Tumour Biology[JOURNAL]
Sun
200 papers
VDR gene FokI polymorphism as a poor prognostic factor for papillary thyroid cancer.
Beysel S, Eyerci N, Pinarli FA … +6 more , Apaydin M, Kizilgul M, Caliskan M, Ozcelik O, Kan S, Cakal E
Tumour Biol · 2018 Nov · PMID 30486759 · Publisher ↗
This is the first study to investigate the effect of vitamin D receptor ( VDR) gene single-nucleotide polymorphisms on the clinicopathologic features of papillary thyroid cancer in Turkey. A total of 165 patients with pa...
This is the first study to investigate the effect of vitamin D receptor ( VDR) gene single-nucleotide polymorphisms on the clinicopathologic features of papillary thyroid cancer in Turkey. A total of 165 patients with papillary thyroid cancer and 172 controls were included in this case-control study. VDR gene single-nucleotide polymorphisms FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) were evaluated using reverse-transcription polymerase chain reaction. VDR gene polymorphisms BsmI, ApaI, and TaqI did not differ between the papillary thyroid cancer group and control group (p > 0.05, each). BsmI, ApaI, and TaqI were not associated with papillary thyroid cancer risk. The VDR gene FokI CT/TT genotype was associated with an increased papillary thyroid cancer risk (CT vs CC: odds ratio = 1.71, 95% confidence interval = 1.15-2.76, p = 0.028; TT vs CC: odds ratio = 2.44, 95% confidence interval = 1.29-4.62, p = 0.005; CT/TT vs CC: odds ratio = 1.88, 95% confidence interval = 1.20-2.96, p = 0.006; CT/CC vs TT: odds ratio = 1.80, 95% confidence interval = 1.05-3.20, p = 0.041). VDR gene polymorphisms were not in linkage disequilibrium. The FokI TT genotype was associated with having T3 and T4, stage III/IV, extra-thyroidal invasion. The FokI CT/TT or TT genotype was associated with developing N1 status, multifocality, tumor size ≥10 mm, and treatment with radioiodine therapy. Persistence/recurrence did not differ between the FokI genotypes. Carriers of the FokI T allele were at an increased risk of more advanced tumor-node-metastasis stage, greater tumor size, multifocality, and extra-thyroidal invasion of papillary thyroid cancer compared with the CC genotype. VDR gene FokI T allele and TT genotype correlated with aggressiveness of papillary thyroid cancer; thus, FokI could be useful as a poor prognostic factor to assess the high risk of papillary thyroid cancer.
Cell-adhesion molecules and their soluble forms: Promising predictors of "tumor progression" and relapse in leukemia.
Fonseca ICCFE, da Luz FAC, Uehara IA … +1 more , Silva MJB
Tumour Biol · 2018 Nov · PMID 30486756 · Publisher ↗
Some surface markers are used to discriminate certain leukemic subpopulations that retain a greater oncogenic potential than others, and, for this reason, they were termed as leukemic stem cells, similar to the concept o...
Some surface markers are used to discriminate certain leukemic subpopulations that retain a greater oncogenic potential than others, and, for this reason, they were termed as leukemic stem cells, similar to the concept of cancer stem cells in carcinoma. Among these surface markers are proteins involved in cell-cell adhesion or cell-matrix adhesion, and they may play a role in the relapse of leukemia, similar to metastasis in carcinomas. The most important are epithelial cadherin, neural cadherin, epithelial cell-adhesion molecule, and CD44, which can be cleaved and released, and their soluble forms were found increased in serum levels of cancer patients, being implicated, in some cases, with progression, metastases, and relapse. In this review, we highlighted the role of these four adhesion molecules in carcinomas and hematological malignancies, mainly leukemia, and discuss if the serum levels of soluble forms can be correlated with the surface protein status on the leukemic cells. Accession of the soluble forms looks attractive, but their use as markers in cancer must be studied in association with other parameters, as there are significant changes in levels in other pathological conditions besides cancer. Studies correlating the levels of the forms with the status of the membrane-bound proteins in leukemic (stem) cells and correlating those parameters with relapse in leukemia may afford important knowledge and applicability of those serum markers in clinical practice. For instance, the expression of the membrane-bound forms of these adhesion proteins may have promising clinical use in leukemia and other hematological malignancies.
Nivolumab in never-smokers with advanced squamous non-small cell lung cancer: Results from the Italian cohort of an expanded access program.
Garassino MC, Crinò L, Catino A … +19 more , Ardizzoni A, Cortesi E, Cappuzzo F, Bordi P, Calabrò L, Barbieri F, Santo A, Altavilla G, Ambrosio F, Mini E, Vasile E, Morgillo F, Scoppola A, Bengala C, Follador A, Tedde N, Giannarelli D, Lo Russo G, Vitiello F
Tumour Biol · 2018 Nov · PMID 30486741 · Publisher ↗
OBJECTIVES:: Never-smokers may be a distinct subgroup among patients with advanced non-small cell lung cancer, appearing to benefit less from immunotherapy than smokers. We report results from never-smokers enrolled in t...
OBJECTIVES:: Never-smokers may be a distinct subgroup among patients with advanced non-small cell lung cancer, appearing to benefit less from immunotherapy than smokers. We report results from never-smokers enrolled in the Italian cohort of the nivolumab expanded access program in pre-treated patients with advanced squamous non-small cell lung cancer. MATERIALS AND METHODS:: Nivolumab (3 mg/kg every 2 weeks for ≤24 months) was available on physician request. Efficacy data included objective tumor response, date of progression, and survival information. Safety was monitored. RESULTS:: Overall, 371 patients received at least one dose of nivolumab, including 31 never-smokers (8%). Objective response rate, disease-control rate, and median overall survival were 23%, 45%, and 12.1 months (95% confidence interval: 3.7-20.4), respectively, in never-smokers, and 18%, 47%, and 7.9 months (95% confidence interval: 6.2-9.6), respectively, in the overall expanded access program population. Any-grade and grade 3-4 treatment-related adverse events were reported in 12 (39%) and 3 (10%) never-smokers, respectively, and in 109 (29%) and 21 (6%) patients, respectively, in the overall expanded access program population. Grade 3-4 treatment-related adverse events in non-smokers were increased transaminases (n = 2; 6%) and diarrhea (n = 1; 3%). Treatment-related adverse events led to treatment discontinuation in 4 non-smokers (17%) and in 26 patients (9%) overall. CONCLUSION:: Pre-treated never-smokers with advanced squamous non-small cell lung cancer in this Italian expanded access program demonstrated efficacy and safety that were consistent with those in the overall expanded access program population and clinical trials. These results suggest that a proportion of never-smoker patients with squamous non-small cell lung cancer may be responsive to immunotherapy. Other factors, such as the tumor mutational load and the status of programmed death-ligand 1, anaplastic lymphoma kinase, and epidermal growth factor receptor, might play a potential key role.
B7-H3 and B7-H4 expression in phyllodes tumors of the breast detected by RNA in situ hybridization and immunohistochemistry: Association with clinicopathological features and T-cell infiltration.
Kim GE, Kim NI, Park MH … +1 more , Lee JS
Tumour Biol · 2018 Nov · PMID 30486739 · Publisher ↗
Phyllodes tumors are rare biphasic breast tumors with the potential for both local recurrence and distant metastasis. The aberrant expression of B7-H3 and B7-H4 B7 molecules could be potential targets for future developm...
Phyllodes tumors are rare biphasic breast tumors with the potential for both local recurrence and distant metastasis. The aberrant expression of B7-H3 and B7-H4 B7 molecules could be potential targets for future development of immunotherapeutic approaches. This work was undertaken to evaluate the expression of B7-H3 and B7-H4 in phyllodes tumors and assess the association with the grade and clinical behavior of phyllodes tumors. In addition, the roles of B7-H3 and B7-H4 in the regulation of tumor immune surveillance were evaluated by assessing the relationship between B7-H3/B7-H4 expression and T-cell infiltration. The messenger RNA and protein expression of B7-H3/B7-H4 were determined by RNAscope in situ hybridization and immunohistochemistry, respectively, in 101 phyllodes tumors (60 benign, 26 borderline, and 15 malignant) using a tissue microarray. Immunohistochemistry for CD3 and CD8 was also performed. B7-H3 messenger RNA and protein appeared to be concentrated mainly in the stromal compartment of phyllodes tumors. However, B7-H4 messenger RNA and protein were undetectable in the stromal compartment of phyllodes tumors. Stromal B7-H3 messenger RNA and protein expression were noted in 10 (16.7%) and 31 (51.7%) of 60 benign phyllodes tumors, 12 (46.1%) and 20 (76.9%) of 26 borderline phyllodes tumors, and 10 (66.7%) and 13 (86.7%) of 15 malignant phyllodes tumors, respectively. Stromal B7-H3 messenger RNA and protein expression increased as phyllodes tumors progressed from benign to borderline and finally to the malignant grade (Pearson's R = 0.411, p < 0.001 and Pearson's R = 0.293, p = 0.003, respectively). The recurrence rate was higher in the stromal B7-H3 messenger RNA or protein-positive group than in the negative group, but this difference was not significant. Stromal B7-H3 protein expression inversely correlated with the densities of CD3 and CD8 T-cell infiltrates ( p = 0.001 and p = 0.027, respectively). These results suggest that B7-H3 is involved in the progression of phyllodes tumors and may contribute to their immune surveillance.
The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer.
De la Fuente López M, Landskron G, Parada D … +17 more , Dubois-Camacho K, Simian D, Martinez M, Romero D, Roa JC, Chahuán I, Gutiérrez R, Lopez-K F, Alvarez K, Kronberg U, López S, Sanguinetti A, Moreno N, Abedrapo M, González MJ, Quera R, Hermoso-R MA
Tumour Biol · 2018 Nov · PMID 30419802 · Publisher ↗
A complex network of chemokines can influence cancer progression with the recruitment and activation of hematopoietic cells, including macrophages to the supporting tumor stroma promoting carcinogenesis and metastasis. T...
A complex network of chemokines can influence cancer progression with the recruitment and activation of hematopoietic cells, including macrophages to the supporting tumor stroma promoting carcinogenesis and metastasis. The aim of this study was to investigate the relation between tissue and plasma chemokine levels involved in macrophage recruitment with tumor-associated macrophage profile markers and clinicopathological features such as tumor-node-metastases stage, desmoplasia, tumor necrosis factor-α, and vascular endothelial growth factor plasma content. Plasma and tumor/healthy mucosa were obtained from Chilean patients undergoing colon cancer surgery. Chemokines were evaluated from tissue lysates (CCL2, CCL3, CCL4, CCL5, and CX3CL1) by Luminex. Statistical analysis was performed using Wilcoxon match-paired test ( p < 0.05). Macrophage markers (CD68, CD163, and iNOS) were evaluated by immunohistochemistry samples derived from colorectal cancer patients. Correlation analysis between chemokines and macrophage markers and clinicopathological features were performed using Spearman's test. Plasmatic levels of chemokines and inflammatory mediators' vascular endothelial growth factor and tumor necrosis factor-α were evaluated by Luminex. Tumor levels of CCL2 (mean ± standard deviation = 530.1 ± 613.9 pg/mg), CCL3 (102.7 ± 106.0 pg/mg), and CCL4 (64.98 ± 48.09 pg/mg) were higher than those found in healthy tissue (182.1 ± 116.5, 26.79 ± 22.40, and 27.06 ± 23.69 pg/mg, respectively p < 0.05). The tumor characterization allowed us to identify a positive correlation between CCL4 and the pro-tumor macrophages marker CD163 ( p = 0.0443), and a negative correlation of iNOS with desmoplastic reaction ( p = 0.0467). Moreover, we identified that tumors with immature desmoplasia have a higher CD163 density compared to those with a mature/intermediated stromal tissue ( p = 0.0288). Plasmatic CCL4 has shown a positive correlation with inflammatory mediators (tumor necrosis factor-α and vascular endothelial growth factor) that have previously been associated with poor prognosis in patients. In conclusion High expression of CCL4 in colon cancer could induce the infiltration of tumor-associated macrophages and specifically a pro-tumor macrophage profile (CD163 cells). Moreover, plasmatic chemokines could be considered inflammatory mediators associated to CRC progression as well as tumor necrosis factor-α and vascular endothelial growth factor. These data reinforce the idea of chemokines as potential therapeutic targets or biomarker in CRC.
Dysregulated cancer cell transdifferentiation into erythrocytes is an additional metabolic stress in hepatocellular carcinoma.
Hughes A, Dhoot GK
Tumour Biol · 2018 Nov · PMID 30419801 · Publisher ↗
A number of human and canine hepatocellular carcinoma tissues showed clear signs of hypoxia indicated by HIF1α-activation and the presence of large clusters of cells resembling erythrocytes at different stages of nuclear...
A number of human and canine hepatocellular carcinoma tissues showed clear signs of hypoxia indicated by HIF1α-activation and the presence of large clusters of cells resembling erythrocytes at different stages of nuclear elimination without any defined endothelial cell lining or blood vessel walls. Differentiated erythrocytic identity of such cells in hepatocellular carcinoma tissues was apparent from their non-nucleated and evolving basophilic to eosinophilic staining characteristics. In addition to the fully differentiated non-nucleated mesenchymal cell clusters, the onset of erythroblastic transdifferentiation was apparent from the activation of Glycophorin A, a marker of erythrocytic progenitors, in some epithelial cancer cells. Activation of canonical Wnt signalling in such tumours was apparent from the expression of Wnt2 ligand and active β-catenin translocation into the nucleus indicating Wnt signalling to be one of the key signalling pathways participating in such cell transdifferentiation. Sonic hedgehog and bone morphogenetic protein signalling along with Sulf1/Sulf2 activation was also observed in such hepatocellular carcinoma tissue samples. The presence of stem cell markers and the cell signalling pathways associated with erythropoiesis, and the detection of messenger RNAs for both α and β haemoglobins, support the assumption that hepatocellular carcinoma cells have the potential to undergo cell fate change despite this process being dysregulated as indicated by the lack of simultaneous generation of endothelial cell lining. Lack of blood vessel walls or endothelial cell lining around erythrocytic clusters was confirmed by non-detection of multiple blood vessel markers such as vWF, CD146 and smooth muscle α-actin that were clearly apparent in normal and unaffected adjacent regions of hepatocellular carcinoma livers. In addition to the activation of Glycophorin A, transdifferentiation of some hepatocellular carcinoma hepatocytes into other cell fates was further confirmed by the activation of some stem cell markers, for example, NANOG and OCT4 transcription factors, not only by reverse transcription polymerase chain reaction but also by their restricted expression in such cells at protein level.
MicroRNA-23b and microRNA-27b plus flutamide treatment enhances apoptosis rate and decreases CCNG1 expression in a castration-resistant prostate cancer cell line.
Pimenta RC, Viana NI, Amaral GQ … +9 more , Park R, Morais DR, Pontes J, Guimaraes VR, Camargo JA, Leite KR, Nahas WC, Srougi M, Reis ST
Tumour Biol · 2018 Nov · PMID 30400755 · Publisher ↗
The acquisition of a castration-resistant prostate cancer phenotype by prostate cancer cells is the alteration that has the worst prognosis for patients. The aim of this study was to evaluate the role of the microRNAs-23...
The acquisition of a castration-resistant prostate cancer phenotype by prostate cancer cells is the alteration that has the worst prognosis for patients. The aim of this study was to evaluate the role of the microRNAs-23b/-27b as well as the possible CCNG1 target gene in tissue samples from patients with localized prostate cancer that progressed to castration-resistant prostate cancer and in a castration-resistant prostate cancer cell line (PC-3). The microRNAs and target gene expression levels of the surgical specimens were analyzed by quantitative real-time polymerase chain reaction. The prostate cancer cell line, PC-3, was transfected with pre-miR-23b, pre-miR-27b, and their respective controls using Lipofectamine RNAiMAX and exposed or not to flutamide. After transfections, expression levels of both the microRNAs and the gene, CCNG1, were analyzed by quantitative real-time polymerase chain reaction. The apoptosis and cell cycle assays were performed on the mini MUSE cytometer. MicroRNAs-23b/-27b were underexpressed in surgical specimens of prostate cancer; however, their target gene, CCNG1, was overexpressed in 69% of the cases. After transfection with the microRNAs-23b/-27b and flutamide, we observed a reduction in gene expression compared with cells that were treated only with microRNAs or only with flutamide. In the apoptosis assay, we demonstrated cell sensitization following transfection with microRNAs-23b/-27b and potentiation when co-administered with flutamide. The number of cells in apoptosis was almost three times higher with the simultaneous treatments (miR + flutamide) compared with the control (p < 0.05). In the cell cycle assay, only flutamide treatment showed better results; a higher number of cells were found in the G0-G1 phase, and a lower percentage of cells completed the final phase of the cycle (p < 0.05). We conclude that microRNAs-23b/-27b are downexpressed in prostate cancer, and their target gene, CCNG1, is overexpressed. We postulated that microRNAs-23b/-27b sensitize the PC-3 cell line and that after the addition of flutamide in the apoptosis assay, we would observe synergism in the treatments between miR and flutamide. In the cell cycle assay, the use of flutamide was sufficient to decrease the number of cells in mitosis. Therefore, we postulate that microRNAs, along with other drugs, may become very useful therapeutic tools in the treatment of castration-resistant prostate cancer.
Dual loss of USP10 and p14ARF protein expression is associated with poor prognosis in patients with small intestinal adenocarcinoma.
Song JS, Yi JM, Cho H … +6 more , Choi CH, Park Y, Chung EJ, Song J, Chung JY, Hong SM
Tumour Biol · 2018 Oct · PMID 30375264 · Publisher ↗
Oncogene-induced senescence occurs following oncogene activation in normal cells and is considered as a critical tumor-suppressing mechanism. Ubiquitin-specific protease 10 (USP10) has been reported to play a vital role...
Oncogene-induced senescence occurs following oncogene activation in normal cells and is considered as a critical tumor-suppressing mechanism. Ubiquitin-specific protease 10 (USP10) has been reported to play a vital role in oncogene-induced senescence via the deubiquitination-dependent stabilization of p14ARF. However, knowledge of the clinical significance of USP10 and p14ARF expression in patients with small intestinal adenocarcinoma is limited. To study the clinical significance of USP10 and p14ARF expression, we performed immunohistochemistry for USP10 and p14ARF on 195 surgically resected small intestinal adenocarcinoma specimens. Furthermore, we performed methylation analysis on five small intestinal adenocarcinoma samples and matched adjacent normal intestinal tissue samples. UPS10 ( p = 0.023) and p14ARF ( p = 0.007) expression were significantly decreased in adenocarcinoma in comparison with normal tissue. The loss of USP10 was observed in 124/194 (63.9%) of small intestinal adenocarcinoma samples and was correlated with a higher pT stage ( p = 0.044), lymphatic invasion ( p = 0.033), and the absence of sporadic adenoma ( p = 0.024) and peritumoral dysplasia ( p = 0.019). p14ARF expression was downregulated in 75/195 (38.5%) of small intestinal adenocarcinoma samples and was associated with vascular ( p = 0.011) and lymphatic ( p = 0.013) invasions. The loss of USP10 expression was associated with the loss of p14ARF expression ( r = 0.342, p < 0.001). Multivariate survival analysis revealed that the combined loss of USP10 and p14ARF expression could be an independent prognostic factor for overall survival in small intestinal adenocarcinoma. Furthermore, the aberrant hypermethylation of the USP10 and p14ARF promoter could be a key mechanism for the downregulation of USP10 and p14ARF proteins in small intestinal adenocarcinoma. These findings suggest that the dual loss of USP10 and p14ARF could be used as a prognostic indicator of small intestinal adenocarcinoma.
Tamoxifen suppresses paclitaxel-, vincristine-, and bortezomib-induced neuropathy via inhibition of the protein kinase C/extracellular signal-regulated kinase pathway.
Tsubaki M, Takeda T, Matsumoto M … +6 more , Kato N, Yasuhara S, Koumoto YI, Imano M, Satou T, Nishida S
Tumour Biol · 2018 Oct · PMID 30360692 · Publisher ↗
Chemotherapy-induced neuropathy is a highly problematic, dose-limiting effect of potentially curative regimens of cancer chemotherapy. When neuropathic pain is severe, patients often either switch to less-effective chemo...
Chemotherapy-induced neuropathy is a highly problematic, dose-limiting effect of potentially curative regimens of cancer chemotherapy. When neuropathic pain is severe, patients often either switch to less-effective chemotherapy agents or choose to discontinue chemotherapy entirely. Conventional chemotherapy drugs used to treat lung and breast cancer, multiple myeloma, and lymphoma include paclitaxel, vincristine, and bortezomib. Approximately 68% of patients receiving these anticancer drugs develop neuropathy within the first month of treatment, and while strategies to prevent chemotherapy-induced neuropathy have been investigated, none have yet been proven as effective. Recent reports suggest that chemotherapy-induced neuropathy is associated with signal transduction molecules, including protein kinase C and mitogen-activated protein kinases. It is currently unclear whether protein kinase C inhibition can prevent chemotherapy-induced neuropathy. In this study, we found that tamoxifen, a protein kinase C inhibitor, suppressed paclitaxel-, vincristine-, and bortezomib-induced cold and mechanical allodynia in mice. In addition, chemotherapy drugs induce neuropathy via the protein kinase C/extracellular signal-regulated kinase pathway in the spinal cord in lumbar segments 4-6 and dorsal root ganglions. In addition, tamoxifen was shown to act synergistically with paclitaxel to inhibit tumor-growth in mice injected with tumor cells. Our results indicated that paclitaxel-, vincristine-, and bortezomib-induced neuropathies were associated with the protein kinase C/extracellular signal-regulated kinase pathway in the lumbar spinal cord and dorsal root ganglions, which suggest that protein kinase C inhibitors may be therapeutically effective for the prevention of chemotherapy-induced neuropathy when administered with standard chemotherapy agents.
Assessment of the clinicopathological relevance of mesothelin level in plasma, peritoneal fluid, and tumor tissue of epithelial ovarian cancer patients.
Okła K, Surówka J, Frąszczak K … +5 more , Czerwonka A, Kaławaj K, Wawruszak A, Kotarski J, Wertel I
Tumour Biol · 2018 Oct · PMID 30319054 · Publisher ↗
Ovarian cancer remains the most lethal gynecologic malignancy. This is due to lack of effective screening, diagnosis predominance in late stage of disease, a high recurrence rate after primary therapy, and poor treatment...
Ovarian cancer remains the most lethal gynecologic malignancy. This is due to lack of effective screening, diagnosis predominance in late stage of disease, a high recurrence rate after primary therapy, and poor treatment response in platinum-resistant tumor. Thus, unique biomarkers, predictive of individual disease course, and prognosis are urgently needed. The aim of our study was to assess the clinicopathological significance of plasma, peritoneal fluid, and tumor tissue levels of mesothelin in epithelial ovarian cancer patients. Plasma and peritoneal fluid levels of mesothelin were measured by enzyme-linked immunosorbent assay. Tissue expression of MSLN was evaluated using quantitative real-time polymerase chain reaction. Preoperative plasma mesothelin levels were significantly higher in epithelial ovarian cancer patients in comparison to the patients with benign tumor and controls. There have been noticed significant differences in the plasma mesothelin levels based on International Federation of Gynecology and Obstetrics stage, grade, and histology type. No significant changes were observed between Kurman and Shih type I versus type II epithelial ovarian cancer. Interestingly, peritoneal fluid mesothelin levels revealed significant differences based on both grade and Kurman and Shih-type epithelial ovarian cancer. There were no relevant changes in the mesothelin level in peritoneal fluid between different stages and histology types compared to benign tumor. MSLN expression level in tumor tissue was significantly higher based on stage, grade, and Kurman and Shih-type epithelial ovarian cancer than in the benign masses. In addition, data showed significant higher MSLN expression in endometrioid tumors compared to benign masses and serous tumors. Plasma, peritoneal fluid, and tumor tissue levels of mesothelin positively correlated with level of CA125. Low mesothelin concentrations in plasma were also associated with prolonged patient survival. More importantly, we revealed that plasma mesothelin level was correlated with both peritoneal fluid mesothelin level and tumor MSLN expression. This study highlights that plasma mesothelin level may be a useful noninvasive biomarker surrogate for local tumor mesothelin status in monitoring of epithelial ovarian cancer patients.
Deep learning approach for survival prediction for patients with synovial sarcoma.
Han I, Kim JH, Park H … +2 more , Kim HS, Seo SW
Tumour Biol · 2018 Sep · PMID 30261823 · Publisher ↗
Synovial sarcoma is a rare disease with diverse progression characteristics. We developed a novel deep-learning-based prediction algorithm for survival rates of synovial sarcoma patients. The purpose of this study is to...
Synovial sarcoma is a rare disease with diverse progression characteristics. We developed a novel deep-learning-based prediction algorithm for survival rates of synovial sarcoma patients. The purpose of this study is to evaluate the performance of the proposed prediction model and demonstrate its clinical usage. The study involved 242 patients who were diagnosed with synovial sarcoma in three institutions between March 2001 and February 2013. The patients were randomly divided into a training set (80%) and a testing set (20%). Fivefold cross validation was performed utilizing the training set. The test set was retained for the final testing. A Cox proportional hazard model, simple neural network, and the proposed survival neural network were all trained utilizing the same training set, and fivefold cross validation was performed. The final testing was performed utilizing the isolated test data to determine the best prediction model. The multivariate Cox proportional hazard regression analysis revealed that size, initial metastasis, and margin were independent prognostic factors. In fivefold cross validation, the median value of the receiver-operating characteristic curve (area under the curve) was 0.87 in the survival neural network, which is significantly higher compared to the area under the curve of 0.792 for the simple neural network (p = 0.043). In the final test, survival neural network model showed the better performance (area under the curve: 0.814) compared to the Cox proportional hazard model (area under the curve: 0.629; p = 0.0001). The survival neural network model predicted survival of synovial sarcoma patients more accurately compared to Cox proportional hazard model.
Sequence analysis of cell-free DNA derived from cultured human bone osteosarcoma (143B) cells.
Bronkhorst AJ, Wentzel JF, Ungerer V … +5 more , Peters DL, Aucamp J, de Villiers EP, Holdenrieder S, Pretorius PJ
Tumour Biol · 2018 Sep · PMID 30261820 · Publisher ↗
The true importance of cell-free DNA in human biology, together with the potential scale of its clinical utility, is tarnished by a lack of understanding of its composition and origin. In investigating the cell-free DNA...
The true importance of cell-free DNA in human biology, together with the potential scale of its clinical utility, is tarnished by a lack of understanding of its composition and origin. In investigating the cell-free DNA present in the growth medium of cultured 143B cells, we previously demonstrated that the majority of cell-free DNA is neither a product of apoptosis nor necrosis. In the present study, we investigated the composition and origin of this cell-free DNA population using next-generation sequencing. We found that the cell-free DNA comprises mainly of repetitive DNA, including α-satellite DNA, mini satellites, and transposons that are currently active or exhibit the capacity to become reactivated. A significant portion of these cell-free DNA fragments originates from specific chromosomes, especially chromosomes 1 and 9. In healthy adult somatic cells, the centromeric and pericentromeric regions of these chromosomes are normally densely methylated. However, in many cancer types, these regions are preferentially hypomethylated. This can lead to double-stranded DNA breaks or it can directly impair the formation of proper kinetochore structures. This type of chromosomal instability is a precursor to the formation of nuclear anomalies, including lagging chromosomes and anaphase bridges. DNA fragments derived from these structures can recruit their own nuclear envelope and form secondary nuclear structures known as micronuclei, which can localize to the nuclear periphery and bud out from the membrane. We postulate that the majority of cell-free DNA present in the growth medium of cultured 143B cells originates from these micronuclei.
Toll-like receptor 2 and Toll-like receptor 4 predict favorable prognosis in local pancreatic cancer.
Lanki MA, Seppänen HE, Mustonen HK … +4 more , Böckelman C, Juuti AT, Hagström JK, Haglund CH
Tumour Biol · 2018 Sep · PMID 30246618 · Publisher ↗
Toll-like receptors play an essential role in our innate immune system and are a focus of interest in contemporary cancer research. Thus far, Toll-like receptors have shown promising prognostic value in carcinomas of the...
Toll-like receptors play an essential role in our innate immune system and are a focus of interest in contemporary cancer research. Thus far, Toll-like receptors have shown promising prognostic value in carcinomas of the oral cavity, colon, and ovaries, but the prognostic role of Toll-like receptors in pancreatic ductal adenocarcinoma has not been established. We set out to investigate whether Toll-like receptor expression could serve in prognostic evaluation in pancreatic ductal adenocarcinoma, as well. Our study comprised 154 consecutive stage I-III pancreatic ductal adenocarcinoma patients surgically treated at Helsinki University Hospital between 2002 and 2011. Patients who received neoadjuvant therapy were excluded. Tissue microarrays and immunohistochemistry allowed assessment of the expression of Toll-like receptor 2 and Toll-like receptor 4 in pancreatic ductal adenocarcinoma tissue, and we matched staining results against clinicopathological parameters using Fisher's test. For survival analysis, we used the Kaplan-Meier method and the log-rank test, and the Cox regression proportional hazard model for univariate and multivariate analyses. The hazard ratios were calculated for disease-specific overall survival. Strong Toll-like receptor 2 expression was observable in 51 (34%) patients and strong Toll-like receptor 4 in 50 (33%) patients. Overall, neither marker showed any direct coeffect on survival. However, strong Toll-like receptor 2 expression predicted better survival when tumor size was less than 30 mm (hazard ratio = 0.30; 95% confidence interval = 0.13-0.69; p = 0.005), and strong Toll-like receptor 4 expression predicted better survival in patients with lymph-node-negative disease (hazard ratio = 0.21; 95% confidence interval = 0.07-0.65; p = 0.006). In conclusion, we found strong Toll-like receptor 2 and Toll-like receptor 4 expressions to be independent factors of better prognosis in pancreatic ductal adenocarcinoma patients with stage I-II disease.
Effect of Pseuderanthemum palatiferum (Nees) Radlk fresh leaf ethanolic extract on human breast cancer MDA-MB-231 regulated cell death.
Komonrit P, Banjerdpongchai R
Tumour Biol · 2018 Sep · PMID 30226114 · Publisher ↗
Leaf extracts of Pseuderanthemum palatiferum (Nees) Radlk were investigated for their effects on human breast cancer MDA-MB-231 cell growth inhibition. Pseuderanthemum palatiferum (Nees) Radlk extracts were prepared usin...
Leaf extracts of Pseuderanthemum palatiferum (Nees) Radlk were investigated for their effects on human breast cancer MDA-MB-231 cell growth inhibition. Pseuderanthemum palatiferum (Nees) Radlk extracts were prepared using fresh or dried leaves and extracted by either water or 95% ethanol, respectively. Fresh leaf ethanolic extract was the most toxic to MDA-MB-231 cells measured by 3-(4,5-dimethyl)-2,5-diphenyl tetrazolium bromide assay. Fresh leaf ethanolic extract-treated MDA-MB-231 cell death was stained with propidium iodide and examined under fluorescence microscopy. Cell death was confirmed by annexin V-fluorescein isothiocyanate/propidium iodide and propidium iodide-stained cells employing flow cytometry. The mitochondrial transmembrane potential was disrupted in fresh leaf ethanolic extract-treated MDA-MB-231 cells and the percentage of cells with reduced mitochondrial transmembrane potential increased according to concentrations. Mitochondrial transmembrane potential-driven regulated cell deaths were in the form of both apoptosis and necrosis. Oxidative stress probe, 2',7'-dichlorodihydrofluorescein diacetate, was used to indicate the redox status. Dichlorofluorescein level was significantly lower at high fresh leaf ethanolic extract concentrations. Total phenolic contents were found in all Pseuderanthemum palatiferum (Nees) Radlk extracts, whereas Ca level in the cytosol increased, indicating Ca overload and endoplasmic reticulum stress involvement with the activation of caspase-3, -8, and -9. In conclusion, fresh leaf ethanolic extract induced human breast cancer MDA-MB-231 programmed cell death via endoplasmic reticulum and oxidative stress by activating both extrinsic and intrinsic signaling pathways.
Targeted next-generation sequencing of 50 cancer-related genes in Japanese patients with oral squamous cell carcinoma.
Nakagaki T, Tamura M, Kobashi K … +7 more , Omori A, Koyama R, Idogawa M, Ogi K, Hiratsuka H, Tokino T, Sasaki Y
Tumour Biol · 2018 Sep · PMID 30226113 · Publisher ↗
Somatic mutation analysis is a standard of practice for human cancers to identify therapeutic sensitization and resistance mutations. We performed a multigene sequencing screen to explore mutational hotspots in cancer-re...
Somatic mutation analysis is a standard of practice for human cancers to identify therapeutic sensitization and resistance mutations. We performed a multigene sequencing screen to explore mutational hotspots in cancer-related genes using a semiconductor-based sequencer. DNA from oral squamous cell carcinoma samples was used as a template to amplify 207 regions from 50 cancer-related genes. Of the 80 oral squamous cell carcinoma specimens from Japanese patients, including formalin-fixed paraffin-embedded samples, 56 specimens presented at least one somatic mutation among the 50 investigated genes, and 17 of these samples showed multiple gene somatic mutations. TP53 was the most commonly mutated gene (50.0%), followed by CDKN2A (16.3%), PIK3CA (7.5%), HRAS (5.0%), MET (2.5%), and STK11 (2.5%). In total, 32 cases (40.0%) were human papillomavirus positive and they were significantly less likely to have a TP53, mutation than human papillomavirus-negative oral squamous cell carcinomas (8/32, 25.0% vs 32/48, 66.7%, p = 0.00026). We also detected copy number variations, in which segments of the genome could be duplicated or deleted from the sequencing data. We detected the tumor-specific TP53 mutation in the plasma cell-free DNA from two oral squamous cell carcinoma patients, and after surgery, the test for these mutations became negative. Our approach facilitates the simultaneous high-throughput detection of somatic mutations and copy number variations in oral squamous cell carcinoma samples.
Acetylcholine induces stem cell properties of gastric cancer cells of diffuse type.
Nguyen PH, Touchefeu Y, Durand T … +6 more , Aubert P, Duchalais E, Bruley des Varannes S, Varon C, Neunlist M, Matysiak-Budnik T
Tumour Biol · 2018 Sep · PMID 30207200 · Publisher ↗
Gastric cancer is the third leading cause of cancer-related death worldwide, but the mechanisms of gastric carcinogenesis are not completely understood. Recently, the role of cholinergic neuronal pathways in promoting th...
Gastric cancer is the third leading cause of cancer-related death worldwide, but the mechanisms of gastric carcinogenesis are not completely understood. Recently, the role of cholinergic neuronal pathways in promoting this process has been demonstrated. Our aim was to extend these studies and to evaluate, using an in vitro model of tumorspheres, the effect of acetylcholine on human gastric cancer cells, and the role of acetylcholine receptors and of the nitric oxide pathway, in this effect. The gastric cancer cell line MKN-45 of the diffuse type of gastric cancer was cultured in the presence of acetylcholine, or different agonists or inhibitors of muscarinic and nicotinic acetylcholine receptors, or nitric oxide donor or inhibitor of the nitric oxide pathway, and the number and size of tumorspheres were assessed. The expression of cancer stem cell markers (CD44 and aldehyde dehydrogenase) was also evaluated by immunofluorescence and quantitative reverse transcription polymerase chain reaction. We showed that acetylcholine increased both the number and size of tumorspheres and that this effect was reproduced with both muscarinic and nicotinic acetylcholine receptors agonists and was inhibited by both receptor antagonists. The nitric oxide donor stimulated the tumorsphere formation, while the nitric oxide synthesis inhibitor inhibited the stimulatory effect of acetylcholine. Moreover, acetylcholine increased the expression of stem cell markers on gastric cancer cells. These results indicate that acetylcholine induces the stem cell properties of gastric cancer cells and both muscarinic and nicotinic receptors and a nitrergic pathway might be involved in this effect.
Are localized prostate cancer biomarkers useful in the clinical practice?
Carneiro A, Priante Kayano P, Gomes Barbosa ÁR … +8 more , Langer Wroclawski M, Ko Chen C, Cavlini GC, Reche GJ, Sanchez-Salas R, Tobias-Machado M, Sowalsky AG, Bianco B
Tumour Biol · 2018 Sep · PMID 30204063 · Full text
Prostate cancer presents itself in a heterogeneous way with both aggressive and indolent forms. Despite the controversy surrounding its use, prostate-specific antigen screening ultimately leads to a greater number of dia...
Prostate cancer presents itself in a heterogeneous way with both aggressive and indolent forms. Despite the controversy surrounding its use, prostate-specific antigen screening ultimately leads to a greater number of diagnosed patients. One of the biggest challenges in clinical practice is to select the right patients for biopsy and, among diagnosed patients, to differentiate tumors with an indolent course from those with an unfavorable prognosis, in order to determine the best therapeutic decision for each case, avoiding unnecessary interventions. Currently, several types of biomarkers are available for clinical use in patients with prostate cancer, which include blood-based (prostate-specific antigen, Prostate Health Index®, 4K score®); urine sample-based (PCA3, SelectMDx®, ExoDx Prostate IntelliScore®); and biopsy, transurethral resection, or radical prostatectomy tissue-based (ConfirmMDx®, Oncotype®, Prolaris®, Decipher®). The aim of this review is to provide an overview of the current state of evidence and to highlight recent advances in the evaluation and diagnosis of prostate cancer, with emphasis on biomarkers related to diagnosis and to prognostic evaluation of localized prostate cancer.
Lymph node CXCL17 messenger RNA: A new prognostic biomarker for colon cancer.
Rashad Y, Olsson L, Israelsson A … +5 more , Öberg Å, Lindmark G, Hammarström ML, Hammarström S, Sitohy B
Tumour Biol · 2018 Sep · PMID 30198422 · Publisher ↗
Lymph node metastasis is the most important prognostic characteristic of colorectal cancer. Carcinoembryonic antigen messenger RNA was shown to detect tumor cells that have disseminated to lymph nodes of colorectal cance...
Lymph node metastasis is the most important prognostic characteristic of colorectal cancer. Carcinoembryonic antigen messenger RNA was shown to detect tumor cells that have disseminated to lymph nodes of colorectal cancer patients and to be at least as good as the hematoxylin and eosin method to predict survival in colorectal cancer patients. CXCL17 was recently shown to be ectopically expressed in colon cancer tumors. Therefore, CXCL17 may serve as prognostic marker alone or in combination with carcinoembryonic antigen. CXCL17 and carcinoembryonic antigen messenger RNA levels were determined using quantitative reverse transcription polymerase chain reaction with RNA copy standard in 389 lymph nodes of 120 colon cancer patients (stages I-IV) and 67 lymph nodes of 12 control patients with inflammatory bowel disease as well as in 68 primary tumors and 30 normal colon tissue samples. Lymph nodes of colon cancer patients were analyzed for CXCL17 and carcinoembryonic antigen protein expression by immunohistochemistry. CXCL17 messenger RNA was expressed in primary tumors at high levels, while it was barely detected in normal colon tissue ( p < 0.0001). Similarly, CXCL17 messenger RNA levels were significantly higher in hematoxylin- and eosin-positive (hematoxylin and eosin (+)) lymph nodes compared to hematoxylin- and eosin-negative nodes ( p < 0.0001). CXCL17 messenger RNA levels were investigated in lymph nodes grouped according to carcinoembryonic antigen messenger RNA levels: low (-), intermediate (int), and high (+). CXCL17 messenger RNA levels were higher in the carcinoembryonic antigen (int) and carcinoembryonic antigen (+) groups compared to the carcinoembryonic antigen (-) group ( p = 0.03 and p < 0.0001, respectively). In lymph nodes of stage III and IV patients, CXCL17 messenger RNA levels correlated with carcinoembryonic antigen messenger RNA levels ( p < 0.0001, r = 0.56 and p = 0.0002, r = 0.66, respectively). Staining of consecutive lymph node sections for CXCL17 and carcinoembryonic antigen demonstrated that the same cells expressed both proteins. Altogether, these results indicate that CXCL17 in lymph nodes is expressed by tumor cells. Patients were grouped according to the CXCL17 messenger RNA levels in the highest lymph node with low levels (-) and high levels (+). CXCL17(+) colon cancer patients showed 2.8-3.6 fold increased risk for recurrence ( p = 0.03) and decreased mean disease-free survival time of 8 months compared to CXCL17(-) colon cancer patients ( p = 0.03). CXCL17(+) carcinoembryonic antigen (int) colon cancer patients showed increased risk for recurrence by 8.3 fold ( p = 0.04) and decreased mean disease-free survival time of 46 months compared to CXCL17(-) carcinoembryonic antigen (int) colon cancer patient at follow-up after 12 years ( p = 0.02). The presence of tumor cells expressing CXCL17 in regional lymph nodes is a sign of poor prognosis. Analysis of CXCL17 messenger RNA is particularly useful to detect less differentiated colon cancer tumors expressing relatively low carcinoembryonic antigen messenger RNA levels. Thus, CXCL17 messenger RNA in combination with carcinoembryonic antigen messenger RNA may be used as a complementary tool to the hematoxylin and eosin method for detection of poorly differentiated, aggressive tumors.
Clinically relevant radioresistant cells exhibit resistance to HO by decreasing internal HO and lipid peroxidation.
Tomita K, Kuwahara Y, Takashi Y … +7 more , Igarashi K, Nagasawa T, Nabika H, Kurimasa A, Fukumoto M, Nishitani Y, Sato T
Tumour Biol · 2018 Sep · PMID 30192208 · Publisher ↗
Radiation therapy is one of the choices to treat malignant tumors. In radiation therapy, existence of radiation-resistant cell is a major problem to overcome. We established clinically relevant radioresistant cells that...
Radiation therapy is one of the choices to treat malignant tumors. In radiation therapy, existence of radiation-resistant cell is a major problem to overcome. We established clinically relevant radioresistant cells that had been obtained by exposing to 2 Gy/day X-rays for more than 30 days. These cells are resistant to 2 Gy/day X-ray exposure and anticancer agents. However, the underlying resistance mechanism remains unclear. We investigated the resistance of clinically relevant radioresistant cells to hydrogen peroxide (HO), confirming a degree of resistance. Neither catalase enzyme activity nor aquaporins appeared to be involved in HO resistance. Mitochondrial DNA copy number, adenosine triphosphate (ATP) concentration, and plasma membrane potential were decreased. The timing of HO intake was delayed and lipid peroxidation was decreased. Sensitivity of clinically relevant radioresistant cells to HO was enhanced by 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine administration. These results suggest that the membrane status is a major factor conferring HO resistance in clinically relevant radioresistant cells, and we should further investigate how membrane status could be used to enhance the therapeutic effect on cancer.
Serum MMP-8 and TIMP-1 as prognostic biomarkers in gastric cancer.
Laitinen A, Hagström J, Mustonen H … +5 more , Kokkola A, Tervahartiala T, Sorsa T, Böckelman C, Haglund C
Tumour Biol · 2018 Sep · PMID 30192205 · Publisher ↗
Despite gastric cancer being rare nowadays in Western countries, it remains one of the leading causes of cancer death worldwide. The course of the disease varies, so the individual gastric cancer patient's prognosis is d...
Despite gastric cancer being rare nowadays in Western countries, it remains one of the leading causes of cancer death worldwide. The course of the disease varies, so the individual gastric cancer patient's prognosis is difficult to determine. The need for new biomarkers is crucial. The aim of this study was to evaluate the prognostic value of serum matrix metalloproteinase-8, serum tissue inhibitor of metalloproteinase-1, and tissue matrix metalloproteinase-8 in patients with gastric cancer. Preoperative serum samples from 233 patients with gastric cancer were retrospectively analyzed. Serum levels of matrix metalloproteinase-8 were analyzed with immunofluorometric assay, and tissue inhibitor of metalloproteinase-1 levels were determined by enzyme-linked immunosorbent assay. We also determined the tissue expression of matrix metalloproteinase-8 in 276 gastric cancer samples by immunohistochemistry. Survival data and death causes came from patient records, the Population Register Center of Finland, and Statistics Finland. Patients with a low (<31 ng/mL) or high (>131 ng/mL) serum matrix metalloproteinase-8 level had a considerably unfavorable prognosis (p = 0.002). Those patients with a high (≥170 ng/mL) serum tissue inhibitor of metalloproteinase-1 level also had a poor prognosis (p < 0.001), and the latter remained significant in multivariable analysis (hazard ratio = 1.85; 95% confidence interval: 1.26-2.72; p = 0.002). The molar ratio of serum matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 levels with low (<0.07) or high (>0.30) molar ratios predicted a worse prognosis (p = 0.020). Tissue matrix metalloproteinase-8 did not influence prognosis. These results suggest that serum matrix metalloproteinase-8, tissue inhibitor of metalloproteinase-1, and the ratio of matrix metalloproteinase-8/ tissue inhibitor of metalloproteinase-1 may prove useful biomarkers for prediction of prognosis in patients with gastric cancer.
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