Biomarker Research最新文献

Background: Claudin-3 (CLDN3) participates in the formation of the tight-junctions (TJs) that regulate intercellular permeability. Altered CLDN3 expression has been linked to tumor progression in multiple tumor types. Despite its widespread expression in normal epithelial cells, CLDN3 is considered an attractive drug target candidate, since it may be more accessible in cancer cells than in normal cells due to their less orchestrated cell growth.

Methods: To comprehensively determine the prevalence of CLDN3 expression in cancer, a tissue microarray containing 14,966 samples from 133 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry.

Results: CLDN3 immunostaining was observed in 8,479 (68.9%) of 12,314 analyzable tumors, including 11.6% with weak, 6.2% with moderate, and 51.1% with strong positivity. CLDN3 staining was found in 96 of 133 tumor categories, 80 of which contained at least one strongly positive case. CLDN3 positivity was most seen in neuroendocrine neoplasms (92-100%) and in adenocarcinomas (67-100%), tumors of the female genital tract, including various subtypes of ovarian and endometrial carcinoma (up to 100%), as well as different subtypes of breast cancer (95.3-100%). CLDN3 positivity was less common in squamous cell carcinomas (0-43.2%) and mainly absent in melanoma, mesenchymal, and hematolymphatic neoplasms. In clear cell renal cell carcinoma (ccRCC), low CLDN3 was strongly linked to poor ISUP (p < 0.0001), Fuhrman (p < 0.0001), and Thoenes (p < 0.0001) grades, advanced pT category (p < 0.0001), high UICC stage (p = 0.0006) and distant metastasis (p = 0.0011), as well as shortened overall (p = 0.0118) and recurrence-free (p < 0.0001) survival. In papillary RCC (pRCC), low CLDN3 was associated with poor grade (p < 0.05), high pT (p = 0.0273) and distant metastasis (p = 0.0357). In urothelial carcinoma high CLDN3 was linked to high grade (p < 0.0001) and nodal metastasis (p = 0.0111). The level of CLDN3 staining was unrelated to parameters of tumor aggressiveness in pancreatic, gastric, and breast cancer.

Conclusion: In conclusion, our data demonstrate significant levels of CLDN3 expression in many different tumor entities and identify reduced CLDN3 expression as a potential prognostic marker in RCC.

Early detection of cancer significantly improves patient outcomes, with biomarkers offering a promising avenue for earlier and more precise diagnoses. Microfluidic biosensors have emerged as a powerful tool for detecting these biomarkers in body fluids, providing enhanced sensitivity, specificity, and rapid analysis. This review focuses on recent advances in microfluidic biosensors from 2018 to 2024, detailing their operational principles, fabrication techniques, and integration with nanotechnology for cancer biomarker detection. Additionally, we have reviewed recent innovations in several aspects of microfluidic biosensors, such as novel detection technologies, nanomaterials and novel microfluidic chip structures, which significantly enhance detection capabilities. We highlight key biomarkers pertinent to early cancer detection and explore how these innovations in biosensor technology contribute to the evolving landscape of personalized medicine. We further explore how these technologies could be incorporated into clinical cancer diagnostic workflows to improve early detection and treatment outcomes. These innovations could help enable more precise and personalized cancer diagnostics. In addition, this review addresses several important issues such as enhancing the scalability and sensitivity of these biosensors in clinical settings and points out future possibilities of combining artificial intelligence diagnostics with microfluidic biosensors to optimize their practical applications. This overview aims to guide future research and clinical applications by addressing current challenges and identifying opportunities for further development in the field of biomarker research.

The transient receptor potential melastatin (TRPM) channel family has been previously implicated in various diseases, including those related to temperature sensing, cardiovascular health, and neurodegeneration. Nowadays, increasing evidence indicates that TRPM family members also play significant roles in various types of cancers, exhibiting both pro- and anti-tumorigenic functions. They are involved in tumor cell proliferation, survival, invasion, and metastasis, serving as potential diagnostic and prognostic biomarkers for cancer. This paper begins by describing the structure and physiological functions of the TRPM family members. It then outlines their roles in several common malignancies, including pancreatic, prostate, colorectal, breast, brain cancer, and melanoma. Subsequently, we focused on investigating the specific mechanisms by which TRPM family members are involved in tumorigenesis and development from both the tumor microenvironment (TME) and intracellular signaling. TRPM channels not only transmit signals from the TME to regulate tumor cell functions, but also mediate extracellular matrix remodeling, which is conducive to the malignant transformation of tumor cells. Importantly, TRPM channels depend on the regulation of the inflow of various ions in cells, and participate in key signaling pathways involved in tumor progression, such as Wnt/β-catenin, MAPK, PI3K/AKT, p53, and autophagy. Finally, we summarize the current strategies and challenges of targeting TRPM channels in tumor treatment, and discuss the feasibility of combining targeted TRPM channel drugs with cancer immunotherapy.

Immune checkpoints are crucial for regulating immune responses and maintaining self-tolerance, as they play a pivotal role in preventing autoimmunity and facilitating tumor immune evasion. This review concentrates on the immune checkpoint molecules PSGL-1 and VISTA. Both molecules are highly expressed in hematopoietic cells, including T cells and myeloid cells. VISTA functions both as a ligand on myeloid cells, where it regulates cytokine production, chemotaxis, and phagocytosis while promoting their differentiation into a tolerogenic phenotype and as a receptor on T cells, where it contributes to T cell quiescence. PSGL-1, which acts as a binding partner for VISTA, further inhibits T-cell activation and fosters tolerance within the acidic tumor microenvironment. Our review provides a comprehensive analysis of the structure, expression, and biological functions of PSGL-1 and VISTA and emphasizes their therapeutic potential in cancer treatment, autoimmune diseases, and transplantation. The dual role of these checkpoints in immune regulation presents novel opportunities for advancing cancer immunotherapy and developing new strategies for managing autoimmune conditions.

Increasing scRNA-seq data in cardiovascular research have substantially improved our knowledge on the development of the cardiovascular system and the mechanisms underlying cardiovascular diseases. However, the single-cell transcriptome datasets were dispersed in literature and no resource for cardiovascular systems and diseases. Here, we constructed an organized resource CardioAtlas, which provides comprehensive analysis results for > 1,929,000 cells in 27 human data sets and > 1,088,000 cells in 39 mouse data sets. Through large-scale literature retrieval and manual annotation, we constructed 12 and 15 scRNA-seq reference atlas for common human and mouse cardiovascular systems and diseases, covering 43 and 39 cell types. In particular, CardioAtlas provides five analytic modules, including cell-type prediction, identification of marker genes, functional enrichment analysis, identification of cell-type-specific transcription regulons, and cell-cell communication analysis. In addition, users can upload scRNA-seq data for personalized analysis. CardioAtlas is available at http://bio-bigdata.hrbmu.edu.cn/CardioAtlas . CardioAtlas provides the first comprehensive and well-crafted reference atlas of cardiovascular systems and diseases and describes in detail previously unrecognized cell populations across a large number of humans and mice.

Circulating tumor DNA (ctDNA) has shown potential as a non-invasive tumor biomarker in neuroblastoma. Previous studies used generic assays for detection of selected predefined oncogenic variants as markers of ctDNA, which limits the sensitivity and excludes a subset of patients from analysis. Here we assessed patient-specific ctDNA analysis for treatment evaluation and detection of relapse in neuroblastoma. We generated personalized sequencing panels targeting 10 tumor-specific single nucleotide variants (SNVs) for each patient and performed ctDNA analysis of 136 plasma samples collected longitudinally in 13 children with neuroblastoma. ctDNA was detected using ultra-deep next generation sequencing with unique molecular identifiers to eliminate polymerase-induced errors. We found that the levels of ctDNA at diagnosis correlated with risk group and decreased gradually during effective treatment. All samples collected during follow-up in patients without disease relapse were ctDNA-negative. All four relapses were associated with elevated ctDNA levels, and a majority of the analyzed SNVs were detected at time of relapse. In one case, ctDNA became positive 78 days before the relapse was diagnosed with routine assessment and increased by over a thousandfold before the start of additional treatment. Overall, ctDNA was more uniformly elevated at diagnosis, showed less putative false positive results, and was more sensitive for detection of relapse compared to five serum or urine tumor markers used in clinical routine. In conclusion, personalized ctDNA analysis is suitable for clinical monitoring of tumor burden and may be used in all neuroblastoma patients regardless of risk group or tumor genetics.

Background: Bone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC.

Methods: We comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed.

Results: A total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16).

Conclusions: GDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.

Cancer metastasis remains the most lethal characteristic of tumors mediating the majority of cancer-related deaths. Identifying key molecules responsible for metastasis, understanding their biological functions and therapeutically targeting these molecules is therefore of tremendous value. Metastasis Associated in Colon Cancer 1 (MACC1), a gene first described in 2009, is such a key driver of metastatic processes, initiating cellular proliferation, migration, invasion, and metastasis in vitro and in vivo. Since its discovery, the value of MACC1 as a prognostic biomarker has been confirmed in over 20 cancer entities. Additionally, several therapeutic strategies targeting MACC1 and its pro-metastatic functions have been developed. In this review, we will provide a comprehensive overview on MACC1, from its clinical relevance, towards its structure and role in signaling cascades as well as molecular networks. We will highlight specific biological consequences of MACC1 expression, such as an increase in stem cell properties, its immune-modulatory effects and induced therapy resistance. Lastly, we will explore various strategies interfering with MACC1 expression and/or its functions. Conclusively, this review underlines the importance of understanding the role of individual molecules in mediating metastasis.

Bile acid (BA) and its receptor FXR play crucial roles in metabolism, and dysregulated BA synthesis regulated by hepatic and bacterial enzymes causes metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Moreover, because ~ 75% of hepatic blood is from the gut, liver metabolism is influenced by intestinal bacteria and their metabolites. Thus, we used gut microbiota and metabolites from the urine and serum to uncover biomarkers for metabolic distress caused by Western diet (WD) intake, aging, and FXR inactivity. Hepatic transcriptomes were profiled to define liver phenotypes. There were 654 transcriptomes commonly altered by differential diet intake, ages, and FXR functional status, representing the signatures of liver dysfunction, and 76 of them were differentially expressed in healthy human livers and HCC. Machine learning approaches classified urine and serum metabolites for differential dietary intake and age difference. Additionally, the gut microbiota could predict FXR functional status. Furthermore, FXR was essential for differentiating dietary effects in colonizing age-related gut microbes. The integrated analysis established the relationships between the metabolites and gut microbiota correlated with hepatic transcripts commonly altered by diet, age, and FXR functionality. Remarkably, the changes in metabolites involved in the urea cycle, mitochondrial metabolism, and amino acid metabolism are associated with hepatic dysfunction (i.e. FXF deactivation). Taken together, noninvasive specimens and biomarkers are promising resources for identifying metabolic distress.