Clinical and translational discovery最新文献

Cancer stem cells (CSCs) are a small subset of tumor cells, efficient in self-renewal within the tumor and also play a vital role in cancer resistance and metastasis. Recent cancer research has focused on exosomes, a tiny subpopulation of extracellular vesicles (EVs), known for their role in intercellular communication, and significantly contributing to tumor development and metastasis (Tumor derived exosomes-TEXs). These exosomes complicate cancer treatment by promoting tumor and CSC formation and developing drug and therapeutic resistance. This article explores how tumor-derived exosomes impact CSC survival, proliferation, and resistance to therapies, leading to tumor recurrence. In a tumor microenvironment (TME), exosomes facilitate tumor growth and metastasis. Targeting exosomes could disrupt CSC communication and improve cancer treatment efficacy. Current studies highlight the role of CSCs exosomes in cancer progression and therapeutic resistance. Understanding CSCs exosome-based cell-to-cell communication in tumor opens a new horizon in cancer therapeutics development.

Exosomes, are a subpopulation of extracellular vesicles, that originate from endosomes. The major role of exosomes is cellular communication (in this process exosomes display the status of the parental cell's nature, healthy or the cell suffers any pathological complication). In recent decades, research evidence highlighted that exosomes are the masterminds of cancer development and they appear as smart solutions for early diagnosis, prognosis and therapeutic (eg. stem cell, plant and immune cell-derived exosomes) approaches. Exosomes transform the cancer liquid biopsy into a new orientation. Several biofluids (blood, plasma, serum, saliva, urine, CSF (Cerebrospinal Fluid) and cancer tissue are used for exosome-based cancer biomarkers detection. Liquid biopsy becomes more efficient for exosomes, compared to tissue biopsy. Exosomes biocompatibility, low toxicity, and ability to cross biological membranes make it a potential tool for cancer therapeutic development. Exosome-based cancer therapeutics introduce a cutting-edge era of cell-free cancer therapy. This article explores the critical role of exosomes in cancer development, progression, treatment, and clinical trials. Exosome-based clinical trials indicate that we are close to cancer precision medicine.

Human Immunodeficiency Virus (HIV) significantly increases the risk of various cancers due to chronic immune suppression and viral oncogenes. Traditional therapies, including antiretroviral therapy (ART), chemotherapy, and radiation, often face limitations such as drug resistance and systemic toxicity. PROteolysis TArgeting Chimeras (PROTACs) have emerged as a promising approach for targeted protein degradation, offering significant advantages over conventional treatments. However, effective delivery remains a challenge. This paper explores the innovative use of tear exosome-based delivery systems for PROTACs in treating HIV-mediated cancers. Tear exosomes, due to their natural origin, biocompatibility, and inherent targeting capabilities, present a novel and effective platform for delivering PROTACs, enhancing therapeutic specificity and reducing adverse effects. Integrating the unique properties of tear exosomes with the therapeutic potential of PROTACs could revolutionize the treatment of HIV-mediated cancers by overcoming current therapeutic challenges and improving patient outcomes.

Human papillomavirus (HPV) is a significant aetiological agent in cervical cancer, leading to a considerable burden of disease worldwide.¹ The persistence of high-risk HPV types results in the expression of oncoproteins E6 and E7, which disrupt key tumour suppressor pathways.² Traditional treatment modalities for cervical cancer, such as surgery, chemotherapy and radiation, often come with substantial side effects and limitations.³ Emerging therapies, including exosome-based delivery systems and Proteolysis Targeting Chimeras (PROTACs), offer promising new avenues for targeted molecular medicine.^4-6 Exosomes, in particular, have garnered attention due to their natural biocompatibility, ability to target specific cells and capacity to protect therapeutic cargo from degradation, making them an ideal vehicle for PROTAC delivery.^{7, 8}

Exosomes are small extracellular vesicles (30–150 nm) secreted by various cell types into bodily fluids such as blood, urine and saliva.⁹ These vesicles are formed through the inward budding of the endosomal membrane, creating multivesicular bodies that fuse with the plasma membrane to release exosomes into the extracellular environment. Exosomes carry a diverse array of biomolecules, including proteins, lipids and RNAs, reflective of their cell of origin.¹⁰ This intrinsic characteristic enables exosomes to act as natural delivery vehicles for therapeutic agents. Furthermore, exosomes exhibit low immunogenicity and can be engineered to display specific ligands on their surface, facilitating targeted delivery to particular cell types, such as HPV-infected or cervical cancer cells.

PROTACs represent a novel class of therapeutic agents designed to induce the degradation of specific target proteins by harnessing the cellular ubiquitin-proteasome system. A PROTAC molecule consists of two ligands connected by a linker: one ligand binds to the target protein, while the other recruits an E3 ubiquitin ligase. This proximity leads to the ubiquitination and subsequent proteasomal degradation of the target protein.^{10, 11} PROTACs offer several advantages over traditional small molecule inhibitors, including the ability to target proteins previously considered ‘undruggable,’ a reduced likelihood of drug resistance, and the potential for complete elimination of pathogenic proteins. In the context of HPV-mediated cervical cancer, PROTACs can be designed to specifically degrade the E6 and E7 oncoproteins, thereby restoring normal cell cycle control and promoting apoptosis of cancer cells.

Combining exosomes with PROTAC technology offers a synergistic approach to treating HPV-mediated cervical cancer. Exosomes can be engineered to carry PROTACs directly to the cancer cells, ensuring targeted delivery and minimising off-target eff

Cancers that can manifest in the oral cavity, nasal cavity, larynx, pharynx, sinuses, and other head and neck areas are collectively called “head and neck cancers” (HNC). HNC can be broadly classified into five types: salivary gland; oral and oropharyngeal; nasal cavity and paranasal sinus; nasopharyngeal, and laryngeal and hypopharyngeal cancers. HNC accounts for one million new diagnoses annually, making it the seventh most common form of the disease globally. Among all HNCs, 90% are head and neck squamous cell carcinoma (HNSCC) which is highly heterogenous, relapsing, and metastatic with poor survival. Despite the availability of new treatments, the five-year survival rate for HNSCC patients has been reported to be approximately 50%. An early diagnosis may increase the disease management and outcomes, but it is challenging to detect smaller-sized lesions and differentiate malignant and non-malignant lesions with the available tools. Current circumstances demand an improvement in existing diagnostic strategies and the advent of novel diagnostic tools.

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable global challenge, with a grim prognosis and limited treatment options.¹ Prior to the advent of molecular targeted therapies, patients with PDAC typically received chemotherapy and surgical resection, with limited efficacies.² Genetic analyses have revealed that KRAS mutation importantly drives the pathogenesis of PDAC, prompting an increasing number of investigations into the potential of targeted therapies addressing this genetic alteration.^{3, 4} Recent advances in molecular targeted therapies, in particular Cyclin Dependent Kinase inhibitors, have shown promise in preclinical studies.^{5, 6}

The recent study by Huang et al.⁷ presented a compelling application for the targeted agent THZ1, a small-molecule covalent CDK7/12/13 inhibitor, and provided intriguing insights into its efficacy. THZ1 demonstrated differential inhibitory effects based on specific KRAS mutant subtypes and showed selective efficacy against PDAC harbouring the KRAS-G12V mutation compared to cancer with the KRAS-G12D mutation.

Huang et al.’s study⁷ employed a combination of in vitro and in vivo models to demonstrate that THZ1 was more effective in inhibiting KRAS-G12V PDAC. The importance of the PI3K/AKT/mTOR signalling pathway in KRAS mutation-driven pancreatic cancer has been previously highlighted.⁸ A previous study⁹ showed that in Ewing sarcoma, THZ1 reduced the phosphorylation of RNA polymerase II (RNAPOLII) by inhibiting CDK7 activity, which attenuated transcriptional activity, and that THZ1 inhibited the PI3K/AKT/mTOR signalling pathway by affecting the binding of H3K27ac to PIK3CA, which encodes the catalytic subunit of PI3K.

The present study⁷ further explored how THZ1 differentially inhibited PDAC cells by affecting this pathway: THZ1 inhibited KRAS-G12V PDAC cells through the inhibition of RNAPOLII phosphorylation, PIK3CA activity, and AKT and mTOR phosphorylation, with enhanced PTEN expression, thus weakening the proliferation of cancer cells. This specificity represents a significant advance, as it paves the way for personalized management of PDAC.

The study⁷ discovered that the discrepancies in the sensitivity of different PDAC subtypes to THZ1 were related to the differential effects of THZ1 on the activity of super-enhancers (SEs). THZ1 significantly inhibited the activity of SEs marked by H3K27ac, which bound to PIK3CA, in PDAC cells with the KRAS-G12V mutation, whereas it had a minor effect on SEs in cells with the KRAS-G12D mutation.

Huang et al.’s study⁷ is of particular interest, given the critical role of KRAS mutatio

Heart failure is the final symptom of most cardiovascular diseases with a poor prognosis and remains a major cause of death in the United States for 100 years. Myocardial fibrosis (MF), which occurs during the evolution of heart failure, is associated with almost all forms of heart disease. MF is specified by the excessive accumulation or deposition of extracellular matrix (ECM), such as fibrillar collagen, in the myocardial tissue cells, consequently resulting in increased matrix stiffness and abnormalities in normal heart function. Cardiac fibroblast is the primary cell type responsible for the deposition of ECM in the heart, regulating the proliferation of cardiomyocytes, and maintaining the integrity of the matrix network.^1-3 Certain pathological conditions cause fibroblast activation and collagen secretion, eventually leading to cardiac fibrosis.^{3, 4} However, the underlying molecular and cellular mechanisms of cardiac remodelling and dysfunction in heart failure still require further research.

The heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), a member of the hnRNP family, is a nuclear m⁶A reader recognizing m⁶A modification in a subset of primary microRNAs (pri-miRNAs).⁵ The hnRNPA2B1 interacts with DiGeorge syndrome critical region 8 (DGCR8), an essential component of the pri-miRNA processing complex, and mediates the processing of pri-miRNAs containing m⁶A modification.⁵ In the acute myocardial infarction and MF, m⁶A regulators including hnRNPA2B1 are highly upregulated, and the dysregulated m⁶A signalling is significantly associated with the infiltration of immune cells, suggesting the role of m⁶A in the development of cardiovascular disease.⁶ The recent investigation led by Li et al. demonstrated that hnRNPA2B1, a key regulator of MF, regulates the miR-221-3p/Foxo4-mediated inflammatory response and the proliferation of cardiac fibroblasts.⁷ This study group found that hnRNPA2B1 is also upregulated in MF in an isoproterenol (ISO)-induced model and ISO-treated primary cardiac fibroblasts. The deletion of hnRNPA2B1 significantly diminished the ISO-induced inflammatory infiltration and collagen deposition as well as the cardiac fibroblast proliferation and activation. Furthermore, they found hnRNPA2B1-regulated miRNAs (miR-210, miR-99b and miR-221) in MF. More importantly, they demonstrated that Foxo4, one of the widely expressed forkhead box (Fox) transcription factor O family members, is a target of miR-221-3p of hnRNPA2B1 and hnRNPA2B1/miR-221-3p/Foxo4 axis regulates inflammatory response and myofibroblast activation in the development of MF.

In conclusion, elucidating the role of hnRNPA2B1 as a key regulator of cardiac fibrosis is crucial to demonstrate a new molecular mechanism regulating inflammatory