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Cancer Cell Oct 2019Widespread adaptation of liquid biopsy for the early detection of cancer has yet to reach clinical utility. Circulating tumor DNA is commonly detected though the... (Review)
Review
Widespread adaptation of liquid biopsy for the early detection of cancer has yet to reach clinical utility. Circulating tumor DNA is commonly detected though the presence of genetic alterations, but only a minor fraction of tumor-derived cell-free DNA (cfDNA) fragments exhibit mutations. The cellular processes occurring in cancer development mark the chromatin. These epigenetic marks are reflected by modifications in the cfDNA methylation, fragment size, and structure. In this review, we describe how going beyond DNA sequence information alone, by analyzing cfDNA epigenetic and immune signatures, boosts the potential of liquid biopsy for the early detection of cancer.
Topics: Biomarkers, Tumor; Chromatin; Circulating Tumor DNA; DNA Methylation; Early Detection of Cancer; Epigenesis, Genetic; Epigenomics; Humans; Liquid Biopsy; Mutation; Neoplasms; Sequence Analysis, DNA
PubMed: 31614115
DOI: 10.1016/j.ccell.2019.09.003 -
Journal of Clinical Pathology May 2004MUCs are glycoproteins with various roles in homeostasis and carcinogenesis. Among other actions, MUC1 may inhibit cell-cell and cell-stroma interactions and function as... (Review)
Review
MUCs are glycoproteins with various roles in homeostasis and carcinogenesis. Among other actions, MUC1 may inhibit cell-cell and cell-stroma interactions and function as a signal transducer, participating in cancer progression. In contrast, MUC2 is normally found only in goblet cells, where it contributes to the protective barrier function of these cells. Recently, a tumour suppressor role has been demonstrated for MUC2, and both MUC1 and MUC2 appear to have important roles in pancreatic neoplasia. MUC1 appears to be a marker of aggressive phenotype and may facilitate the vascular spread of carcinoma cells. In contrast, MUC2 is rarely detectable in aggressive pancreatic tumours, but is commonly expressed in intraductal papillary mucinous neoplasms (IPMNs), which are rare, indolent tumours, in intestinal IPMNs, and in indolent colloid carcinomas. MUC2 appears to be not only a marker of this indolent pathway, but also partly responsible for its less aggressive nature. Thus, in pancreatic neoplasia, MUC1 and MUC2 have potential diagnostic and prognostic value as markers of aggressive and indolent phenotypes, respectively, and have potential as therapeutic targets.
Topics: Cell Transformation, Neoplastic; Humans; Mucin-1; Mucin-2; Mucins; Neoplasm Invasiveness; Neoplasm Proteins; Pancreatic Neoplasms; Peptide Fragments
PubMed: 15113850
DOI: 10.1136/jcp.2003.013292 -
Cell Communication and Signaling : CCS Mar 2023Cancer is a leading cause of morbidity and death worldwide. While various factors are established as causing malignant tumors, the mechanisms underlying cancer... (Review)
Review
Cancer is a leading cause of morbidity and death worldwide. While various factors are established as causing malignant tumors, the mechanisms underlying cancer development remain poorly understood. Early diagnosis and the development of effective treatments for cancer are important research topics. Transfer RNA (tRNA), the most abundant class of RNA molecules in the human transcriptome, participates in both protein synthesis and cellular metabolic processes. tRNA-derived fragments (tRFs) are produced by specific cleavage of pre-tRNA and mature tRNA molecules, which are highly conserved and occur widely in various organisms. tRFs were initially thought to be random products with no physiological function, but have been redefined as novel functional small non-coding RNA molecules that help to regulate RNA stability, modulate translation, and influence target gene expression, as well as other biological processes. There is increasing evidence supporting roles for tRFs in tumorigenesis and cancer development, including the regulation of tumor cell proliferation, invasion, migration, and drug resistance. Understanding the regulatory mechanisms by which tRFs impact these processes has potential to inform malignant tumor diagnosis and treatment. Further, tRFs are expected to become new biological markers for early diagnosis and prognosis prediction in patients with tumors, as well as a targets for precision cancer therapies. Video abstract.
Topics: Humans; Neoplasms; Transcriptome; RNA, Transfer
PubMed: 36964534
DOI: 10.1186/s12964-023-01079-3 -
BioMed Research International 2016. To investigate sperm DNA fragmentation and sperm functional maturity in men from infertile couples (IC) and men with testicular germ cell tumor (TGCT). . Semen samples... (Clinical Trial)
Clinical Trial
. To investigate sperm DNA fragmentation and sperm functional maturity in men from infertile couples (IC) and men with testicular germ cell tumor (TGCT). . Semen samples were collected from 312 IC men and 23 men with TGCT before unilateral orchiectomy and oncological treatment. The sperm chromatin dispersion test was performed to determine DNA fragmentation index (DFI) and the ability of sperm to bind with hyaluronan (HA) was assessed. . In comparison with the IC men, the men with TGCT had a higher percentage of sperm with fragmented DNA (median 28% versus 21%; < 0.01) and a lower percentage of HA-bound sperm (24% versus 66%; < 0.001). Normal results of both analyses were observed in 24% of IC men and 4% of men with TGCT. Negative Spearman's correlations were found between DFI and the percentage of HA-bound sperm in the whole group and in IC subjects and those with TGCT analyzed separately. . Approximately 76% of IC men and 96% with TGCT awaiting orchiectomy demonstrated DNA fragmentation and/or sperm immaturity. We therefore recommend sperm banking after unilateral orchiectomy, but before irradiation and chemotherapy; the use of such a deposit appears to be a better strategy to obtain functionally efficient sperms.
Topics: Adult; DNA Fragmentation; Humans; Hyaluronic Acid; Infertility, Male; Male; Middle Aged; Neoplasms, Germ Cell and Embryonal; Spermatozoa; Testicular Neoplasms
PubMed: 27999814
DOI: 10.1155/2016/7893961 -
The British Journal of Radiology Jan 2019The complement system is an innate immune pathway typically thought of as part of the first line of defence against "non-self" species. In the context of cancer,... (Review)
Review
The complement system is an innate immune pathway typically thought of as part of the first line of defence against "non-self" species. In the context of cancer, complement has been described to have an active role in facilitating cancer-associated processes such as increased proliferation, angiogenesis and migration. Several cellular members of the tumour microenvironment express and/or produce complement proteins locally, including tumour cells. Dysregulation of the complement system has been reported in numerous tumours and increased expression of complement activation fragments in cancer patient specimens correlates with poor patient prognosis. Importantly, genetic or pharmacological targeting of complement has been shown to reduce tumour growth in several cancer preclinical models, suggesting that complement could be an attractive therapeutic target. Hypoxia (low oxygen) is frequently found in solid tumours and has a profound biological impact on cellular and non-cellular components of the tumour microenvironment. In this review, we focus on hypoxia since this is a prevailing feature of the tumour microenvironment that, like increased complement, is typically associated with poor prognosis. Furthermore, interesting links between hypoxia and complement have been recently proposed but never collectively reviewed. Here, we explore how hypoxia alters regulation of complement proteins in different cellular components of the tumour microenvironment, as well as the downstream biological consequences of this regulation.
Topics: Combined Modality Therapy; Complement System Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Neoplasms; Oxygen Consumption; Prognosis; Signal Transduction; Treatment Outcome; Tumor Hypoxia; Tumor Microenvironment; Up-Regulation
PubMed: 29544344
DOI: 10.1259/bjr.20180069 -
Cancer Science Jan 2021Reliable biomarkers for upper-tract urothelial carcinoma (UTUC) have yet to be found. Plasma cell-free DNA (cfDNA) has been clinically applied as a minimally invasive...
Reliable biomarkers for upper-tract urothelial carcinoma (UTUC) have yet to be found. Plasma cell-free DNA (cfDNA) has been clinically applied as a minimally invasive blood biomarker for various types of cancer. We investigated the utility of plasma cfDNA as a blood biomarker in UTUC patients. The fragment size of plasma cfDNA was shorter and the concentration of plasma cfDNA was higher in UTUC patients than in healthy controls. The fragment size of plasma cfDNA had a moderate accuracy of diagnosing UTUC (area under the curve [AUC] = 0.72), and multivariate analysis indicated that the fragment size of plasma cfDNA was significantly associated with the presence of UTUC (odds ratio = 0.807, 95% confidence interval [CI] 0.653-0.955, P = .024). Furthermore, we found that the size of plasma cfDNA shortens alongside disease progression (P < .001). The fragment size of plasma cfDNA in UTUC patients may be an auxiliary tool for the diagnosis of UTUC patients. We also found a high correlation between the fragmentation of plasma cfDNA and serum levels of three inflammatory cytokines (TNFα [r = -.837], interleukin-6 [IL-6] [r = -.964], interleukin-1 receptor antagonist [IL-1ra] [r = -.911]), which were reported to associate with poor prognosis. Also, we found that the proportion of short fragments of cfDNA was significantly increased in the supernatant of peripheral blood mononuclear cells (PBMCs) from healthy controls cultured in media containing TNFα. These results supposed that cancer-associated systemic inflammation, especially tumor necrosis factor-α (TNFα), may contribute to the fragmentation of plasma cfDNA in UTUC patients.
Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Cell-Free Nucleic Acids; Cytokines; Disease Progression; Female; Humans; Inflammation; Leukocytes, Mononuclear; Male; Middle Aged; Prognosis; Urologic Neoplasms; Urothelium
PubMed: 33027843
DOI: 10.1111/cas.14679 -
Nature Communications Oct 2023Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains...
Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1 in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD enhances renal cystogenesis without inducing pancreatic cysts in Pkd1 mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD cleavage, crucial for cystogenesis mechanisms.
Topics: Mice; Animals; Receptors, Cell Surface; Kidney; Polycystic Kidney, Autosomal Recessive; TRPP Cation Channels; Kidney Tubules; Pancreatic Cyst
PubMed: 37845212
DOI: 10.1038/s41467-023-42196-4 -
Asian Pacific Journal of Cancer... 2016The commonest cancer in Egyptian females occurs in the breast cfDNA is a non-invasive marker for tumor detetion and prognostic assessment in many types of cancer... (Comparative Study)
Comparative Study
The commonest cancer in Egyptian females occurs in the breast cfDNA is a non-invasive marker for tumor detetion and prognostic assessment in many types of cancer including breast cancer. This study aimed to assess the role of cfDNA and its fragmentation pattern in breast cancer prognosis and treatment response. Forty female patients with malignant breast tumors and a comparable group of healthy blood donors were enrolled prospectively. cfDNA levels and fragmentation patterns were investigated after cfDNA extraction, gel electrophoresis and gel analysis. The percentage of breast cancer patients positive for cfDNA (92.5%) was significantly higher than that of controls (55%). Also, mean concentration of cfDNA was significantly higher than in the control group (<0.05). Most Her-2 positive patients had long cfDNA fragments, this being significant as compared to Her-2 negative patients (<0.05). Metastasis was also positively linked to significantly higher cfDNA (<0.05) and the mean cfDNA integrity index was significantly higher in non-responders compared to treatment responders (<0.05). In conclusion, both qualitative and quantitative aspects of cfDNA and its different fragments in breast cancer patients could be related to prognosis, metastasis and treatment response. Long cfDNA fragments could be particularly useful for prediction purposes.
Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Case-Control Studies; Combined Modality Therapy; DNA, Neoplasm; Egypt; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Prognosis; Prospective Studies
PubMed: 27356723
DOI: No ID Found -
PloS One 2015Diagnostic and prognostic indicators are key components to achieve the goal of personalized cancer therapy. Two distinct approaches to this goal include predicting...
Diagnostic and prognostic indicators are key components to achieve the goal of personalized cancer therapy. Two distinct approaches to this goal include predicting response by genetic analysis and direct testing of possible therapies using cultures derived from biopsy specimens. Optimally, the latter method requires a rapid assessment, but growing xenograft tumors or developing patient-derived cell lines can involve a great deal of time and expense. Furthermore, tumor cells have much different responses when grown in 2D versus 3D tissue environments. Using a modification of existing methods, we show that it is possible to make tumor-fragment (TF) spheroids in only 2-3 days. TF spheroids appear to closely model characteristics of the original tumor and may be used to assess critical therapy-modulating features of the microenvironment such as hypoxia. A similar method allows the reproducible development of spheroids from mixed tumor cells and fibroblasts (mixed-cell spheroids). Prior literature reports have shown highly variable development and properties of mixed-cell spheroids and this has hampered the detailed study of how individual tumor-cell components interact. In this study, we illustrate this approach and describe similarities and differences using two tumor models (U87 glioma and SQ20B squamous-cell carcinoma) with supporting data from additional cell lines. We show that U87 and SQ20B spheroids predict a key microenvironmental factor in tumors (hypoxia) and that SQ20B cells and spheroids generate similar numbers of microvesicles. We also present pilot data for miRNA expression under conditions of cells, tumors, and TF spheroids.
Topics: Biomarkers; Cell Line, Tumor; Fibroblasts; Humans; MicroRNAs; Neoplasms; Neovascularization, Pathologic; Spheroids, Cellular; Stromal Cells; Tumor Cells, Cultured; Tumor Microenvironment
PubMed: 26208323
DOI: 10.1371/journal.pone.0133895 -
Cancer Oct 2002DNA fragmentation and cell proliferation in patients with hepatocellular carcinoma (HCC) have not been well described on fine-needle aspiration biopsies (FNABs). To...
BACKGROUND
DNA fragmentation and cell proliferation in patients with hepatocellular carcinoma (HCC) have not been well described on fine-needle aspiration biopsies (FNABs). To investigate the contribution of apoptosis, a major mechanism of cell death, to the growth of HCC, the authors analyzed both apoptosis and cell proliferation in patients with HCC.
METHODS
The authors studied 50 tumors from 50 patients with HCC: Ten tumors were well-differentiated HCC, 24 tumors were moderately differentiated HCC, and 16 tumors were poorly differentiated HCC. The detection of DNA fragments in situ using the terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay was applied to investigate active cell death (apoptosis), and the MIB-1 antigen was used to investigate cell proliferation.
RESULTS
The TUNEL indices were 0.34 +/- 0.08, 082 +/- 0.30, and 2.0 +/- 0.95 in well-differentiated HCC, moderately differentiated HCC, and poorly differentiated HCC, respectively. The MIB-1 antigen labeling indices were 6.7 +/- 0.10, 13.2 +/- 3.4; and 26.9 +/- 6.5, respectively, in the same order of tumor differentiation. The differences in both TUNEL and MIB-1 labeling indices were significant between well differentiated HCC, moderately differentiated HCC, and poorly differentiated HCC, and a positive correlation was found between the TUNEL indices and the MIB-1 indices.
CONCLUSIONS
Apoptosis (cell death) and cell proliferation increase as the grade of differentiation decreases in HCC, suggesting a rapid turnover of tumor cells in tumors with lower grades of differentiation, and apoptosis may play an important role in the growth of tumors in patients with HCC.
Topics: Apoptosis; Biopsy, Needle; Carcinoma, Hepatocellular; DNA Fragmentation; Female; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Ki-67 Antigen; Liver; Liver Neoplasms; Male; Middle Aged
PubMed: 12378598
DOI: 10.1002/cncr.10748