International review of cell and molecular biology最新文献

Prostate cancer is the second most prevalent cancer in men globally. De novo neuroendocrine prostate cancer (NEPC) is uncommon at initial diagnosis, however, (treatment-induced) t-NEPC emerges in up to 25% of prostate adenocarcinoma (PRAD) cases treated with androgen deprivation, carrying a drastically poor prognosis. The transition from PRAD to t-NEPC is underpinned by several key genetic mutations; TP53, RB1, and MYCN are the main genes implicated, bearing similarities to other neuroendocrine tumours. A broad range of epigenetic alterations, such as aberrations in DNA methylation, histone post-translational modifications, and non-coding RNAs, may drive lineage plasticity from PRAD to t-NEPC. The clinical diagnosis of NEPC is hampered by a lack of accessible biomarkers; recent advances in liquid biopsy techniques assessing circulating tumour cells and ctDNA in NEPC suggest that the advent of non-invasive means of monitoring progression to NEPC is on the horizon. Such techniques are vital for NEPC management; diagnosis of t-NEPC is crucial for implementing effective treatment, and precision medicine will be integral to providing the best outcomes for patients.

The self-renewing cancer stem cells (CSCs) represent one of the distinct cell populations occurring in a tumour that can differentiate into multiple lineages. This group of sparsely abundant cells play a vital role in tumour survival and resistance to different treatments during cancer. The lack of exclusive markers associated with CSCs makes diagnosis and prognosis in cancer patients extremely difficult. This calls for the identification of unique regulators and markers for CSCs. Various signalling pathways like the Wnt/β-catenin pathway, Hedgehog pathway, Notch pathway, and TGFβ/BMP play a major role in the regulation and maintenance of CSCs. Epigenetic regulatory mechanisms add another layer of complexity to control these signalling pathways. In this chapter, we discuss about the role of epigenetic mechanisms in regulating the cellular signalling pathways in CSCs. The epigenetic regulatory mechanisms such as DNA methylation, histone modification and microRNAs can modulate the diverse effectors of signalling pathways and consequently the growth, differentiation and tumorigenicity of CSCs. In the end, we briefly discuss the therapeutic potential of targeting these epigenetic regulators and their target genes in CSCs.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, characterized by its aggressiveness and metastatic potential, with a 5-year survival rate of only 8-11%. Despite significant improvements in PDAC treatment and management, therapeutic alternatives are still limited. One of the main reasons is its high degree of intra- and inter-individual tumor heterogeneity which is established and maintained through a complex network of transcription factors and epigenetic regulators. Epigenetic drugs, have shown promising preclinical results in PDAC and are currently being evaluated in clinical trials both for their ability to sensitize cancer cells to cytotoxic drugs and to counteract the immunosuppressive characteristic of PDAC tumor microenvironment. In this review, we discuss the current status of epigenetic treatment strategies to overcome molecular and cellular PDAC heterogeneity in order to improve response to therapy.

Since the dawn of anticancer immunotherapy, the clinical use of immune checkpoint inhibitors (ICI) has increased exponentially. Monoclonal antibodies targeting CTLA-4 and the PD-1/PD-L1 interaction were first introduced for the treatment of patients with unresectable melanoma. In melanoma, ICI lead to durable regression in a significant number of patients and have thus been clinically approved as a first-line treatment of advanced disease. Over the past years an increasing number of regulatory approvals have been granted for the use of ICI in patients affected by a large range of distinct carcinomas. In retrospect surprisingly, it has been discovered that particularly successful chemotherapeutic treatments are able to trigger anticancer immune responses because they induce immunogenic cell death (ICD), hence killing cancer cells in a way that they elicit an immune response against tumor-associated antigens. Logically, preclinical studies as well as clinical trials are currently exploring the possibility to combine ICD inducers with ICI to obtain optimal therapeutic effects. Here, we provide a broad overview of current strategies for the implementation of combinatorial approaches involving ICD induction followed by ICI in anticancer therapy.

The immune system, a central player in maintaining homeostasis, emerges as a pivotal factor in the pathogenesis and progression of two seemingly disparate yet interconnected categories of diseases: autoimmunity and cancer. This chapter delves into the intricate and multifaceted role of the immune system, particularly T cells, in orchestrating responses that govern the delicate balance between immune surveillance and self-tolerance. T cells, pivotal immune system components, play a central role in both diseases. In autoimmunity, aberrant T cell activation drives damaging immune responses against normal tissues, while in cancer, T cells exhibit suppressed responses, allowing the growth of malignant tumors. Immune checkpoint receptors, example, initially explored in autoimmunity, now revolutionize cancer treatment via immune checkpoint blockade (ICB). Though effective in various tumors, ICB poses risks of immune-related adverse events (irAEs) akin to autoimmunity. This chapter underscores the importance of understanding tumor-associated antigens and their role in autoimmunity, immune checkpoint regulation, and their implications for both diseases. It also explores autoimmunity resulting from cancer immunotherapy and shared molecular pathways in solid tumors and autoimmune diseases, highlighting their interconnectedness at the molecular level. Additionally, it sheds light on common pathways and epigenetic features shared by autoimmunity and cancer, and the potential of repurposing drugs for therapeutic interventions. Delving deeper into these insights could unlock therapeutic strategies for both autoimmunity and cancer.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature and limited therapeutic options. The interplay between DNA damage response (DDR) mechanisms and the emergence of neoantigens represents a promising avenue for developing targeted immunotherapeutic strategies and vaccines for TNBC. The DDR is a complex network of cellular mechanisms designed to maintain genomic integrity. In TNBC, where genetic instability is a hallmark, dysregulation of DDR components plays a pivotal role in tumorigenesis and progression. This review explores the intricate relationship between DDR and neoantigens, shedding light on the potential vulnerabilities of TNBC cells. Neoantigens, arising from somatic mutations in cancer cells, represent unique antigens that can be recognized by the immune system. TNBC's propensity for genomic instability leads to an increased mutational burden, consequently yielding a rich repertoire of neoantigens. The convergence of DDR and neoantigens in TNBC offers a distinctive opportunity for immunotherapeutic targeting. Immunotherapy has revolutionized cancer treatment by harnessing the immune system to selectively target cancer cells. The unique immunogenicity conferred by DDR-related neoantigens in TNBC positions them as ideal targets for immunotherapeutic interventions. This review also explores various immunotherapeutic modalities, including immune checkpoint inhibitors (ICIs), adoptive cell therapies, and cancer vaccines, that leverage the DDR and neoantigen interplay to enhance anti-tumor immune responses. Moreover, the potential for developing vaccines targeting DDR-related neoantigens opens new frontiers in preventive and therapeutic strategies for TNBC. The rational design of vaccines tailored to the individual mutational landscape of TNBC holds promise for precision medicine approaches. In conclusion, the convergence of DDR and neoantigens in TNBC presents a compelling rationale for the development of innovative immunotherapies and vaccines. Understanding and targeting these interconnected processes may pave the way for personalized and effective interventions, offering new hope for patients grappling with the challenges posed by TNBCs.

Tumor formation is supported by metabolic reprogramming, characterized by increase nutrient uptake, glycolysis and glutaminolysis. The c-Myc proto-oncogene is a transcription factor, upregulated in most cancers and several reports showed the role of c-Myc in other metabolic pathways such as glucose, amino acid, and nucleotide metabolism. In this short report, we tried to summarize the existing takeaway points from studies conducted in different cancer types with respect to c-Myc and lipid and serine metabolism. Here, we report that c-Myc can activate both lipid and serine metabolism against the backdrop of tumor formation, and different therapies like aspirin and lomitapide target the links between c-Myc and metabolism to slow down tumor progression and invasion. We also report diverse upstream regulators that influence c-Myc in different cancers, and interestingly components of the lipid metabolism (like lipid phosphate phosphatase and leptin) and serine metabolism can also act upstream of c-Myc in certain occasions. Finally, we also summarize the existing knowledge on the involvement of epigenetic pathways and non-coding RNAs in regulating lipid and serine metabolism and c-Myc in tumor cells. Identification of non-coding factors and epigenetic mechanisms present a promising avenue of study that could empower researchers with novel anticancer treatment targeting c-Myc and lipid and serine metabolism pathways!

Advanced Glycation End-products (AGEs), with their prolonged half-life in the human body, are emerging as potent diagnostic indicators. Early intervention studies, focusing on AGE cross-link breakers, have shown encouraging results in heart failure patients, paving the way for disease progression monitoring and therapy effectiveness evaluation. AGEs are the byproducts of a non-enzymatic reaction where sugars interact with proteins, lipids, and nucleic acids. These compounds possess the power to alter numerous biological processes, ranging from disrupting molecular conformation and promoting cross-linking to modifying enzyme activity, reducing clearance, and impairing receptor recognition. The damage inflicted by AGEs through the stimulation of intracellular signaling pathways is associated with the onset of chronic diseases across various organ systems. This review consolidates the characteristics of AGEs and the challenges posed by their expression in diverse physiological and pathological states. Furthermore, it highlights the clinical relevance of AGEs and the latest research breakthroughs aimed at reducing AGE accumulation.

Breast cancer (BC) heterogeneity is a key trait of BC tumors with crucial implications on tumorigenesis, diagnosis, and therapeutic modalities. It is influenced by tumor intrinsic features and by the tumor microenvironment (TME) composition of different intra-tumoral regions, which in turn affect cancer progression within patients. In this mini review, we will highlight the mechanisms that generate cancer heterogeneity in BC and how they affect the responses to cancer therapies.

Cancer stem cells (CSCs) have emerged as prime players in the intricate landscape of cancer development, progression, and resistance to traditional treatments. These unique cellular subpopulations own the remarkable capability of self-renewal and differentiation, giving rise to the diverse cellular makeup of tumors and fostering their recurrence following conventional therapies. In the quest for developing more effective cancer therapeutics, the focus has now shifted toward targeting the signaling pathways that govern CSCs behavior. This chapter underscores the significance of these signaling pathways in CSC biology and their potential as pivotal targets for the development of novel chemotherapy approaches. We delve into several key signaling pathways essential for maintaining the defining characteristics of CSCs, including the Wnt, Hedgehog, Notch, JAK-STAT, NF-κB pathways, among others, shedding light on their potential crosstalk. Furthermore, we highlight the latest advancements in CSC-targeted therapies, spanning from promising preclinical models to ongoing clinical trials. A comprehensive understanding of the intricate molecular aspects of CSC signaling pathways and their manipulation holds the prospective to revolutionize cancer treatment paradigms. This, in turn, could lead to more efficacious and personalized therapies with the ultimate goal of eradicating CSCs and enhancing overall patient outcomes. The exploration of CSC signaling pathways represents a key step towards a brighter future in the battle against cancer.