of BPA exposure on colorectal cancer cell lines, focusing on GOLPH3 expression and its implications for cancer progression. Our findings demonstrated that BPA exposure significantly promoted the progression of colorectal cancer by upregulating GOLPH3, which in turn enhanced the malignant phenotype of colorectal cancer cells. Comparative analysis revealed elevated GOLPH3 protein levels in cancerous tissues versus normal tissues, with single-cell analysis indicating widespread GOLPH3 presence across various cell types in the cancer microenvironment. GOLPH3 was also associated with multiple carcinogenic pathways, including the G2M checkpoint. Furthermore, our investigation into the colorectal cancer microenvironment and genomic mutation signature underscored the oncogenic potential of GOLPH3, exacerbated by BPA exposure. This study provides novel insights into the complex interactions between BPA exposure and GOLPH3 in the context of colorectal cancer, emphasizing the need for heightened awareness and measures to mitigate BPA exposure risks. Our findings advocate for further research to validate these observations in clinical and epidemiological settings and explore potential therapeutic targets within these pathways.

Abstract 5569: Mechano-chemical control of secretory cues regulating immune tolerance, survival and invasion in oral squamous cell carcinomas

Abstract Tissue fibrosis and extracellular matrix (ECM) stiffening have been shown to promote tumor cell proliferation, metastasis, and chemoresistance in a range of cancers. Stiffness of the ECM can lead to changes in cancer cell behavior, including enhanced proliferation, activation of mechano-sensitive signaling pathways, and potential genomic damage, with implications for cancer progression and immune responses. Recent research suggests stiff matrix may also induce the release of tumor-derived small extracellular vesicles (sEVs) that promote tumor growth. Tumor-derived sEVs carry bioactive cargo, such as micro-RNAs (miRNAs) and DNA fragments, and function as a unique form of intracellular communication promoting cell survival, growth, and metastasis. Understanding these mechano-sensing mechanisms is essential for identifying potential targets in precision medicine for solid tumor treatment. However, the influence of tumor stiffness on secretory cues, and their subsequent role in immunomodulation and/or chemo-resistance has not been extensively studied. This project aims to explore how tumor stiffness can alter cell responses to genotoxic stress and how these responses can perpetuate feedback to the immune system through the release of secretory cues such as sEVs. Here, we outline the isolation and characterization of tumor-derived sEVs obtained from culture media of oral squamous cell carcinoma (OSCC) spheroids, cultured at varying stiffness (0.2kPa-1.5kPa). In this project, we use OSCC lines that are either sensitive or resistant to cisplatin (HSC-3 and HN-5, respectively). To explore the immunomodulatory effects of these tumor-derived sEVs, we first established a consistent supply of CD206+ve macrophages differentiated from human induced pluripotent stem cells (iMacs), following the established protocol of Douthwaite et al (2021). iMacs were then treated with sEVs with their resulting immunophenotype, and activation assessed. These preliminary experiments provide a step towards understanding how the biophysical environment influences tumor cell resistance to therapy and how sEVs can modulate the relationship between cancer cells and macrophages. Citation Format: Bethany R. Bareham, Matthew Dibble, Leila Mouhib, Aitor Bermejo Arteagabeitia, Subhankar Mukhopadhyay, Maddy Parsons. Mechano-chemical control of secretory cues regulating immune tolerance, survival and invasion in oral squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5569.

Abstract 4912: Unsupervised detection of stromal phenotypes with distinct fibrogenic and inflamed properties in NSCLC

Abstract Background: Understanding the composition of cancer-associated stroma (CAS) is vital, as the number and location of immune cells and fibroblasts, as well as the degree of extracellular matrix deposition, have implications for cancer progression and response to treatment, including in non-small cell lung cancer (NSCLC). Manual analysis of CAS does not fully describe the stromal milieu, especially from a spatial perspective, and is highly subjective. To this end, we have developed an unsupervised machine learning (ML) model to characterize the CAS in NSCLC from hematoxylin and eosin (H&amp;E) stained whole slide images (WSI) at scale. Methods: PathExploreTM models were deployed to predict stromal tissue and cell types, while another ML model was used to detect collagen fibers from H&amp;E stained WSIs from the TCGA LUAD (N=536) and LUSC (N=464) datasets. Stroma was divided into small regions (median = 0.02 mm2), and 88 features characterizing cell distribution, tissue composition and fiber density were extracted from each region. Graphs were generated connecting neighboring regions (nodes), and an unsupervised variational graph auto-encoder (VGAE) model was trained to learn 8 latent features through dimensionality reduction. Stromal phenotypes were then derived from the latent features using k-means clustering. The fraction of each phenotype in the stroma was correlated against immune- and stroma-related gene expression signatures (GES) and overall survival (OS). Results: Deployment of VGAE on LUAD and LUSC WSIs revealed three distinct stromal phenotypes - P0, P1 and P2. Fibroblast density was elevated in P0 and P1 regions (p&amp;lt;0.001), immune cell density was elevated in P2 regions (p&amp;lt;0.001), and collagen fiber intensity was highest in P1 regions (p&amp;lt;0.001). P2 enrichment was correlated with elevated expression of the T cell-inflamed gene expression profile (TGEP; Spearman ρ = 0.43 in LUAD; ρ = 0.27 in LUSC) and with improved OS (HR = 0.696; 95% CIs: 0.571-0.847 in LUSC). Conversely, P1 enrichment was positively associated with a transforming growth factor-β-induced cancer associated fibroblast GES (TGFβ-CAF: ρ = 0.19 in LUAD and ρ = 0.12 in LUSC) and poor OS (HR = 1.358; 95% CIs: 1.149-1.603 in LUSC). These phenotypes are consistent with fibroblast-enriched, collagen-depleted stroma (P0), collagen-rich, fibroblast-enriched tumor-promoting stroma (P1), and immune cell-enriched, tumor-suppressive stroma (P2). Conclusions: We describe an unsupervised, data-driven method of predicting stromal regions with discrete patterns of cell composition and collagen deposition in NSCLC. This approach identified three phenotypes of NSCLC stroma. These results highlight the ability of ML models to characterize and find meaningful patterns within the cell, tissue, and matrix components of a tumor. This work provides further evidence of the potential of ML to discover novel precision medicine biomarkers in NSCLC. Citation Format: Neel Patel, Nhat Le, Tan Nguyen, Fedaa Najdawi, Sandhya Srinivasan, Adam Stanford-Moore, Deeksha Kartik, Jun Zhang, Jacqueline Brosnan-Cashman, Robert Egger, Justin Lee, Matthew Bronnimann. Unsupervised detection of stromal phenotypes with distinct fibrogenic and inflamed properties in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4912.

Shaping the immune-suppressive microenvironment on tumor-associated myeloid cells through tumor-derived exosomes.

Tumor-associated myeloid cells (TAMCs) play a crucial role in orchestrating the dynamics of the tumor immune microenvironment. This heterogeneous population encompasses myeloid-derived suppressor cells, tumor-associated macrophages and dendritic cells, all of which contribute to the establishment of an immunosuppressive milieu that fosters tumor progression. Tumor-derived exosomes (TEXs), small extracellular vesicles secreted by tumor cells, have emerged as central mediators in intercellular communication within the tumor microenvironment. In this comprehensive review, we explore the intricate mechanisms through which TEXs modulate immune-suppressive effects on TAMCs and their profound implications in cancer progression. We delve into the multifaceted ways in which TEXs influence TAMC functions, subsequently affecting tumor immune evasion. Furthermore, we elucidate various therapeutic strategies aimed at targeting TEX-mediated immune suppression, with the ultimate goal of bolstering antitumor immunity.

Exploring the Influence of the Selected Conjugated Fatty Acids Isomers and Cancerous Process on the Fatty Acids Profile of Spleen

The spleen, traditionally associated with blood filtration and immune surveillance, has recently been recognized for its role in systemic lipid metabolism and potential influence on cancer development and progression. This study investigates effects of dietary supplements, specifically conjugated linolenic acids from pomegranate seed oil and bitter melon extract, on the fatty acid (FA) composition of the spleen in the context of cancerous processes. Advanced methods, including gas chromatography–mass spectrometry and silver ion-impregnated high-performance liquid chromatography, were employed to analyze the spleen’s FA profile. Our research uncovered that dietary supplementation leads to alterations in the spleen’s FA profile, especially under the carcinogenic influence of 7,12-dimethylbenz[a]anthracene. These changes did not align with a simple protective or anti-carcinogenic pattern, as previously suggested in in vitro studies. We observed shifts in conjugated FA isomer concentrations and variations in desaturase activities, suggesting disrupted lipid metabolism in cancerous conditions. The findings underscore the spleen’s vital role in lipid metabolism within the body’s systemic health framework, highlighting the complexity of dietary supplements’ impact on FA profiles in the spleen and their potential implications in cancer progression and treatment. This study adds valuable insight into the complex interplay between diet, disease, and metabolic regulation, particularly in cancerous environments.

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment.

The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS-STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS-STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements.

A Disulfidptosis-Related Gene Signature Associated with Prognosis and Immune Cell Infiltration in Osteosarcoma.

Osteosarcoma (OS) stands as a leading aggressive bone malignancy that primarily affects children and adolescents worldwide. A recently identified form of programmed cell death, termed Disulfidptosis, may have implications for cancer progression. Yet, its role in OS remains elusive. To elucidate this, we undertook a thorough examination of Disulfidptosis-related genes (DRGs) within OS. This involved parsing expression data, clinical attributes, and survival metrics from the TARGET and GEO databases. Our analysis unveiled a pronounced association between the expression of specific DRGs, particularly MYH9 and LRPPRC, and OS outcome. Subsequent to this, we crafted a risk model and a nomogram, both honed for precise prognostication of OS prognosis. Intriguingly, risks associated with DRGs strongly resonated with immune cell infiltration levels, myriad immune checkpoints, genes tethered to immunotherapy, and sensitivities to systematic treatments. To conclude, our study posits that DRGs, especially MYH9 and LRPPRC, hold potential as pivotal architects of the tumor immune milieu in OS. Moreover, they may offer predictive insights into treatment responses and serve as reliable prognostic markers for those diagnosed with OS.

Hydrogen Sulfide Signaling in the Tumor Microenvironment: Implications in Cancer Progression and Therapy.

Significance: Cancer is a complex and heterotypic structure with a spatial organization that contributes to challenges in therapeutics. Enzymes associated with producing the gasotransmitter hydrogen sulfide (H2S) are differentially expressed in tumors. Indeed, critical and paradoxical roles have been attributed to H2S in cancer-promoting characteristics by targeting both cancer cells and their milieu. This review focuses on the evidence and knowledge gaps of H2S on the tumor redox microenvironment and the pharmacological effects of H2S donors on cancer biology. Recent Advances: Endogenous and pharmacological concentrations of H2S evoke different effects on the same cell type: physiological H2S concentrations have been associated with tumor development and progression. In contrast, pharmacological concentrations have been associated with anticancer effects. Critical Issues: The exact threshold between the promotion and inhibition of tumorigenesis by H2S is largely unknown. The main issues covered in this review include H2S-modulated signaling pathways that are critical for cancer cells, the potential effects of H2S on cellular components of the tumor microenvironment, temporal modulation of H2S in promoting or inhibiting tumor progression (similar to observed for inflammation), and pharmacological agents that modulate H2S and which could play a role in antineoplastic therapy. Future Directions: Given the complexity and heterogeneity of tumor composition, mechanistic studies on context-dependent pharmacological effects of H2S donors for cancer therapy are necessary. These studies must determine the critical signaling pathways and the cellular components involved to allow advances in the rational use of H2S donors as antineoplastic agents. Antioxid. Redox Signal. 40, 250-271.

BMSC-HNC Interaction: Exploring Effects on Bone Integrity and Head and Neck Cancer Progression.

In recent research, the tumor microenvironment has been shown to attract mesenchymal stromal cells (MSCs), which is of particular interest due to its implications for cancer progression. The study focused on understanding the interaction between bone marrow-derived MSCs (BMSCs) and head and neck cancer (HNC) cells. This interaction was found to activate specific markers, notably the osteogenic marker alkaline phosphatase and the oncogene Runx2. These activations corresponded with the release of collagenase enzymes, MMP9 and MMP2. To gain insights into bone resorption related to this interaction, bovine bone slices were used, supporting the growth of "heterogeneous spheroids" that contained both BMSCs and HNC cells. Through scanning electron microscopy and energy-dispersive X-ray (EDX) analysis, it was observed that these mixed spheroids were linked to a notable increase in bone degradation and collagen fiber exposure, more so than spheroids of just BMSCs or HNC cells. Furthermore, the EDX results highlighted increased nitrogen content on bone surfaces with these mixed clusters. Overall, the findings underscore the significant role of BMSCs in tumor growth, emphasizing the need for further exploration in potential cancer treatment strategies.

E3 ubiquitin ligase APC/CCdh1 regulates SLC35F2 protein turnover and inhibits cancer progression in HeLa cells

BackgroundThe solute carrier family 35 F2 (SLC35F2), belongs to membrane-bound carrier proteins that control various physiological functions and are activated in several cancers. However, the molecular mechanism regulating SLC35F2 protein turnover and its implication in cancer progression remains unexplored. Therefore, screening for E3 ligases that promote SLC35F2 protein degradation is essential during cancer progression. MethodsThe immunoprecipitation and Duolink proximity ligation assays (PLA) were used to determine the interaction between APC/CCdh1 and SLC35F2 proteins. A CRISPR/Cas9-mediated knockdown and rescue experiment were used to validate the functional significance of APC/CCdh1 on SLC35F2 protein stabilization. The ubiquitination function of APC/CCdh1 on SLC35F2 protein was validated using in vitro ubiquitination assay and half-life analysis. The role of APC/CCdh1 regulating SLC35F2-mediated tumorigenesis was confirmed by in vitro oncogenic experiments in HeLa cells. ResultsBased on the E3 ligase screen and in vitro biochemical experiments, we identified that APC/CCdh1 interacts with and reduces SLC35F2 protein level. APC/CCdh1 promotes SLC35F2 ubiquitination and decreases the half-life of SLC35F2 protein. On the other hand, the CRISPR/Cas9-mediated depletion of APC/CCdh1 increased SLC35F2 protein levels. The mRNA expression analysis revealed a negative correlation between APC/CCdh1 and SLC35F2 across a panel of cancer cell lines tested. Additionally, we demonstrated that depletion in APC/CCdh1 promotes SLC35F2-mediated cell proliferation, colony formation, migration, and invasion in HeLa cells. ConclusionOur study highlights that APC/CCdh1 is a critical regulator of SLC35F2 protein turnover and depletion of APC/CCdh1 promotes SLC35F2-mediated tumorigenesis. Thus, we envision that APC/CCdh1-SLC35F2 axis might be a therapeutic target in cancer.

Involvement of CXCL12/CXCR4 axis in colorectal cancer: a mini-review.

Migration of metastatic tumor cells is similar to the traffic of leukocytes and has been reported that can be guided by chemokines and their receptors, through the circulation to distant organs. The chemokine CXCL12 and its receptor CXCR4 play an essential role in hematopoietic stem cell homing and the activation of this axis supports malignant events. Binding of CXCL12 to CXCR4 activates signal transduction pathways, with broad effects on chemotaxis, cell proliferation, migration and gene expression. Thus, this axis serves as a bridge for tumor-stromal cell communication, creating a permissive microenvironment for tumor development, survival, angiogenesis and metastasis. Evidence suggests that this axis may be involved in the colorectal cancer (CRC) carcinogenesis. Therefore, we review emerging data and correlations between CXCL12/CXCR4 axis in CRC, the implications for cancer progression and possible therapeutic strategies that exploit this system.

Exosome-mediated crosstalk between tumor cells and innate immune cells: implications for cancer progression and therapeutic strategies.

The increasing number of cancer-associated deaths despite the substantial improvement in diagnosis and treatment has sparked discussions on the need for novel biomarkers and therapeutic strategies for cancer. Exosomes have become crucial players in tumor development and progression, largely due to the diverse nature of their cargo content released to recipient cells. Importantly, exosome-mediated crosstalk between tumor and stromal cells is essential in reprogramming the tumor microenvironment to facilitate tumor progression. As a result, exosomes have gradually become a marker for the early diagnosis of many diseases and an important tool in drug delivery systems. However, the precise mechanisms by which exosomes participate in tumor progression remain elusive, multifaceted, and a double-edged sword, thus requiring further clarification. The available evidence suggests that exosomes can facilitate communication between innate immune cells and tumor cells to either support or inhibit tumor progression. Herein, this review focused on exosome-mediated intercellular communication between tumor cells and macrophages, neutrophils, mast cells, monocytes, dendritic cells, and natural killer cells. Specifically, how such intercellular communication affects tumor progression has been described. It has also been discussed that, depending on their cargo, exosomes can suppress or promote tumor cell progression. In addition, the potential application of exosomes and strategies to target exosomes in cancer treatment has been comprehensively discussed.

Signal Transducer and Activator of Transcription 6 Changes and Protein Frustration by Single Amino Acid Substitutions: Implications for Cancer Progression.

Signal transducer and activator of transcription 6 (STAT6) is a multifunctional protein that plays critical functions in cell proliferation, apoptosis, differentiation, and angiogenesis. Mutations in STAT6 may contribute to the development of certain complex diseases such as cancer. This study examined single amino acid substitutions in STAT6 to pinpoint deleterious variants and their related structural and functional impairments. Data on STAT6 mutations were obtained from the Ensembl database and analyzed to evaluate the selected mutations for their pathogenicity and destabilizing or harmful effects. Specifically, we analyzed aggregation propensity, nonpacking density, and accessible surface area on the chosen mutations. The results suggest that seven out of eight mutations are less soluble, which might lead to aggregation, disrupt ordered helices, and alter strand propensity. Four mutations lay in the conserved regions of the protein, as revealed by the Consurf analysis. We found that three mutations, E318G, L365F, and R562H, change hydrophobic contacts and lead to frustration of STAT6, which can alter its stability, contributing to disease progression in cancer. In conclusion, these findings inform how single amino acid changes can destabilize STAT6. This has implications for cancer progression which warrants further experimental research.

Long noncoding RNAs induced control of ferroptosis: Implications in cancer progression and treatment.

A novel kind of nonapoptotic, iron-dependent cell death brought on by lipid peroxidation is known as ferroptosis. Numerous pathological processes, including neurotoxicity, neurological disorders, ischemia-reperfusion damage, and particularly cancer, have been demonstrated to be influenced by changes in the ferroptosis-regulating network. Recent studies have established the critical roles that ferroptosis can play in cancer development and the evolution of resistance to standard chemoradiotherapy, thus suggesting that ferroptosis may be a feasible therapeutic strategy for cancer management. Gene expression may be regulated at the transcriptional and posttranscriptional levels by long noncoding RNAs (lncRNAs). They have been implicated in tumorigenesis. Some lncRNAs participate in the biological process of ferroptosis, which represents an exciting alternative to regulate ferroptosis as a means of cancer therapy. Even though there is evidence that lncRNAs have a mechanistic role in the ferroptosis of cancer cells, research on the mechanism and potential treatments for these lncRNAs is still lacking. We elucidate the potential mechanisms by which lncRNAs modulate ferroptosis in cancer and examine the promise and challenges of employing lncRNAs as novel therapeutic targets in cancer.

Insomnia in Cancer Survivors

Abstract: Insomnia is among the most prevailing and distressing iatrogenic complaints reported by cancer survivors. Untreated insomnia negatively impacts survivors’ functioning, quality of life and health, and may have implications for cancer progression. Cognitive behavioral therapy is recommended as the first-line treatment for cancer-related insomnia but remains largely unavailable in European oncology care. For cancer survivors, it may be prudent to expand the scope of insomnia treatment. In this paper, we analyze the etiopathogenesis of insomnia among cancer populations and review the latest developments in cognitive behavioral therapeutics for cancer-related insomnia. Pondering upon the distinctive nature and pathophysiology of cancer-related insomnia, we discuss opportunities to optimize insomnia treatment in cancer care. We suggest adapting the content and format delivery of standard cognitive behavioral therapy for insomnia to meet the needs of cancer survivors and surmount resource availability. Digital therapeutics may provide cancer survivors who would otherwise be limited to pharmacologic treatment options with the guideline treatment for insomnia. Internet-delivered cognitive behavioral interventions may be integrated into survivorship care programs within healthcare systems.

The crosstalk between the gut microbiota and tumor immunity: Implications for cancer progression and treatment outcomes.

The gastrointestinal tract is inhabited by trillions of commensal microorganisms that constitute the gut microbiota. As a main metabolic organ, the gut microbiota has co-evolved in a symbiotic relationship with its host, contributing to physiological homeostasis. Recent advances have provided mechanistic insights into the dual role of the gut microbiota in cancer pathogenesis. Particularly, compelling evidence indicates that the gut microbiota exerts regulatory effects on the host immune system to fight against cancer development. Some microbiota-derived metabolites have been suggested as potential activators of antitumor immunity. On the contrary, the disequilibrium of intestinal microbial communities, a condition termed dysbiosis, can induce cancer development. The altered gut microbiota reprograms the hostile tumor microenvironment (TME), thus allowing cancer cells to avoid immunosurvelliance. Furthermore, the gut microbiota has been associated with the effects and complications of cancer therapy given its prominent immunoregulatory properties. Therapeutic measures that aim to manipulate the interplay between the gut microbiota and tumor immunity may bring new breakthroughs in cancer treatment. Herein, we provide a comprehensive update on the evidence for the implication of the gut microbiota in immune-oncology and discuss the fundamental mechanisms underlying the influence of intestinal microbial communities on systemic cancer therapy, in order to provide important clues toward improving treatment outcomes in cancer patients.