Experientia supplementum (2012)最新文献

The whole human genome sequence analysis has identified a large proportion of transcripts that lack protein-encoding function known as noncoding RNAs (ncRNAs). Long ncRNAs (lncRNAs) are transcripts consisting of more than 200 nucleotides. LncRNAs are identified as key regulators for diverse biological processes, including gene expressions, epigenetic modulations, transcriptional and translational regulation. LncRNAs-based mechanisms control gene activation, and cellular processes, while the dysregulated lncRNAs are associated with various disorders, including cancer. Moreover, lncRNAs have potential in diagnosis and prognosis of cancer. Several lncRNAs contribute to cancer development, metastatic cascade, and their molecular regulations in cancer development. The aberrant expression of lncRNAs regulates tumorigenesis, proliferation, metastasis, cancer stage, tumor size, and overall survival rates. Several lncRNAs are highly expressed or downregulated in several human tumors, behaving as oncogenes or tumor suppressors, respectively. The unique expression level of oncogenic lncRNAs provides a possibility to utilize them as a promising predictive biomarker of cancer.

Our current knowledge of the translational mechanisms and the detailed structural insights of its components have highlighted the characteristically exclusive role of tRNAs and aminoacyl-tRNA synthetase diversity in the evolution of the genetic codes. Phenomenal advancements in mass spectrometry and high-throughput sequencing have enabled the researchers in developing a better understanding of the complex landscape of tRNA modifications. Emerging evidence has started to shed light on linchpin role of tRNAs in carcinogenesis and metastatic dissemination. In this chapter, we have provided an overview of the role of tRNAs, aminoacyl-tRNA synthetases, and tRNA-derived small RNAs in the onset and progression of cancer.

The complex interplay between solute carrier (SLC) transporters and noncoding RNAs (ncRNAs) in regulating genetic and metabolic pathways in hematological disorders remains underexplored. This chapter addresses the critical need to understand how these regulators influence the development, progression, and therapeutic resistance of leukemia. By elucidating these mechanisms, this chapter aims to contribute to the development of novel, targeted interventions for improved clinical outcomes. This chapter delves into the multifaceted roles of SLC transporters and ncRNAs in blood cell regulation, highlighting their impact on hematopoiesis and leukemogenesis. Topics include the hierarchical differentiation of hematopoietic stem cells, the molecular subtypes of leukemia, and the regulatory roles of transcription factors and chromatin modifiers in leukemia progression. Additionally, this chapter explores how SLC transporters mediate nutrient uptake, drug resistance, and metabolic adaptations in leukemic cells. It further examines the involvement of ncRNAs-such as microRNAs, long noncoding RNAs, and circular RNAs-in modulating transporter activity, impacting both normal and malignant hematopoietic processes. Through these discussions, this chapter offers critical insights into the therapeutic potential of targeting SLC transporters and ncRNAs in leukemia treatment. It underscores the importance of understanding the genetic and epigenetic landscapes of blood disorders to develop precision medicine approaches. By integrating recent advancements and highlighting gaps in knowledge, this chapter provides a foundation for future research aimed at overcoming the challenges of multidrug resistance and enhancing treatment efficacy in hematological malignancies.

The research on noncoding RNAs has come a long way since the realization that these RNA molecules hold a lot of promise, particularly in terms of diagnosis, prognosis, and perhaps treatment of several human diseases. A number of noncoding RNAs, ranging from linear microRNAs and long-noncoding RNAs to circular RNAs, and several others are now under investigation. A logical way forward is the testing of these noncoding RNAs to bring them from bench to diagnostic laboratories, clinics, and bedside. However, the transition has not been very smooth, and even challenging at times, because of the unique nature of these biological molecules and the expertise and fine technologies needed to evaluate them, along with the refinement of methodologies to deliver them as therapeutics. This chapter specifically focuses on the associated challenges, such as expression/detection, target validation, immunogenicity, and delivery, that are hampering the utilization of noncoding RNAs in clinics.

As obligate intracellular parasites with reduced genomes, microsporidia must infect host cells in order to replicate and cause disease. They can initiate infection by utilizing a harpoon-like invasion organelle called the polar tube (PT). The PT is both visually and functionally a striking organelle and is a characteristic feature of the microsporidian phylum. Outside the host, microsporidia exist as transmissible, single-celled spores. Inside each spore, the PT is arranged as a tight coil. Upon germination, the PT undergoes a large conformational change into a long, linear tube and acts as a tunnel for the delivery of infectious cargo from the spore to a host cell. The firing process is extremely rapid, occurring on a millisecond timescale, and the emergent tube may be as long as 20 times the size of the spore body. In this chapter, we discuss what is known about the structure of the PT, the mechanics of the PT firing process, and how it enables movement of material from the spore body.

The understanding of how normal cells transform into tumor cells and progress to invasive cancer and metastases continues to evolve. The tumor mass is comprised of a heterogeneous population of cells that include recruited host immune cells, stromal cells, matrix components, and endothelial cells. This tumor microenvironment plays a fundamental role in the acquisition of hallmark traits, and has been the intense focus of current research. A key regulatory mechanism triggered by these tumor-stroma interactions includes processes that resemble epithelial-mesenchymal transition, a physiologic program that allows a polarized epithelial cell to undergo biochemical and cellular changes and adopt mesenchymal cell characteristics. These cellular adaptations facilitate enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components. Indeed, it has been postulated that cancer cells undergo epithelial-mesenchymal transition to invade and metastasize.In the following discussion, the physiology of chronic inflammation, wound healing, fibrosis, and tumor invasion will be explored. The key regulatory cytokines, transforming growth factor β and osteopontin, and their roles in cancer metastasis will be highlighted.

Emphasizing the dynamic processes between cancer and host immune system, the initially discovered concept of cancer immunosurveillance has been replaced by the current concept of cancer immunoediting consisting of three phases: elimination, equilibrium, and escape. Solid tumors composed of both cancer and host stromal cells are an example how the three phases of cancer immunoediting functionally evolve and how tumor shaped by the host immune system gets finally resistant phenotype. The elimination, equilibrium, and escape have been described in this chapter in details, including the role of immune surveillance, cancer dormancy, disruption of the antigen-presenting machinery, tumor-infiltrating immune cells, resistance to apoptosis, as well as the function of tumor stroma, microvesicles, exosomes, and inflammation.

Tumor microenvironment (TME) is a dynamic network that apart from tumor cells includes also cells of the immune system, e.g., neutrophils, which are recruited from blood circulation. In TME, neutrophils are strongly implicated in the direct and indirect interactions with tumor cells or other immune cells, and they play roles in both preventing and/or facilitating tumor progression and metastasis. The dual role of neutrophils is determined by their high plasticity and heterogeneity. Analogous to the macrophages, neutrophils can express antitumoral (N1) and protumoral (N2) phenotypes which differ substantially in morphology and function. N1 phenotype characterizes with a high cytotoxic and proinflammatory activities, while N2 phenotype with immunosuppressive and prometastatic properties. The antitumoral effect of neutrophils includes for example the production of reactive oxygen species or proapoptotic molecules. The protumoral action of neutrophils relies on releasing of proangiogenic and prometastatic mediators, immunosuppressive factors, as well as on direct helping tumor cells in extravasation process. This chapter summarizes the heterogeneity of neutrophils in TME, as well as their dual role on tumor cells.

Cancer stem cells are a population of cells enable to reproduce the original phenotype of the tumor and capable to self-renewal, which is crucial for tumor proliferation, differentiation, recurrence, and metastasis, as well as chemoresistance. Therefore, the cancer stem cells (CSCs) have become one of the main targets for anticancer therapy and many ongoing clinical trials test anti-CSCs efficacy of plenty of drugs. This chapter describes CSCs starting from general description of this cell population, through CSCs markers, signaling pathways, genetic and epigenetic regulation, role of epithelial-mesenchymal transition (EMT) transition and autophagy, cooperation with microenvironment (CSCs niche), and finally role of CSCs in escaping host immunosurveillance against cancer.

As an important part of the immune system, T lymphocytes exhibit undoubtedly an important role in targeting and eradicating cancer. However, despite these characteristics, their natural antitumor response may be insufficient. Numerous clinical trials in terminally ill cancer patients testing the design of novel and efficient immunotherapeutic approaches based on the adoptive transfer of autologous tumor-specific T lymphocytes have shown encouraging results. Moreover, this also led to the approval of engineered T-cell therapies in patients. Herein, we will expand on the development and the use of such strategies using tumor-infiltrating lymphocytes or genetically engineered T-cells. We will also comment on the requirements and potential hurdles encountered when elaborating and implementing such treatments as well as the exciting prospects for this kind of emerging personalized medicine therapy.