Tumour Biology[JOURNAL]
Sun
200 papers
HE4 and CA125 serum biomarker monitoring in women with epithelial ovarian cancer.
Samborski A, Miller MC, Blackman A … +5 more , MacLaughlan-David S, Jackson A, Lambert-Messerlian G, Rowswell-Turner R, Moore RG
Tumour Biol · 2022 · PMID 36189508 · Publisher ↗
BACKGROUND: CA125 is the gold standard serum biomarker for monitoring patients with epithelial ovarian cancer (EOC). Human epididymal protein 4 (HE4) is a novel serum biomarker for EOC patients. OBJECTIVE: The objective...
BACKGROUND: CA125 is the gold standard serum biomarker for monitoring patients with epithelial ovarian cancer (EOC). Human epididymal protein 4 (HE4) is a novel serum biomarker for EOC patients. OBJECTIVE: The objective of this trial was to examine the utility of measuring serum HE4 levels for monitoring EOC patients and to compare HE4 performance parameters to serum CA125. METHODS: A retrospective trial using residual longitudinal serum samples drawn during treatment and monitoring from EOC patients. Serum CA125 and HE4 levels were analyzed at each time point, and a velocity of change was calculated and correlated with clinical status. The null hypothesis was that HE4 is inferior to CA125, and this was tested using concordance and two-sided Fisher's exact testing. McNemar's test was used to assess the overall agreement of the two assays with the clinical status. RESULTS: A total of 129 patients with 272 separate clinical periods and 1739 events (serum samples) were evaluated. Using a 25% change in serum biomarker levels to indicate change in disease status, the accuracy and NPV determined for HE4 versus CA125 were 81.8% versus 82.6% (p = 0.846) and 87.4% versus 89.7% (p = 0.082), respectively. Concordance comparison of HE4 accuracy / CA125 accuracy was 0.990, indicating HE4 was not inferior to CA125 (McNemar's test p-value = 0.522). Performing a velocity of change analysis, the accuracy and NPV determined for HE4 versus CA125 were 78.3% versus 78.6% (p = 0.995) and 74.9% versus 76.3% (p = 0.815), respectively. Concordance comparison of HE4 velocity accuracy / CA125 velocity accuracy was 0.996, again indicating HE4 was not inferior to CA125 (McNemar's test p-value = 0.884). The combination of HE4 and CA125 velocity changes showed a similar accuracy of 81.3% (p = 0.797 compared to HE4 and CA125 alone) and NPV of 81.1% (p≥0.172 compared to HE4 and CA125 alone), and an increased sensitivity of 70.5% (p≤0.070 compared to HE4 and CA125 alone). CONCLUSION: HE4 is equivalent to CA125 for monitoring of EOC patients. The combination of CA125 and HE4 velocities is superior to either marker alone.
Induction of alternative NF-κB within TAg-induced basal mammary tumors in activation-resistant inhibitor of κ-B kinase (IKKα) mutant mice.
Ould-Brahim F, Sau A, Carr DA … +2 more , Jiang T, Pratt MAC
Tumour Biol · 2022 · PMID 36093651 · Publisher ↗
BACKGROUND: The alternative NF-κB pathway is activated by the NF-κB-inducing kinase (NIK) mediated phosphorylation of the inhibitor of κ-B kinase α (IKKα). IKKα then phosphorylates p100/NFKB2 to result in its processing...
BACKGROUND: The alternative NF-κB pathway is activated by the NF-κB-inducing kinase (NIK) mediated phosphorylation of the inhibitor of κ-B kinase α (IKKα). IKKα then phosphorylates p100/NFKB2 to result in its processing to the active p52 subunit. Evidence suggests that basal breast cancers originate within a subpopulation of luminal progenitor cells which is expanded by signaling to IKKα. OBJECTIVE: To determine the role of IKKα in the development of basal tumors. METHODS: Kinase dead IkkαAA/AA mice were crossed with the C3(1)-TAg mouse model of basal mammary cancer. Tumor growth and tumor numbers in WT and IkkαAA/AA mice were assessed and immunopathology, p52 expression and stem/progenitor 3D colony forming assays were performed. Nik-/- mammary glands were isolated and mammary colonies were characterized. RESULTS: While tumor growth was slower than in WT mice, IkkαAA/AA tumor numbers and pathology were indistinguishable from WT tumors. Both WT and IkkαAA/AA tumors expressed p52 except those IkkαAA/AA tumors where NIK, IKKαAA/AA and ErbB2 were undetectable. Colonies formed by WT and IkkαAA/AA mammary cells were nearly all luminal/acinar however, colony numbers and sizes derived from IkkαAA/AA cells were reduced. In contrast to IkkαAA/AA mice, virgin Nik-/- mammary glands were poorly developed and colonies were primarily derived from undifferentiated bipotent progenitor cells. CONCLUSIONS: C3(1)-TAg induced mammary tumors express p100/p52 even without functional IKKα. Therefore the development of basal-like mammary cancer does not strictly rely on IKKα activation. Signal-induced stabilization of NIK may be sufficient to mediate processing of p100NFKB2 which can then support basal-like mammary tumor formation. Lastly, in contrast to the pregnancy specific role of IKKα in lobuloalveogenesis, NIK is obligatory for normal mammary gland development.
Unfavorable prognosis and clinical consequences of APOBEC3B expression in breast and other cancers: A systematic review and meta-analysis.
Jafarpour S, Yazdi M, Nedaeinia R … +2 more , Ghobakhloo S, Salehi R
Tumour Biol · 2022 · PMID 36093650 · Publisher ↗
INTRODUCTION: Controversy exists regarding the association of apolipoprotein B mRNA editing enzyme catalytic subunit 3B APOBEC3B, (A3B) overexpression and poor prognosis, metastasis, and chemotherapy drug resistance in c...
INTRODUCTION: Controversy exists regarding the association of apolipoprotein B mRNA editing enzyme catalytic subunit 3B APOBEC3B, (A3B) overexpression and poor prognosis, metastasis, and chemotherapy drug resistance in cancers. Here we conducted a systematic review and meta-analysis to determine its prognostic value and clinicopathological features in breast cancer and some other malignancies. MATERIALS AND METHODS: PubMed, Scopus, Cochrane Library, Web of Science, and EMBASE were searched up to Feb 2022 for the association of A3B with breast, ovarian, gastrointestinal and lung cancers. The pooled hazard ratios with 95% confidence interval (CI) were evaluated to assess disease-free survival (DFS), overall survival (OS), and recurrence-free survival (RFS) in cancers under study. RESULTS: Over 3700 patients were included in this meta-survey. Elevated levels of A3B were significantly related to low OS (pooled HR = 1.30; 95% CI:1.09-1.55, P < 0.01), poor DFS (pooled HR = 1.66; 95% CI:1.17-2.35, P < 0.01) and poor RFS (HR = 1.51, 95% CI:1.11-2.04, P = 0.01). Subgroup analysis revealed that high A3B expression was associated with poor OS in lung (HR = 1.85, 95% CI: 1.40-2.45), and breast cancers (HR = 1.38, 95% CI: 1.00-1.89). High expression of A3B did not display any significant association with clinicopathologic features. CONCLUSION: APOBEC3B overexpression is related to poor OS, DFS and RFS only in some cancer types and no generalized role could be predicted for all cancers.
CT imaging phenotypes linked to CA125 and HE4 biomarkers are highly predictive in discriminating between hereditary and sporadic ovarian cancer patients.
Manganaro L, Celli V, Viggiani V … +7 more , Berardelli E, Granato T, Tartaglione S, Farina A, Catalano C, Angeloni A, Anastasi E
Tumour Biol · 2022 · PMID 36093649 · Publisher ↗
BACKGROUND: Hereditary ovarian cancers (HOC) represent about 23% of ovarian cancer (OC) cases: they are most frequently related to germline mutations in the BRCA genes. OBJECTIVE: We aimed to compare CA125/HE4 serum leve...
BACKGROUND: Hereditary ovarian cancers (HOC) represent about 23% of ovarian cancer (OC) cases: they are most frequently related to germline mutations in the BRCA genes. OBJECTIVE: We aimed to compare CA125/HE4 serum levels and Computed Tomography (CT) features at time of ovarian cancer (OC) diagnosis in two populations: BRCA mutant and BRCA wild-type (WT) OC, and to investigate the relationship between this laboratory and radiological biomarker and BRCA mutation status. METHODS: This retrospective study included 60 newly diagnosed OC patients with FIGO stage IIIC-IV disease, tested for BRCA1/2 germline mutation status of which preoperative CT scan and serum tumor marker assay were available. RESULTS: The median level of CA125 (708 U/mL) was significantly higher (p < 0.002) in BRCA1/2 mutated patients than in WT patients (176 U/mL), whereas the median level of HE4 (492 pmol/L) was significantly higher (p < 0.002) in WT than in BRCA-mutated patients (252 pmol/L). BRCA mutation carriers showed a higher incidence of bilateral ovarian masses (p = 0.0303) characterized by solid structures (p < 0.00001), higher peritoneal tumor load, macronodular implants >2 cm (p = 0.000099), increased frequency of lymphadenopathies (p = 0.019), and metastasis (p = 0.052) compared to patients with BRCA WT. CONCLUSIONS: Tumor markers and CT patterns may help in identifying BRCA mutation status in OC directing patients towards a personalized treatment.
Exosomes in the visual system: New avenues in ocular diseases.
Manukonda R, Attem J, Yenuganti VR … +2 more , Kaliki S, Vemuganti GK
Tumour Biol · 2022 · PMID 35964221 · Publisher ↗
Exosomes are a subgroup of membrane-bound extracellular vesicles secreted by all cell types and present virtually in all biological fluids. The composition of exosomes in the same cell type varies in healthy and disease...
Exosomes are a subgroup of membrane-bound extracellular vesicles secreted by all cell types and present virtually in all biological fluids. The composition of exosomes in the same cell type varies in healthy and disease conditions. Hence, exosomes research is a prime focus area for clinical research in cancer and numerous age-related metabolic syndromes. Functions of exosomes include crucial cell-to-cell communication that mediates complex cellular processes, such as antigen presentation, stem cell differentiation, and angiogenesis. However, very few studies reported the presence and role of exosomes in normal physiological and pathological conditions of specialized ocular tissues of the eye and ocular cancers. The eye being a protected sense organ with unique connectivity with the rest of the body through the blood and natural passages, we believe that the role of exosomes in ocular tissues will significantly improve our understanding of ocular diseases and their interactions with the rest of the body. We present a review that highlights the existence and function of exosomes in various ocular tissues, their role in the progression of some of the neoplastic and non-neoplastic conditions of the eyes.
MicroRNA-99b-5p targets mTOR/AR axis, induces autophagy and inhibits prostate cancer cell proliferation.
Niture S, Tricoli L, Qi Q … +3 more , Gadi S, Hayes K, Kumar D
Tumour Biol · 2022 · PMID 35811549 · Publisher ↗
OBJECTIVES: MicroRNAs (miRNAs) are the small non-coding regulatory RNA molecules involved in gene regulation via base-pairing with complementary sequences in mRNAs. The dysregulation of specific miRNAs, such as miR-99b-5...
OBJECTIVES: MicroRNAs (miRNAs) are the small non-coding regulatory RNA molecules involved in gene regulation via base-pairing with complementary sequences in mRNAs. The dysregulation of specific miRNAs, such as miR-99b-5p (miR-99b), is associated with prostate cancer (PCa) progression. However, the mechanistic role of miR-99b in PCa remains to be determined. In this study, we aimed to investigate the functional and clinical significance of miR-99b in PCa. STUDY DESIGN: The expression of miR-99b and its downstream targets mTOR/AR in the PCa samples were analyzed by RT/qPCR. The effects of miR-99b overexpression/inhibition on PCa cell survival/proliferation, spheroid formation, and cell migration were examined by specific assays. Luciferase reporter assays were performed to determine the binding of miR-99b to 3' untranslated region (UTR) of the mTOR gene. The effects of miR-99b on the expression of mTOR, AR, and PSA proteins, as well as on AKT/mTOR signaling, autophagy, and neuroendocrine differentiation markers were analyzed by western blotting. The expression of miR-99b, mTOR, AR, PSA in AR-negative PC3 and AR-positive LNCaP cells was analyzed by RT/qPCR. The effect of miR-99b on global gene expression in PC3 cells was analyzed by RNA-seq. RESULTS: The expression of miR-99b was downregulated in tumor samples from PCa patients, whereas the expression of mTOR and AR was upregulated. In PCa cell lines, overexpression of miR-99b inhibited cell proliferation and cell colony/spheroid formation; induced apoptosis, and increased sensitivity towards docetaxel (DTX). In contrast, inhibition of miR-99b by miR-99b inhibitor resulted in increased cell growth in PCa cells. Mechanistically, miR-99b inhibited the expression of the mammalian target of the rapamycin (mTOR) gene by binding to its 3' UTR and induced autophagy. Furthermore, miR-99b inhibited androgen receptor (AR) activity in LNCaP cells and induced apoptosis. Activation of AR signaling by dihydrotestosterone (DHT) downregulated miR-99b expression and promoted cell PCa cell growth/survival, whereas inactivation of mTOR by rapamycin or AR by enzalutamide decreased miR-99b mediated PCa cell growth. CONCLUSION: Our data suggest that miR-99b functions as a tumor suppressor by targeting the mTOR/AR axis in PCa cells, implicating miR-99b as a novel biomarker and therapeutic target for PCa management.
β-Catenin is reduced in membranes of human prolactinoma cells and it is inhibited by temozolomide in prolactin secreting tumor models.
Demarchi G, Valla S, Perrone S … +9 more , Chimento A, Bonadeo N, Vitale DL, Spinelli FM, Cervio A, Sevlever G, Alaniz L, Berner S, Cristina C
Tumour Biol · 2022 · PMID 35811548 · Publisher ↗
INTRODUCTION: Prolactinomas are the most frequent pituitary tumor subtype. Despite most of them respond to medical treatment, a proportion are resistant and become a challenge in clinical management. Wnt/β-Catenin pathwa...
INTRODUCTION: Prolactinomas are the most frequent pituitary tumor subtype. Despite most of them respond to medical treatment, a proportion are resistant and become a challenge in clinical management. Wnt/β-Catenin pathway has been implicated in several cancers including pituitary tumors and other sellar region malignancies. Interestingly, Wnt/β-Catenin inhibition augments the cytotoxicity of the chemotherapeutic agent Temozolomide (TMZ) in different cancers. TMZ is now being implemented as rescue therapy for aggressive pituitary adenoma treatment. However, the molecular mechanisms associated with TMZ action in pituitary tumors remain unclear. OBJECTIVES: Our aims in the present study were to evaluate differential β-Catenin expression in human resistant prolactinomas and Wnt/β-Catenin signaling activation and involvement in Prolactin (PRL) secreting experimental models treated with TMZ. RESULTS: We first evaluated by immunohistochemistry β-Catenin localization in human resistant prolactinomas in which we demonstrated reduced membrane β-Catenin in prolactinoma cells compared to normal pituitaries, independently of the Ki-67 proliferation indexes. In turn, in vivo 15 mg/kg of orally administered TMZ markedly reduced PRL production and increased prolactinoma cell apoptosis in mice bearing xenografted prolactinomas. Intratumoral β-Catenin strongly correlated with Prl and Cyclin D1, and importantly, TMZ downregulated both β-Catenin and Cyclin D1, supporting their significance in prolactinoma growth and as candidates of therapeutic targets. When tested in vitro, TMZ directly reduced MMQ cell viability, increased apoptosis and produced G2/M cell cycle arrest. Remarkably, β-Catenin activation and VEGF secretion were inhibited by TMZ in vitro. CONCLUSIONS: We concluded that dopamine resistant prolactinomas undergo a β-Catenin relocalization in relation to normal pituitaries and that TMZ restrains experimental prolactinoma tumorigenicity by reducing PRL production and β-Catenin activation. Together, our findings contribute to the understanding of Wnt/β-Catenin implication in prolactinoma maintenance and TMZ therapy, opening the opportunity of new treatment strategies for aggressive and resistant pituitary tumors.
β-catenin plus PROX1 immunostaining stratifies disease progression and patient survival in neoadjuvant-treated pancreatic cancer.
Eurola A, Ristimäki A, Mustonen H … +6 more , Nurmi AM, Hagström J, Kallio P, Alitalo K, Haglund C, Seppänen H
Tumour Biol · 2022 · PMID 35786664 · Publisher ↗
BACKGROUND: Wnt/β-catenin signaling is a highly conserved signaling pathway that regulates the transcription factor PROX1. The role of β-catenin and PROX1 in pancreatic cancer is ambiguous, as some studies have associate...
BACKGROUND: Wnt/β-catenin signaling is a highly conserved signaling pathway that regulates the transcription factor PROX1. The role of β-catenin and PROX1 in pancreatic cancer is ambiguous, as some studies have associated their expression with tumor regression and some with tumor progression. OBJECTIVE: We have investigated their expression in surgically treated pancreatic cancer patients receiving neoadjuvant therapy (NAT), and patients treated upfront with surgery (US). We furthermore compared the expression of β-catenin and PROX1 between patients who had a good or poor response to NAT. METHODS: We evaluated β-catenin and PROX1 expression through immunohistochemistry in 88 neoadjuvant and 144 upfront surgery patients by scoring the intensity of the immunopositivity as 0-3, corresponding to negative, weak, moderate, or strong. We developed a six-tier grading scheme for the neoadjuvant responses by analyzing the remaining tumor cells in surgical specimen histological sections. RESULTS: Strong β-catenin immunopositivity associated with improved survival in the patients with good NAT-response (≤10% residual tumor cells) (Hazard ratio [HR] 0.26 95%, confidence interval [CI] 0.07-0.88 p = 0.030). Additionally, the combined moderate β-catenin and PROX1 expression associated with improved survival (HR 0.20 95% CI 0.05-0-76 p = 0.018) among the good responders. Among the patients with a poor NAT-response (> 10% residual tumor cells), both strong β-catenin immunopositivity and strong combined β-catenin and PROX1 associated with shorter survival (HR 2.03 95% CI 1.16-3.55 p = 0.013, and HR 3.1 95% CI 1.08-8.94 p = 0.03, respectively). PROX1 alone was not associated with survival. CONCLUSIONS: Strong β-catenin immunopositivity and combined strong or moderate β-catenin and PROX1 immunopositivity associated with improved survival among the good NAT-responders and worse survival among the poor NAT-responders.
Bithiophene derivative induced apoptosis and suppression of Akt pathway in mouse leukemic model.
Algharib AS, Shanab GM, Abdel-Ghaffar AB … +2 more , Ismail MA, Mohamed RH
Tumour Biol · 2022 · PMID 35431190 · Publisher ↗
BACKGROUND: Bithiophene derivatives show a promising anti-cancer potential. We previously showed that Bithienyl Fluorobenzamidine (BFB) has an anti-proliferative effect against several leukemia cell lines. Acute myeloid...
BACKGROUND: Bithiophene derivatives show a promising anti-cancer potential. We previously showed that Bithienyl Fluorobenzamidine (BFB) has an anti-proliferative effect against several leukemia cell lines. Acute myeloid leukemia (AML) accounts for 18% of the total leukemia cases worldwide with heavier burden during the past 30 years. Therefore, the main aim remains the discovery of safe and effective medications. OBJECTIVE: The current research aims to investigate the anti-cancer efficacy of BFB and its effect on the apoptosis in the 7,12-Dimethylbenz[a]anthracene (DMBA) induced AML in mice. METHODS: AML was induced in mice by DMBA and then treated by 2 different doses of BFB. After BFB treatment, the hematological and histological pattern changes was examined. Furthermore, the molecular effect of BFB on apoptosis, cell cycle markers and Protein kinase B (Akt) pathway was examined using qPCR, Western blotting and ELISA. RESULTS: BFB treatment ameliorates leukemia histological and hematological markers significantly, despite non-significant changes in normal mice. This improvement exhibits cell cycle arrest and apoptosis induction, represented by elevation of tp53/p53, p21/p21, Caspase3 and downregulation of ckk1/Cdk1 in the bone marrow, as well as Akt pathway suppression. CONCLUSIONS: Our results establishes BFB as a promising therapeutic candidate against AML through cell cycle arrest, apoptosis induction and Akt pathway modulation.
Tumor-associated CD3- and CD8-positive immune cells in colorectal cancer: The additional prognostic value of CD8+-to-CD3+ ratio remains debatable.
Kasurinen J, Hagström J, Kaprio T … +3 more , Beilmann-Lehtonen I, Haglund C, Böckelman C
Tumour Biol · 2022 · PMID 35404299 · Publisher ↗
BACKGROUND: A large number of infiltrating CD3- and CD8-positive inflammatory cells indicates an improved survival in colorectal cancer (CRC), similar to many other cancers. OBJECTIVE: We investigated the prognostic valu...
BACKGROUND: A large number of infiltrating CD3- and CD8-positive inflammatory cells indicates an improved survival in colorectal cancer (CRC), similar to many other cancers. OBJECTIVE: We investigated the prognostic value of different combinations of CD3- and CD8-positive immune cells in CRC patients. METHODS: The densities of CD3- and CD8-positive cells in intratumoral and stromal tissues were evaluated from 539 patients, for which we calculated a CD3 tumor-stroma index, a CD8 tumor-stroma index, and a CD3-CD8 tumor-stroma index. RESULTS: High CD3 and CD8 tumor-stroma indices associated with stage I to II disease (p < 0.001 for both). The CD3 tumor-stroma index associated with a colonic tumor location (p = 0.006), while the CD8 tumor-stroma index associated with right-sided tumors (p < 0.001) and histological grade 3 tumors (p = 0.032). High intratumoral and stromal densities for CD3- and CD8-positive immune cells, the CD3 tumor-stroma index, the CD8 tumor-stroma index, and the CD3-CD8 tumor-stroma index all indicated a better DSS. CONCLUSIONS: The CD3 tumor-stroma index carries a strong prognostic value in CRC, and none of the CD3 and CD8 combinations we analyzed proved superior.
Vitamin B12 enhances the antitumor activity of 1,25-dihydroxyvitamin D3 via activation of caspases and targeting actin cytoskeleton.
Atoum MF, Alzoughool FE, Al-Mazaydeh ZA … +2 more , Rammaha MS, Tahtamouni LH
Tumour Biol · 2022 · PMID 35180142 · Publisher ↗
BACKGROUND: 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is an effective anticancer agent, and when combined with other agents it shows superior activities. Vitamin B12 has been shown to contribute to increasing the effectiven...
BACKGROUND: 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is an effective anticancer agent, and when combined with other agents it shows superior activities. Vitamin B12 has been shown to contribute to increasing the effectiveness of anticancer drugs when used in combination. Thus, the current study aimed at investigating the anticancer potential of the combination of 1,25(OH)2D3 and vitamin B12. METHODS: MTT assay was used to determine the cytotoxic activity of combining 1,25(OH)2D3 and vitamin B12 against six different cancer cell lines and one normal cell line. The surviving fraction after clonogenic assay was measured, and the effects of 1,25(OH)2D3/B12 combination on the activity of different caspases, cell adhesion, actin cytoskeleton, cell morphology, and percentage of polarized cells were evaluated. RESULTS: Vitamin B12 did not cause cytotoxicity, however, it enhanced the cytotoxicity of 1,25(OH)2D3 against cancer cells. The cytotoxic effects of 1,25(OH)2D3 and its combination with vitamin B12 was not evident in the normal mammary MCF10A cell line indicating cancer cell-specificity. The cytotoxic effects of 1,25(OH)2D3/B12 combination occurred in a dose-dependent manner and was attributed to apoptosis induction which was mediated by caspase 4 and 8. Moreover, 1,25(OH)2D3/B12-treated cells showed enhanced inhibition of clonogenic tumor growth, reduced cell adhesion, reduced cell area, reduced percentage of cell polarization, and disorganized actin cytoskeleton resulting in reduced migratory phenotype when compared to cells treated with 1,25(OH)2D3 alone. CONCLUSION: 1,25(OH)2D3 and vitamin B12 exhibited synergistic anticancer effects against different cancer cell lines. The combination therapy of 1,25(OH)2D3 and vitamin B12 may provide a potential adjunctive treatment option for some cancer types.
Serological cancer-associated protein biomarker levels at bowel endoscopy: Increased risk of subsequent primary malignancy.
Piper TB, Nielsen HJ, Christensen IJ
Tumour Biol · 2022 · PMID 35180141 · Publisher ↗
BACKGROUND: It was previously shown in three subpopulations that subjects not identified with colorectal cancer (CRC) at bowel endoscopy, but with increased serological cancer-associated protein biomarker levels had an i...
BACKGROUND: It was previously shown in three subpopulations that subjects not identified with colorectal cancer (CRC) at bowel endoscopy, but with increased serological cancer-associated protein biomarker levels had an increased risk of being diagnosed with subsequent malignant diseases. OBJECTIVE: The aim of the present study was to perform a pooled analysis of subjects from the three subpopulations and subsequently validate the results in an independent study. The study population denoted the training set includes N = 4,076 subjects with symptoms attributable to CRC and the independent validation set N = 3,774 similar subjects. METHODS: Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy. Follow-up of subjects not diagnosed with CRC at endoscopy, was ten years and identified subjects diagnosed with primary intra- or extra-colonic malignant diseases. The primary analysis was time to a newly diagnosed malignant disease and was analyzed with death as a competing risk in the training set. Subjects with HNPCC or FAP were excluded. The cumulated incidence was estimated for each biomarker and in a multivariate model. The resulting model was then validated on the second study population. RESULTS: In the training set primary malignancies were identified in 515 (12.6%) of the 4,076 subjects, who had a colorectal endoscopy with non-malignant findings. In detail, 33 subjects were subsequently diagnosed with CRC and 482 subjects with various extra-colonic cancers. Multivariate additive analysis of the dichotomized biomarkers demonstrated that CEA (HR = 1.50, 95% CI:1.21-1.86, p < 0.001), CA19-9 (HR = 1.41, 95% CI:1.10-1.81, p = 0.007) and TIMP-1 (HR = 1.25 95% CI: 1.01-1.54, p = 0.041) were significant predictors of subsequent malignancy. The cumulated incidence at 5 years landmark time was 17% for those subjects with elevated CEA, CA19-9 and TIMP-1 versus 6.7% for those with low levels of all. When the model was applied to the validation set the cumulated 5-year incidence was 10.5% for subjects with elevated CEA, CA19-9 and TIMP-1 and 5.6% for subjects with low levels of all biomarkers. Further analysis demonstrated a significant interaction between TIMP-1 and age in the training set. The age dependency of TIMP-1 indicated a greater risk of malignancy in younger subjects if the biomarker was elevated. This observation was validated in the second set. CONCLUSION: Elevated cancer-associated protein biomarker levels in subjects with non-malignant findings at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy. CEA, CA19-9 and TIMP-1 were significant predictors of malignant disease in this analysis. TIMP-1 was found dependent on age. The results were validated in an independent symptomatic population.
Retraction notice regarding several articles published in Tumor Biology.
Tumour Biol · 2021 · PMID 34957978 · Publisher ↗
The publisher and the Editor-in-Chief, in consultation with former publisher of Tumor Biology, retract a total of 15 articles from the journals' online catalog. The articles were published in different issues of the jour...
The publisher and the Editor-in-Chief, in consultation with former publisher of Tumor Biology, retract a total of 15 articles from the journals' online catalog. The articles were published in different issues of the journal during the period 2014-2016. All articles affected by this retraction notice have problems related to image manipulation or misuse. A detailed explanation is given for each retracted article. The investigations were carried out in accordance with the recommendations of the Committee on Publication Ethics (COPE).
Analysis of serum HE4 levels in various histologic subtypes of epithelial ovarian cancer and other malignant tumors.
Blackman A, Mitchell J, Rowswell-Turner R … +8 more , Singh R, Kim KK, Eklund E, Skates S, Bast RC, Messerlian G, Miller MC, Moore RG
Tumour Biol · 2021 · PMID 34957977 · Publisher ↗
BACKGROUND: The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC an...
BACKGROUND: The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC and in women with metastatic non-ovarian primary malignancies have not been widely reported. OBJECTIVE: The goal of this study was to identify how serum HE4 levels vary in women diagnosed with different histologic subtypes of EOC and non-ovarian malignancies. METHODS: Data from six prospective pelvic mass clinical trials was combined and an evaluation of serum HE4 levels in women diagnosed with a malignancy was performed. For all patients, serum was obtained prior to surgery and final pathology, including primary tumor site, histologic subtype, grade and stage, were recorded. The mean, median, standard deviation, maximum, and minimum HE4 levels were determined for each group. RESULTS: A total of 984 patients were included in this study, with the average patient age being 60 years old. There were 230 premenopausal and 754 postmenopausal patients. Serum HE4 levels were elevated (≥70.0 pMol) in 85%of EOCs, 40%of LMP tumors, 21%of non-EOCs (germ cell tumors), 25%of cervical cancers, and 47%of non-gynecologic metastatic cancers. Analysis of histologic subtypes revealed 90%(n = 391) of serous, 85%(n = 73) of endometrioid, 45%(n = 42) of mucinous, 86%(n = 51) of mixed tumors, and 69%(n = 36) of clear cell tumors had elevated serum HE4 levels. CONCLUSIONS: Serum HE4 levels are most often elevated in women with high grade serous and endometrioid EOCs, and though serum elevations are seen more often with advanced stage disease, HE4 is also often elevated in early stage disease and lower grade tumors.
Effect of pentoxifylline on colon cancer patients treated with chemotherapy (Part I).
Meirovitz A, Baider L, Peretz T … +2 more , Stephanos S, Barak V
Tumour Biol · 2021 · PMID 34957976 · Publisher ↗
BACKGROUND: Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple bene...
BACKGROUND: Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple beneficial effects in cancer patients through its anti-inflammatory properties. MAIN OBJECTIVE: To evaluate PTX effects on colon cancer patients treated with chemotherapy. PATIENTS AND METHODS: Forty metastatic colon cancer patients receiving chemotherapy were enrolled in this randomized study. 17 patients were treated with a full dose of PTX (400 mg TID), 9 patients with a reduced dose PTX (200 mg TID) and 23 served as controls (no PTX). RESULTS: Follow-up evaluations of patients included the following: physical examination; leukopenia determination; weight determination; stomatitis determination; and survival rate. Patients treated with PTX (both full and reduced doses), experienced a significant increase in weight and a reduction in stomatitis relative to the control group. Treatment with PTX also significantly increased patient survival rate. All patients treated with PTX, had a median overall survival (OS) rate of 20.4 months as compared to 13.2 months in the control group. CONCLUSIONS: PTX treatment of colon cancer patients, in addition to chemotherapy, significantly improved survival rates, induced weight gain and reduced stomatitis occurrence -all important parameters of cachexia.
Effects of in vitro short- and long-term treatment with telomerase inhibitor in U-251 glioma cells.
Andrade da Mota TH, Reis Guimarães AF, Silva de Carvalho AÉ … +5 more , Saldanha-de Araujo F, Pinto de Faria Lopes G, Pittella-Silva F, do Amaral Rabello D, Madureira de Oliveira D
Tumour Biol · 2021 · PMID 34957975 · Publisher ↗
BACKGROUND: The inhibition of the enzyme telomerase (TERT) has been widely investigated as a new pharmacological approach for cancer treatment, but its real potential and the biochemical consequences are not totally unde...
BACKGROUND: The inhibition of the enzyme telomerase (TERT) has been widely investigated as a new pharmacological approach for cancer treatment, but its real potential and the biochemical consequences are not totally understood. OBJECTIVE: Here, we investigated the effects of the telomerase inhibitor MST-312 on a human glioma cell line after both short- and long-term (290 days) treatments. METHODS: Effects on cell growth, viability, cell cycle, morphology, cell death and genes expression were assessed. RESULTS: We found that short-term treatment promoted cell cycle arrest followed by apoptosis. Importantly, cells with telomerase knock-down revealed that the toxic effects of MST-312 are partially TERT dependent. In contrast, although the long-term treatment decreased cell proliferation at first, it also caused adaptations potentially related to treatment resistance and tumor aggressiveness after long time of exposition. CONCLUSIONS: Despite the short-term effects of telomerase inhibition not being due to telomere erosion, they are at least partially related to the enzyme inhibition, which may represent an important strategy to pave the way for tumor growth control, especially through modulation of the non-canonical functions of telomerase. On the other hand, long-term exposure to the inhibitor had the potential to induce cell adaptations with possible negative clinical implications.
Identification of interleukin-16 production on tumor aggravation in hepatocellular carcinoma by a proteomics approach.
Takeba Y, Ohta Y, Ootaki M … +7 more , Kobayashi T, Kida K, Watanabe M, Koizumi S, Otsubo T, Iiri T, Matsumoto N
Tumour Biol · 2021 · PMID 34897107 · Publisher ↗
BACKGROUND: Cytokines play an important role in the immune response, angiogenesis, cell growth, and differentiation in hepatocellular carcinoma (HCC). OBJECTIVE: We performed a comprehensive study to identify tumor-relat...
BACKGROUND: Cytokines play an important role in the immune response, angiogenesis, cell growth, and differentiation in hepatocellular carcinoma (HCC). OBJECTIVE: We performed a comprehensive study to identify tumor-related cytokines and pathways involved in HCC pathogenesis. METHODS: Cytokine production was evaluated in human HCC tissues and adjacent non-tumor tissues using an antibody-based protein array technique. We compared cytokine expression in HCC tissues with that of hepatic hemangioma (HH), liver metastasis of colorectal cancer, and noncancerous liver tissues from transplantation donors. The protein levels and localization of the candidate cytokines were analyzed by western blotting and immunohistochemistry. RESULTS: Increased expression of interleukin (IL)-1 receptor antagonist, macrophage migration inhibitory factor, and IL-16 was observed in HCC and paired adjacent non-tumor tissues compared with noncancerous livers. In addition, there were increased IL-16 levels in HCC tissues compared with HH. IL-16 treatment significantly increased cell proliferation in vitro. The expression of extracellular signal-regulated kinase (ERK)1/2 and cyclin D1 was markedly increased in cells from two HCC cell lines, Huh7 and HepG2, in a dose- and time-dependent manner. Phosphorylated to total ERK1/2 ratio was increased in Huh7 cells following IL-16 50 ng/ml, but not HepG2 cells. ERK phosphorylation have occurred earlier than protein accumulation at 48 h. Pretreatment with the ERK inhibitor, FR18024, or an anti-IL-16 antibody reduced the increase in IL-16 production in HCC cells. CONCLUSIONS: These results suggest that cell proliferation induced by IL-16 is mediated through the ERK pathway, thus, we identified a new factor associated with HCC tumor growth.
Addendum to: Expression of cGMP-dependent protein kinase, PKGIα, PKGIβ, and PKGII in malignant and benign breast tumors.
Tumour Biol · 2021 · PMID 34690153 · Publisher ↗
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Seeding metastases: The role and clinical utility of circulating tumour cells.
Patel DA, Blay J
Tumour Biol · 2021 · PMID 34690152 · Publisher ↗
Peripheral human blood is a readily-accessible source of patient material in which circulating tumour cells (CTCs) can be found. Their isolation and characterization holds the potential to provide prognostic value for va...
Peripheral human blood is a readily-accessible source of patient material in which circulating tumour cells (CTCs) can be found. Their isolation and characterization holds the potential to provide prognostic value for various solid cancers. Enumeration of CTCs from blood is becoming a common practice in informing prognosis and may guide therapy decisions. It is further recognized that enumeration alone does not capture perspective on the heterogeneity of tumours and varying functional abilities of the CTCs to interact with the secondary microenvironment. Characterizing the isolated CTCs further, in particular assessing their functional abilities, can track molecular changes in the disease progress. As a step towards identifying a suite of functional features of CTCs that could aid in clinical decisions, developing a CTC isolation technique based on extracellular matrix (ECM) interactions may provide a more solid foundation for isolating the cells of interest. Techniques based on size, charge, density, and single biomarkers are not sufficient as they underutilize other characteristics of cancer cells. The ability of cancer cells to interact with ECM proteins presents an opportunity to utilize their full character in capturing, and also allows assessment of the features that reveal how cells might behave at secondary sites during metastasis. This article will review some common techniques and recent advances in CTC capture technologies. It will further explore the heterogeneity of the CTC population, challenges they experience in their metastatic journey, and the advantages of utilizing an ECM-based platform for CTC capture. Lastly, we will discuss how tailored ECM approaches may present an optimal platform to capture an influential heterogeneous population of CTCs.
Erratum to: Validation of a clinical blood-based decision aid to guide immunotherapy treatment in patients with non-small cell lung cancer.
Muller M, Hoogendoorn R, Moritz RJG … +8 more , van der Noort V, Lanfermeijer M, Korse CM, van den Broek D, Ten Hoeve JJ, Baas P, van Rossum HH, van den Heuvel MM
Tumour Biol · 2021 · PMID 34657868 · Full text
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