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Cells, the microscopic building blocks of the human body, operate like a sophisticated symphony orchestra, finely orchestrating numerous life processes. In this diminutive yet intricate world, ribosomes function as conductors, guiding the synthesis of proteins—the essential constituents of life. However, disruptions in ribosomal function are frequently linked to cellular dysfunction, intimately intertwining them with the onset and progression of various diseases.
Anomalies in cellular ribosomes have a close correlation with several diseases, including:
Diamond-Blackfan Anemia: A rare genetic disorder appearing in infancy, Diamond-Blackfan anemia is associated with mutations or defects in ribosomal proteins. These disruptions impede normal protein synthesis, leading to abnormal red blood cell development and resulting in anemia.
Cancer: The critical role of ribosomes in protein synthesis has spurred intense investigation into their relationship with cancer. Cancer cells often exhibit abnormalities in ribosomal function, such as heightened protein synthesis and aberrant expression of specific ribosomal proteins, potentially contributing to the rapid growth and division of cancer cells.
Multiple Myeloma: This cancer, characterized by abnormal proliferation of plasma cells in the bone marrow, may involve ribosomal abnormalities impacting normal cellular regulation and growth.
Given the association between ribosomal abnormalities and various diseases, a comprehensive understanding of ribosomal structure, function, and their roles in cells and diseases is imperative. Techniques for ribosomal analysis facilitate the identification of specific ribosomal changes associated with disease states, aiding in the discovery of potential biomarkers for early disease diagnosis and monitoring.
Current Techniques in Ribosomal Analysis
Ribosome RNA Sequencing: A high-throughput sequencing technique used to analyze the composition of ribosomal RNA. By determining the expression levels and modification states of ribosomal RNA, researchers can comprehend gene expression regulation in cells under different conditions.
Ribosomal Protein Mass Spectrometry: Mass spectrometry is employed to identify and quantify ribosomal proteins. Separating and digesting ribosomal proteins and analyzing the resulting peptide fragments using a mass spectrometer provide valuable information about ribosomal protein composition and function.
Cryo-Electron Microscopy (Cryo-EM): This technique provides high-resolution images of ribosomal structures, aiding scientists in gaining a deep understanding of the three-dimensional structure of ribosomes and their intricate regulation in protein synthesis.
Ribosome Profiling (Ribo-Seq): Also known as Ribo-Seq, this technique explores translational levels by measuring nucleotide fragments bound to ribosomes. Ribo-Seq primarily targets mRNA sequences protected by ribosomes during the translation process, distinguishing it from RNA-Seq, which sequences all mRNA in a given sample.
As pivotal contributors to cellular protein synthesis, ribosomal abnormalities are intricately linked to various diseases. Advanced ribosomal analysis techniques enable scientists to explore the composition and function of ribosomes, revealing their crucial roles in cell biology and disease occurrence. In-depth research in this field not only provides novel insights into fundamental science but also offers robust support for the future treatment and prevention of diseases.
Extracellular vesicles (EVs), particularly exosomes, represent a crucial subgroup in cellular communication. First proposed by Johnstone et al. in 1983 during the study of erythrocyte differentiation, exosomes were officially identified in 1987 through ultracentrifugation. These membrane-bound small bodies, released from cells through the fusion of multivesicular bodies with the cell membrane, range in diameter from 40 nm to 100 nm. Exosomes display diverse shapes, including flat or spherical bodies, some exhibiting a cup-shaped morphology, especially in bodily fluids where they predominantly appear as spherical entities.
Certain proteins overexpressed in tumor cells may also be found in exosomes, and their composition varies depending on the cell origin, expressing unique biological proteins. Tumor-derived exosomes (Tex) play a pivotal role in tumor development, carrying a significant amount of mRNA and microRNA (miRNA). Initially considered cellular waste "garbage bags," exosomes are actively secreted by immune cells, stem cells, and tumor cells under physiological and pathological conditions, facilitating the transport of biomolecules and contributing to tumor pathogenesis.
Exosomes possess distinct biological characteristics, including their small size, allowing evasion of mononuclear phagocytes and traversal of vascular barriers, making them prevalent in bodily fluids. Their phospholipid bilayer structure provides biological stability, rendering them resistant to degradation. Tumor cells secrete more exosomes than normal cells, exhibiting high heterogeneity in size and surface proteins, valuable for distinguishing between different tumors and normal cells.
Within the tumor microenvironment, exosomes play a critical role in cellular communication, influencing tumor initiation, development, metastasis, immune evasion, and drug resistance.
Exosomes for Plastic and Cosmetic
However, cancer therapy by exosomes not only plays a role in the functional research and diagnostic applications of major diseases such as malignant tumors but also garners attention in the field of medical aesthetics. Positioned as "anti-aging treasures" and a "revolutionary innovative technology," exosomes are considered the "fountain of youth" in beauty enhancement. Their applications extend beyond functional skincare to include anti-aging, regenerative repair, and addressing issues like skin aging, texture improvement, skin tone alteration, and hair loss.
The "2022-2040 Exosome Therapy Market Report" by Roots Analysis forecasts a 41% annual growth rate in the exosome therapy market. Exosome beauty therapy, utilizing exosomes rich in ribonucleic acid (RNA) and membrane proteins, involves topical application or skin introduction. Through exosome signaling and nutrient delivery, it regulates cells, promotes continuous regeneration, and improves skin beauty, with applications in anti-aging, whitening, sensitive repair, inflammation repair, and scar repair.
On the market, exosomes are available in three forms:
* Frozen exosomes: Primarily for laboratory research, unsuitable for large-scale production due to complex storage and application requirements.
* Freeze-dried powder exosomes: Susceptible to loss of activity due to changes in membrane structure during vacuum freezing.
* Vitalized exosomes: Suspended in a liquid matrix, maintaining structural integrity and activity at an optimal temperature of 37°C, suitable for storage, transportation, and use.
These forms are closely linked to upstream exosome analysis technologies, including isolation, purification, engineering, and manufacturing. Exosome analysis facilitates the discovery of new biomarkers, providing additional options for early disease diagnosis and treatment.
In cancer immunotherapy, the spotlight has fallen on STING as a pivotal target of recent interest. Biopharmaceutical companies worldwide are vigorously developing innovative therapies targeting STING with the goal of activating immune pathways to combat cancer cells.
While these STING agonists have demonstrated promise in preclinical studies, a perplexing phenomenon has emerged in certain clinical trials. Contrary to expectations, drugs designed to activate the STING pathway have not consistently yielded the desired benefits for advanced cancer patients. For instance, a Phase 1 clinical trial assessing STING agonists reported only one out of 47 patients with advanced or metastatic cancer displaying a definitive partial response. In another Phase 1 clinical trial involving a STING agonist co-administered with a PD-1 inhibitor, the overall remission rate for advanced cancer patients hovered around 10%.
So, what accounts for the unexpected outcomes of STING agonists in the fight against cancer? In their quest for answers, researchers at the Memorial Sloan Kettering Cancer Center, in collaboration with Weill Cornell Medicine, have uncovered a counterintuitive possibility—drugs inhibiting STING activation may prove more beneficial to patients with advanced cancer than STING activators.
This revelation hinges on the nature of the STING signaling pathway itself. Within the human body, the presence of double-stranded DNA molecules in the cytoplasmic matrix serves as an early warning signal, indicating the intrusion of pathogens, the existence of cancer cells, or cell rupture. Once intracellular sensors detect cytoplasmic DNA, they activate the STING protein, which, in turn, triggers the expression of inflammation-associated genes, igniting an innate immune response that shields the body from foreign invaders and abnormal cells—a pivotal process in anti-tumor immunity.
However, the new study suggests that cancer cells disrupt the STING signaling pathway, creating an immunosuppressive tumor microenvironment. Particularly in advanced cancer stages, where cancer cells exhibit high chromosomal instability, the STING pathway remains persistently active, leading to "desensitization." This, in turn, rewires the downstream signaling pathway, inducing endoplasmic reticulum stress—a favorable environment for cancer cell metastasis.
Dr. Samuel Bakhoum, co-corresponding author of the study, analogizes this phenomenon, "think of STING signaling as a car alarm. If it rarely sounds, the loud noise will grab your attention. But if it keeps going off, you become accustomed to it and tune it out."
To understand the interactions between cancer cells and immune cells in the tumor microenvironment, another co-corresponding author, Dr. Ashley Laughney, led the team in developing a specialized computational tool named "Contact Tracing". This tool predicts cell-cell interactions and assesses how ligand-receptor interactions influence signal-receiving cells based on single-cell sequencing data.
Dr. Laughney highlights a significant discovery, "one of our most crucial findings is that altering the degree of chromosomal instability or activating STING significantly changes the response within the tumor and its surroundings."
The researchers confirmed the link between chromosomal instability-driven cancer cell metastasis and STING signaling in mouse models implanted with various tumor cells, as well as in human healthy cells and tumor samples. These findings also open the door to innovative therapeutic concepts—for advanced cancer patients with chromosomal instability, activating STING may prove ineffective due to cellular desensitization". In such cases, inhibiting STING could be a promising alternative.
In experimental settings, the researchers administered STING inhibitors to mouse models of melanoma, breast cancer, and colorectal cancer, effectively reducing metastasis driven by chromosomal instability.
Additionally, these insights suggest that by identifying tumors still capable of robust responses to STING activation, clinicians can select patients who would genuinely benefit from STING agonist therapy.