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Journal of Cancer Research and Clinical... Sep 2023The role of the epithelial cell adhesion molecule (EpCAM) in cancer is still unclear. EpCAM cleavage through regulated intramembrane proteolysis results in fragments...
BACKGROUND
The role of the epithelial cell adhesion molecule (EpCAM) in cancer is still unclear. EpCAM cleavage through regulated intramembrane proteolysis results in fragments which interact with both oncogenic and tumor suppressive pathways. Additionally, the EpCAM molecule itself is used as a descriptive therapeutic target in urothelial cancer (UC), while data on its actual tumor specificity remain limited.
METHODS
Samples from diagnostic formalin-fixed paraffin-embedded (FFPE) UC tissue and fresh-frozen UC cells were immunoblotted and used for qualitative characterization of five different EpCAM fragments. These expression patterns were quantified across a cohort of 76 samples with 52 UC and 24 normal urothelial samples. Cell viability effects of the extracellular EpEX fragment were assessed in the UC cell lines T24 and HT1376.
RESULTS
The proteolytic EpCAM fragments could be identified in clinical FFPE tissue specimens too. Neither overall nor fragment-specific EpCAM expression showed relevant tumor specificity. EpEX and its deglycosylated variant showed an inverse relationship across healthy and tumor tissue with a decrease of deglycosylated EpEX in tumors. However, extracellular EpEX did not show a relevant effect in vitro.
CONCLUSIONS
EpCAM should not be regarded as tumor-specific in UC without patient-specific predictive testing. EpCAM fragment patterns indicate cancer-specific changes and could be involved in its complex tumor-biological role.
Topics: Humans; Epithelial Cell Adhesion Molecule; Cell Adhesion Molecules; Antigens, Neoplasm; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Cell Line, Tumor
PubMed: 37154925
DOI: 10.1007/s00432-023-04809-9 -
Theranostics 2023Attached to proteins, lipids, or forming long, complex chains, glycans represent the most versatile post-translational modification in nature and surround all human... (Review)
Review
Attached to proteins, lipids, or forming long, complex chains, glycans represent the most versatile post-translational modification in nature and surround all human cells. Unique glycan structures are monitored by the immune system and differentiate self from non-self and healthy from malignant cells. Aberrant glycosylations, termed tumour-associated carbohydrate antigens (TACAs), are a hallmark of cancer and are correlated with all aspects of cancer biology. Therefore, TACAs represent attractive targets for monoclonal antibodies for cancer diagnosis and therapy. However, due to the thick and dense glycocalyx as well as the tumour micro-environment, conventional antibodies often suffer from restricted access and limited effectiveness . To overcome this issue, many small antibody fragments have come forth, showing similar affinity with better efficiency than their full-length counterparts. Here we review small antibody fragments against specific glycans on tumour cells and highlight their advantages over conventional antibodies.
Topics: Humans; Immunoglobulin Fragments; Antigens, Tumor-Associated, Carbohydrate; Antibodies, Monoclonal; Neoplasms; Polysaccharides; Tumor Microenvironment
PubMed: 37284439
DOI: 10.7150/thno.80901 -
Cancer Science Feb 2019Reliable biomarkers for renal cell carcinoma (RCC) have yet to be determined. Circulating tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular...
Reliable biomarkers for renal cell carcinoma (RCC) have yet to be determined. Circulating tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular characteristics of various tumors. The present study aims to clarify the clinical utility of ctDNA for RCC. Fifty-three patients histologically diagnosed with clear cell RCC were enrolled. Targeted sequencing was carried out using plasma cell-free DNA (cfDNA) and tumor DNA. We applied droplet digital PCR (ddPCR) to validate detected mutations. cfDNA fragment size was also evaluated using a microfluidics-based platform and sequencing. Proportion of cfDNA fragments was defined as the ratio of small (50-166 bp) to large (167-250 bp) cfDNA fragments. Association of mutant allele frequency of ctDNA with clinical course was analyzed. Prognostic potential was evaluated using log-rank test. A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n = 6) and VHL (n = 5), and median mutant allele frequency of ctDNA was 10%. We designed specific ddPCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA. Positive ctDNA was significantly associated with a higher proportion of cfDNA fragments (P = .033), indicating RCC patients with ctDNA had shorter fragment sizes of cfDNA. Interestingly, the changes of mutant allele frequency in ctDNA concurrently correlated with clinical course. Positive ctDNA and fragmentation of cfDNA were significantly associated with poor cancer-specific survival (P < .001, P = .011). In conclusion, our study shows the clinical utility of ctDNA status and cfDNA fragment size as biomarkers for prognosis and disease monitoring in RCC.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Renal Cell; Circulating Tumor DNA; DNA Fragmentation; DNA, Neoplasm; Female; Gene Frequency; Humans; Kidney Neoplasms; Male; Middle Aged; Mutation
PubMed: 30536551
DOI: 10.1111/cas.13906 -
Clinical and Experimental Immunology Jul 2022The unmet clinical need for effective treatments in ovarian cancer has yet to be addressed using monoclonal antibodies (mAbs), which have largely failed to overcome... (Review)
Review
The unmet clinical need for effective treatments in ovarian cancer has yet to be addressed using monoclonal antibodies (mAbs), which have largely failed to overcome tumour-associated immunosuppression, restrict cancer growth, and significantly improve survival. In recent years, experimental mAb design has moved away from solely targeting ovarian tumours and instead sought to modulate the wider tumour microenvironment (TME). Tumour-associated macrophages (TAMs) may represent an attractive therapeutic target for mAbs in ovarian cancer due to their high abundance and close proximity to tumour cells and their active involvement in facilitating several pro-tumoural processes. Moreover, the expression of several antibody crystallisable fragment (Fc) receptors and broad phenotypic plasticity of TAMs provide opportunities to modulate TAM polarisation using mAbs to promote anti-tumoural phenotypes. In this review, we discuss the role of TAMs in ovarian cancer TME and the emerging strategies to target the contributions of these cells in tumour progression through the rationale design of mAbs.
Topics: Antibodies, Monoclonal; Female; Humans; Immunotherapy; Leukocyte Count; Macrophages; Neoplasms; Ovarian Neoplasms; Tumor Microenvironment
PubMed: 35020853
DOI: 10.1093/cei/uxab020 -
Essays in Biochemistry Sep 2023The DNA sensor cGAS (cyclic GMP-AMP synthase) and its adaptor protein STING (Stimulator of Interferon Genes) detect the presence of cytosolic DNA as a sign of infection... (Review)
Review
The DNA sensor cGAS (cyclic GMP-AMP synthase) and its adaptor protein STING (Stimulator of Interferon Genes) detect the presence of cytosolic DNA as a sign of infection or damage. In cancer cells, this pathway can be activated through persistent DNA damage and chromosomal instability, which results in the formation of micronuclei and the exposure of DNA fragments to the cytosol. DNA damage from radio- or chemotherapy can further activate DNA sensing responses, which may occur in the cancer cells themselves or in stromal and immune cells in the tumour microenvironment (TME). cGAS-STING signalling results in the production of type I interferons, which have been linked to immune cell infiltration in 'hot' tumours that are susceptible to immunosurveillance and immunotherapy approaches. However, recent research has highlighted the complex nature of STING signalling, with tumours having developed mechanisms to evade and hijack this signalling pathway for their own benefit. In this mini-review we will explore how cGAS-STING signalling in different cells in the TME can promote both anti-tumour and pro-tumour responses. This includes the role of type I interferons and the second messenger cGAMP in the TME, and the influence of STING signalling on local immune cell populations. We examine how alternative signalling cascades downstream of STING can promote chronic interferon signalling, the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of inflammatory cytokines, which can have pro-tumour functions. An in-depth understanding of DNA sensing in different cell contexts will be required to harness the anti-tumour functions of STING signalling.
Topics: Humans; Immunity, Innate; DNA; Nucleotidyltransferases; Interferon Type I; Neoplasms; Tumor Microenvironment
PubMed: 37534795
DOI: 10.1042/EBC20220241 -
British Journal of Cancer Jan 2021Cell-free DNA (cfDNA) derived from tumours is present in the plasma of cancer patients. The majority of currently available studies on the use of this circulating tumour... (Review)
Review
Cell-free DNA (cfDNA) derived from tumours is present in the plasma of cancer patients. The majority of currently available studies on the use of this circulating tumour DNA (ctDNA) deal with the detection of mutations. The analysis of cfDNA is often discussed in the context of the noninvasive detection of mutations that lead to resistance mechanisms and therapeutic and disease monitoring in cancer patients. Indeed, substantial advances have been made in this area, with the development of methods that reach high sensitivity and can interrogate a large number of genes. Interestingly, however, cfDNA can also be used to analyse different features of DNA, such as methylation status, size fragment patterns, transcriptomics and viral load, which open new avenues for the analysis of liquid biopsy samples from cancer patients. This review will focus on the new perspectives and challenges of cfDNA analysis from mutation detection in patients with solid malignancies.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; DNA Mutational Analysis; Humans; Liquid Biopsy; Neoplasms
PubMed: 32968207
DOI: 10.1038/s41416-020-01047-5 -
Cell Communication and Signaling : CCS Jul 2023Malignant tumours area leading cause of death globally, accounting for approximately 13% of all deaths. A detailed understanding of the mechanism(s) of the occurrence... (Review)
Review
Malignant tumours area leading cause of death globally, accounting for approximately 13% of all deaths. A detailed understanding of the mechanism(s) of the occurrence and development of malignant tumours and identification of relevant therapeutic targets are therefore key to tumour treatment. tsRNAs(tRNA-derived small RNAs)-also known as TRFs (tRNA-derived fragments), tiRNAs (tRNA-derived stress-induced RNAs), tRNA halves, etc.-are a recently identified class of small noncoding RNAs that are generated from mature tRNA or tRNA precursors through cleavage by enzymes such as angiogenin, Dicer, RNase Z, and RNase P. Several studies have confirmed that dysregulation of tsRNAs is closely related to the tumorigenesis of breast cancer, nasopharyngeal cancer, lung cancer, and so on. Furthermore, research indicates that tsRNAs can be used as clinical diagnostic markers and therapeutic targets for cancer. In our review, we summarized the recent research progress on the role and clinical application of tsRNAs in tumorigenesis and progression. Video Abstract.
Topics: Humans; Nasopharyngeal Neoplasms; RNA; RNA, Transfer; Lung Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic
PubMed: 37480078
DOI: 10.1186/s12964-023-01199-w -
Human Genomics Oct 2023Fragmentomics, the investigation of fragmentation patterns of cell-free DNA (cfDNA), has emerged as a promising strategy for the early detection of multiple cancers in...
BACKGROUND
Fragmentomics, the investigation of fragmentation patterns of cell-free DNA (cfDNA), has emerged as a promising strategy for the early detection of multiple cancers in the field of liquid biopsy. However, the clinical application of this approach has been hindered by a limited understanding of cfDNA biology. Furthermore, the prevalence of hematopoietic cell-derived cfDNA in plasma complicates the in vivo investigation of tissue-specific cfDNA other than that of hematopoietic origin. While conventional two-dimensional cell lines have contributed to research on cfDNA biology, their limited representation of in vivo tissue contexts underscores the need for more robust models. In this study, we propose three-dimensional organoids as a novel in vitro model for studying cfDNA biology, focusing on multifaceted fragmentomic analyses.
RESULTS
We established nine patient-derived organoid lines from normal lung airway, normal gastric, and gastric cancer tissues. We then extracted cfDNA from the culture medium of these organoids in both proliferative and apoptotic states. Using whole-genome sequencing data from cfDNA, we analyzed various fragmentomic features, including fragment size, footprints, end motifs, and repeat types at the end. The distribution of cfDNA fragment sizes in organoids, especially in apoptosis samples, was similar to that found in plasma, implying occupancy by mononucleosomes. The footprints determined by sequencing depth exhibited distinct patterns depending on fragment sizes, reflecting occupancy by a variety of DNA-binding proteins. Notably, we discovered that short fragments (< 118 bp) were exclusively enriched in the proliferative state and exhibited distinct fragmentomic profiles, characterized by 3 bp palindromic end motifs and specific repeats.
CONCLUSIONS
In conclusion, our results highlight the utility of in vitro organoid models as a valuable tool for studying cfDNA biology and its associated fragmentation patterns. This, in turn, will pave the way for further enhancements in noninvasive cancer detection methodologies based on fragmentomics.
Topics: Humans; Cell-Free Nucleic Acids; Neoplasms; Liquid Biopsy; Whole Genome Sequencing; Cell Line; Biomarkers, Tumor
PubMed: 37898819
DOI: 10.1186/s40246-023-00533-0 -
Medical Science Monitor : International... Mar 2020Circulating tumor DNA (ctDNA) describes the fragmented DNA released from tumor cells into the blood. The ctDNA may have the same genetic changes as the primary tumor.... (Review)
Review
Circulating tumor DNA (ctDNA) describes the fragmented DNA released from tumor cells into the blood. The ctDNA may have the same genetic changes as the primary tumor. Currently, ctDNA has become a popular biomarker for diagnosis, treatment, real-time clinical response monitoring, and prognosis, for solid tumors. Detection of ctDNA is minimally invasive, and repeat sampling can easily be performed. However, due to its low quality and short DNA fragment length, ctDNA detection still faces challenges and requires highly sensitive analytical techniques. Recently, liquid biopsies for the analysis of circulating tumor cells (CTCs) and circulating tumor-derived exosomes have been studied, and nanotechnology techniques have rapidly developed. Compared to traditional analytical methods, these nanotechnology-based platforms have the advantages of sensitivity, multiplex detection, simplicity, miniaturization, and automation, which support their potential use in clinical practice. This review aims to discuss the recent nanotechnological strategies for ctDNA analysis and the design of reliable techniques for ctDNA detection and to identify the potential clinical applications.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; DNA, Neoplasm; Early Detection of Cancer; Humans; Liquid Biopsy; Nanotechnology; Neoplasms; Neoplastic Cells, Circulating
PubMed: 32200389
DOI: 10.12659/MSM.921040 -
Cancer Jul 2020Patients with chronic conditions are treated by many providers, which can increase the risk of communication gaps across providers and potential harm to patients....
BACKGROUND
Patients with chronic conditions are treated by many providers, which can increase the risk of communication gaps across providers and potential harm to patients. However, to the authors' knowledge, the extent of fragmented care among this population is unknown. In the current study, the authors sought to determine whether cancer survivors have more fragmented care than noncancer controls and to quantify the extent of fragmentation.
METHODS
Data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study linked to Medicare claims were used. The authors included beneficiaries with continuous Part A and B coverage for 12 months at the time of their baseline REGARDS survey. The primary outcome of the current study was claims-based fragmentation over 12 months, which was calculated using the reversed Bice-Boxerman Index so a higher score reflected greater fragmentation. Unadjusted differences in fragmentation were compared between cancer survivors and controls. Beta regression models were used to estimate associations between cancer status and fragmentation, adjusting for potential confounders.
RESULTS
The authors included 4922 participants aged ≥65 years at baseline. Of these patients, approximately 21% were cancer survivors. Survivors had a median of 11 visits (interquartile range, 7-15 visits) with 5 providers compared with controls, who had a median of 9 visits (interquartile range, 6-14 visits) with 4 providers (P < .0001). Cancer survivors had significantly more fragmented care compared with controls (median reversed Bice-Boxerman Index, 0.80 vs 0.76; P < .0001). After adjusting for confounders, cancer survivors had an increased odds of having fragmented care (odds ratio, 1.08; 95% CI, 1.02-1.14).
CONCLUSIONS
Care fragmentation is more prevalent among cancer survivors compared with those without a history of cancer. Future studies should examine whether fragmentation puts survivors at risk of worse outcomes.
Topics: Aged; Aged, 80 and over; Ambulatory Care; Cancer Survivors; Female; Humans; Male; Medicare; Middle Aged; Neoplasms; Stroke; United States
PubMed: 32286692
DOI: 10.1002/cncr.32869