International review of cell and molecular biology最新文献

While the function of αβ T cells in host defense is quite well understood, insight into the role that γδ T cells play in health and disease has lagged behind, despite their discovery approximately forty years ago. Because γδ T cells represent a relatively small population in immune organs, their importance in host defense was previously questioned, which dampened research interest in γδ T cells, even among immunologists. Fortunately, there has been a relatively recent surge in interest in γδ T cells, which has revealed that they do in fact play a central role in human health and disease. They perform diverse functions that impact tissue homeostasis and integrity in addition to their role in pathogen resistance, which positions them at the interface between the innate and adaptive arms of the immune system. Here, we review the progress in understanding how γδ T cells can both promote health and cause disease, and how they are being exploited as a new and perhaps more effective weapon in the treatment of cancer.

Metastasis is a lethal disease of cancer, spreading from primary tumors to the bloodstream as circulating tumor cells (CTCs), which disseminate to distant organs at low efficiency for secondary tumor regeneration, thereby contributing to unfavorable patient outcomes. The detection of dynamic CTC alterations can be indicative of cancer progression (residual cancer, aggressiveness, therapy resistance) or regression (therapy response), serving as biomarkers for diagnoses and prognoses. CTC heterogeneity is impacted by both intrinsic oncogenic changes and extrinsic microenvironmental factors (e.g. the immune system and circadian rhythm), altering the genomic/genetic, epigenomic/epigenetic, proteomic, post-translational, and metabolomic landscapes. In addition to homeostatic dynamics, regenerative stemness, and metabolic plasticity, a newly discovered feature of CTCs that influences metastatic outcomes is its intercellular clustering. While the dogma suggests that CTCs play solo as single cells in the circulation, CTCs can orchestrate with other CTCs or white blood cells to form homotypic or heterotypic multi-cellular clusters, with 20-100 times enhanced metastatic potential than single CTCs. CTC clusters promote cell survival and stemness through DNA hypomethylation and signaling pathways activated by clustering-driving proteins (CD44, CD81, ICAM1, Podocalyxin, etc). Heterotypic CTC clusters may protect CTCs from immune cell attacks if not being cleared by cytotoxic immune cells. This chapter mainly focused on CTC biology related to multi-omic features and metastatic outcomes. We speculate that CTCs could guide therapeutic targeting and be targeted specifically by anti-CTC therapeutics to reduce or eliminate cancer and cancer metastasis.

Previously regarded solely as a digestive entity, the human gut has been revealed to harbor a rich diversity of microbial flora, pivotal in maintaining overall health and organ functionality. Contrary to conventional wisdom, certain microbes confer notable benefits rather than posing threats. The gut microbiota, consisting of Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, plays a crucial role in health maintenance, and dysbiosis can precipitate disease onset. Autoimmune disorders stem from immune system dysregulation, resulting in self-cell attacks. Recent microbiome research underscores a correlation between altered gut microbiota and autoimmune diseases. This chapter delves into the impact of the gut microbiome in autoimmune diseases and presents gut microbiome targeting therapy as a possible treatment alternative.

In preclinical studies, bioactive phytochemicals have shown enormous potential therapeutic efficacy against various human malignancies. These natural compounds have been shown to possess an inherent potential to alter the molecular signaling pathways and epigenetic modulatory activity involved in multiple physiological functions. Recently, epigenetic therapy has emerged as an important therapeutic modality due to the reversible nature of epigenetic alterations. To date, epigenetic modulatory compounds, for example, DNA methyltransferase inhibitors 5-azacytidine and 5'-deoxyazacytidine, as well as histone deacetylase inhibitors Vorinostat, Romidepsin, and Belinostat (PXD101), have been clinically approved by the FDA for the treatment of patients of leukemia and myelodysplastic syndrome. However, these synthetic epigenetic inhibitors are not as effective against many of the solid tumors. Therefore, the epigenetic modulatory phytochemicals provide new hope for improving the treatment modality as neoadjuvant and adjuvant therapy. It has been established that targeting more than one protein in the transformed cells simultaneously, that is, the multi-targeted therapeutic approach, might invoke a better therapeutic response. Therefore, here, we are compiling diverse evidences of the translational potential of novel combinatorial approaches utilizing the epigenetic modulatory phytochemicals with available therapeutics in the course of cancer treatment.

Virtually every cell in the human body contains a molecular circadian clock that orchestrates the rhythmic oscillations of a multitude of tissue-specific functions. This is evident in the heart, where circadian rhythms are seen in various cardiac functions. Genetic disruption of clock genes has underscored their significance in regulating multiple aspects of cardiac physiology. In this review, we report the principal findings regarding the impact of clock gene manipulation (whole body or cardiomyocyte specific) on cardiac function. Furthermore, we present the current knowledge on the circadian clock in the different cell populations in the heart-cardiomyocytes, endothelial cells, fibroblasts, and immune cells. While increasing studies have shown mechanistic links between core clock components and cardiomyocytes-specific genes, the information of clock function within other cardiac cells in the heart is extremely limited. This review underlines the need to gain more information on the temporal segregation of clock processes in cardiac-especially in non-cardiomyocytes-cells, as clock-controlled mechanism may be target of chronotherapy to optimize current treatments for cardiovascular diseases.

During cancer metastasis, tumor cells migrate from the primary tumor site and spread to distant tissue or organs through the circulatory system of the body. While it is challenging to track metastatic tumor cells, circulating tumor cells (CTCs) via liquid biopsy provide a unique and important opportunity for longitudinal monitoring of residual cancer diseases and progression, showing great potential to facilitate precision medicine in cancer patients. The enumeration and characterization of CTCs represent prognostic and predictive biomarkers, which can be used to monitor the response to and efficacy of various therapies. Along with molecular and cellular features of CTCs, this data can inform the detection of early micro-metastases and assess progression of advanced disease in a more sensitive manner than traditional imaging modalities, serving as a complementary approach with added value. Nevertheless, comprehensive multiomic analyses of CTCs at inter-cellular (cluster), single-cell, and subcellular levels to elucidate relevant CTC cancer biology, tumor immune ecosystem biology, and clinical outcomes have yet to be achieved, demanding multidisciplinary collaboration to advance the field. Complementary to the published chapter on multiomic analyses and functional properties of CTCs, this chapter summarizes key methods and integrated strategies in CTC isolation, highlighting an accelerated evolution in high-throughput analysis of CTCs.

Multiple innovative molecular techniques have established compelling connections between the gut microbiome and cancers. Studies have also revealed that the microbiome and microbiome-specific metabolites can significantly influence cancer treatments like chemotherapy, radiotherapy, and immunotherapy. Advancements in cancer immunotherapy driven by a targeted immune system approach have considerably improved the treatment landscape in cancer. However, the full potential of tumor immunotherapy remains to be explored, and many challenges need to be addressed. This review provides a summary of the current evidence regarding the presence of microbiota and how it can impact the response to Food and Drug Administration (FDA) approved cancer immunotherapies, such as immune checkpoint inhibitors (ICIs) or chimeric antigen receptor T (CAR-T) cell therapy. Additionally, it addresses the challenges and limitations of gut microbiome and cancer immunotherapy.

Nectin cell adhesion protein 4 (Nectin-4), a calcium-independent immunoglobulin-like protein, has garnered significant attention in oncology due to its pronounced overexpression in malignant tumors and absence in healthy adult tissues. Elevated levels of Nectin-4 have been implicated in the pathogenesis of various cancers, including lung, breast, and urothelial carcinomas. Notably, Nectin-4 has emerged as a promising serological marker for these malignancies, facilitating early diagnosis and monitoring of disease progression. The clinical relevance of Nectin-4 is underscored by the Food and Drug Administration's approval of enfortumab vedotin (EV), the first antibody-drug conjugate targeting this protein, for the treatment of urothelial carcinoma. Ongoing clinical trials are expanding the therapeutic applications of EV, highlighting the critical role of Nectin-4 in targeted cancer therapy. Furthermore, novel therapeutic agents targeting Nectin-4 are under investigation, offering potential new avenues for cancer treatment. Despite these advancements, the precise molecular mechanisms by which Nectin-4 influences carcinogenesis and tumor progression remain inadequately understood. Challenges such as therapy-related adverse effects and the development of drug resistance further complicate the clinical management of Nectin-4-associated cancers. This review investigates the molecular functions of Nectin-4, emphasizing its diagnostic and prognostic value in cancer. We also explore the landscape of novel drug discoveries targeting Nectin-4 and provide an overview of current clinical trials aimed at utilizing this marker for therapeutic interventions. By elucidating the multifaceted role of Nectin-4 in malignancies, this article aims to advance our understanding and improve the clinical outcomes for patients with Nectin-4 overexpressing tumors.

Renal cell carcinoma (RCC) and Bladder cancer (BC) are two lethal urological cancers that require diagnosis at their earliest stage causing decreasing survival rates in case of aggressive disease. However, there is no reliable circulating marker in blood or urine for their less or non-invasive diagnosis. Our objective was to review the potential circulating biomarkers, namely proteins, micro-RNA (miRNA), long non-coding RNA (lncRNA), and circulating tumour cells (CTCs) for which we performed a PubMed-based literature search of biomolecules (protein, miRNA, lncRNA and CTCs) found as circulating biomarkers in blood and urine for the early detection of RCC and BC. Among the numerous studies, certain biomolecules represent promising early-stage biomarkers such as proteins (NNMT, LCP1, and NM23A; KIM1), mi-RNAs (5-panel: miR-193a-3p, miR-362, miR-572, miR-378, and miR-28-5p; miR-200a) and lncRNAs (5-panel: LET, PVT1, PANDAR, PTENP1 and linc00963; GIHCG) for RCC. Similarly, proteins (APOA1), miRNAs (7-panel: miR-7-5p, miR-22-3p, miR-29a-3p, miR-126-5p, miR- 200a-3p, miR-375, and miR-423-5p; miRNA 181a, miRNA 30c, and miRNA 570) and lncRNAs (3-panel: MALAT1, MEG3, and SNHG16; exosomal derived 3-panel: PCAT-1, UBC1 and SNHG16; H19) were reported in BC subjects. Notably, the majority of the biomarkers presented for early detection in RCC cases were found in blood, while in urine for BC. Our results reveal that though a plethora of circulating biomarkers show early diagnostic ability, all of them are still bench-only biomarkers and require further validation. Adequate clinical trials/studies testing which of these potential markers individually or in combination, will become clinically applicable still remain elusive.

Multiple myeloma (MM) is a complex hematologic malignancy characterized by the abnormal proliferation of plasma cells in the bone marrow, leading to significant clinical challenges and a high burden of morbidity and mortality. Interleukin 10 (IL-10), a cytokine with potent anti-inflammatory properties, has emerged as a critical player in the pathobiology of MM. This work delves into the multifaceted role of IL-10 in MM, exploring its contributions to tumor growth, immune evasion, and drug resistance. Here, we examine IL-10's interactions with various immune cells within the bone marrow microenvironment and its potential as a circulatory biomarker for MM. Furthermore, we particularly lay emphasis on the prognostic and diagnostic implications of IL-10 levels in MM patients and evaluate the therapeutic prospects of targeting IL-10 in MM treatment regimens. By synthesizing current research, this review aims to enhance the understanding of IL-10 as a circulatory biomarker in MM and to highlight novel avenues for therapeutic intervention, thereby translating to improved clinical outcomes for MM patient.