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Construction and Validation of an Immune-Related Prognostic Model Based on TP53 Status in Colorectal Cancer

期刊: CANCERS, 2019; 11 (11)

Growing evidence has indicated that prognostic biomarkers have a pivotal role in tumor and immunity biological processes. TP53 mutation can cause a range of changes in immune response, progression, and prognosis of colorectal cancer (CRC). Thus, we aim to build an immunoscore prognostic model that may enhance the prognosis of CRC from an immunological perspective. We estimated the proportion of immune cells in the GSE39582 public dataset using the CIBERSORT (Cell type identification by estimating relative subset of known RNA transcripts) algorithm. Prognostic genes that were used to establish the immunoscore model were generated by the LASSO (Least absolute shrinkage and selection operator) Cox regression model. We established and validated the immunoscore model in GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) cohorts, respectively; significant differences of overall survival analysis were found between the low and high immunoscore groups or TP53 subgroups. In the multivariable Cox analysis, we observed that the immunoscore was an independent prognostic factor both in the GEO cohort (HR (Hazard ratio) 1.76, 95% CI (confidence intervals): 1.26-2.46) and the TCGA cohort (HR 1.95, 95% CI: 1.20-3.18). Furthermore, we established a nomogram for clinical application, and the results suggest that the nomogram is a better predictive model for prognosis than immunoscore or TNM staging.

IF:6.16

A Review on Curability of Cancers: More Efforts for Novel Therapeutic Options Are Needed

期刊: CANCERS, 2019; 11 (11)

Cancer remains a major cause of death globally. Given its relapsing and fatal features, curing cancer seems to be something hardly possible for the majority of patients. In view of the development in cancer therapies, this article summarizes currently available cancer therapeutics and cure potential by cancer type and stage at diagnosis, based on literature and database reviews. Currently common cancer therapeutics include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, treatment with curative intent by these methods are mainly eligible for patients with localized disease or treatment-sensitive cancers and therefore their contributions to cancer curability are relatively limited. The prognosis for cancer patients varies among different cancer types with a five-year relative survival rate (RSR) of more than 80% in thyroid cancer, melanoma, breast cancer, and Hodgkin's lymphoma. The most dismal prognosis is observed in patients with small-cell lung cancer, pancreatic cancer, hepatocellular carcinoma, oesophagal cancer, acute myeloid leukemia, non-small cell lung cancer, and gastric cancer with a five-year RSR ranging between 7% and 28%. The current review is intended to provide a general view about how much we have achieved in curing cancer as regards to different therapies and cancer types. Finally, we propose a small molecule dual-targeting broad-spectrum anticancer strategy called OncoCiDia, in combination with emerging highly sensitive liquid biopsy, with theoretical curative potential for the management of solid malignancies, especially at the micro-cancer stage.

IF:6.16

Transcription Factor and miRNA Interplays Can Manifest the Survival of ccRCC Patients

期刊: CANCERS, 2019; 11 (11)

Clear cell renal cell carcinoma (ccRCC) still remains a higher mortality rate in worldwide. Obtaining promising biomakers is very crucial for improving the diagnosis and prognosis of ccRCC patients. Herein, we firstly identified eight potentially prognostic miRNAs (hsa-miR-144-5p, hsa-miR-223-3p, hsa-miR-365b-3p, hsa-miR-3613-5p, hsa-miR-9-5p, hsa-miR-183-5p, hsa-miR-335-3p, hsa-miR-1269a). Secondly, we found that a signature containing these eight miRNAs showed obviously superior to a single miRNA in the prognostic effect and credibility for predicting the survival of ccRCC patients. Thirdly, we discovered that twenty-two transcription factors (TFs) interact with these eight miRNAs, and a signature combining nine TFs (TFAP2A, KLF5, IRF1, RUNX1, RARA, GATA3, IKZF1, POU2F2, and FOXM1) could promote the prognosis of ccRCC patients. Finally, we further identified eleven genes (hsa-miR-365b-3p, hsa-miR-223-3p, hsa-miR-1269a, hsa-miR-144-5p, hsa-miR-183-5p, hsa-miR-335-3p, TFAP2A, KLF5, IRF1, MYC, IKZF1) that could combine as a signature to improve the prognosis effect of ccRCC patients, which distinctly outperformed the eight-miRNA signature and the nine-TF signature. Overall, we identified several new prognosis factors for ccRCC, and revealed a potential mechanism that TFs and miRNAs interplay cooperatively or oppositely regulate a certain number of tumor suppressors, driver genes, and oncogenes to facilitate the survival of ccRCC patients.

IF:6.16

Anti-Metastatic Benefits Produced by Hyperthermia and a CCL3 Derivative

期刊: CANCERS, 2019; 11 (11)

Significant numbers of malignant tumor cells that have spread to surrounding tissues and other distant organs are often too small to be picked up in a diagnostic test, and prevention of even such small metastases should improve patient outcomes. Using a mouse model, we show in this article that intravenous administration of a human CCL3 variant carrying a single amino acid substitution after mild local hyperthermia not only induces tumor growth inhibition at the treated site but also inhibits metastasis. Colon26 adenocarcinoma cells (1 x 10(5) cells/mouse) were grafted subcutaneously into the right hind leg of syngeneic BALB/c mice and after nine days, when tumor size reached similar to 11 mm in diameter, the local tumor mass was exposed to high-frequency waves, by which intratumoral temperature was maintained at 42 degrees C for 30 min. Mice received the CCL3 variant named eMIP (2 mu g/mouse/day) intravenously for five consecutive days starting one day after heat treatment. We found that tumor growth in eMIP recipients after hyperthermia was inhibited markedly but no effect was seen in animals treated with either hyperthermia or eMIP alone. Furthermore, the number of lung metastases evaluated at 18 days after hyperthermia treatment was dramatically reduced in animals receiving the combination therapy compared with all other controls. These results encourage future clinical application of this combination therapy.

IF:6.16

Network Meta-Analysis of Efficacy and Safety of Chemotherapy and Target Therapy in the First-Line Setting of Advanced Pancreatic Cancer

期刊: CANCERS, 2019; 11 (11)

Both gemcitabine and fluoropyrimidine are recommended backbones in the first-line treatment of pancreatic ductal adenocarcinoma (PDAC). To compare the efficacy and safety of these two therapeutic backbones, and to investigate the optimal therapies, we conducted a network meta-analysis. By retrospective analysis of randomized controlled trials (RCT), the most preferred therapeutic regimen may be predicted. The eligible RCTs of the gemcitabine-based therapies and fluoropyrimidine-based therapies were searched up to 31 August 2019. In a frequentist network meta-analysis, treatments were compared and ranked according to overall survival (OS) and progression-free survival (PFS). Thirty-two trials with 10,729 patients were included. The network meta-analyses results for overall survival and progression-free survival showed that fluoropyrimidine-based therapy seems to be the most effective treatment choice. Compared to gemcitabine combined with taxanes or immunotherapy, fluoropyrimidine-based therapy had comparable treatment effects (PFS: 0.67, p-Value = 0.11; 0.76, p-Value = 0.32; OS: 0.80, p-Value = 0.16; 0.77, p-Value = 0.21). Moreover, the combination of immunotherapy and gemcitabine had tolerable toxicities. Based on current evidence, fluoropyrimidine-based therapies and the combination of gemcitabine and taxanes were the most effective therapies in the advanced pancreatic cancer, and the combination of immunotherapy and gemcitabine can be developed into a new form of therapy.

IF:6.16

STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma

期刊: CANCERS, 2019; 11 (11)

Hepatocellular carcinoma (HCC) is a major global health problem and its treatment options have been limited. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor important for various cellular processes. Overexpression and constitutive activation of STAT3 have been frequently found in HCC and associated with poor prognosis. Ample evidence has shown that STAT3 plays pivotal roles in the initiation, progression, metastasis and immune suppression of HCC. Thus, STAT3 has attracted attention as a novel therapeutic target in HCC. Clinical trials have investigated STAT3-targeted therapeutics either as monotherapy or in combination with chemotherapeutic agents, immune checkpoint inhibitors and alternative targeted drugs. Some of these studies have yielded encouraging results. Particularly, napabucasin-a cancer stemness inhibitor targeting STAT3-driven gene transcription-has stood out with its promising clinical efficacy and safety profile. Nonetheless, clinical investigations of STAT3-targeted therapies in HCC are limited and more efforts are strongly urged to evaluate their clinical performance in HCC. Here, we provide a comprehensive review of the roles of STAT3 in HCC and follow by comprehensive analysis of STAT3 targeted strategies.

IF:6.16

Systematic Review of Irreversible Electroporation Role in Management of Locally Advanced Pancreatic Cancer

期刊: CANCERS, 2019; 11 (11)

Background: Ablative techniques provide in patients with locally advanced pancreatic cancer (LAPC) symptomatic relief, survival benefit and potential downsizing. Irreversible Electroporation (IRE) represents potentially an ideal solution as no thermal tissue damage occurs. The purpose of this review is to present an overview on safety, feasibility, oncological results, survival and quality of life improvement obtained by IRE. Methods: A systematic search was performed in PubMed, regarding the use of IRE on PC in humans for studies published in English up to March 2019. Results: 15 original studies embodying 691 patients with unresectable LAPC who underwent IRE were included. As emerged, IRE works better on tumour sizes between 3-4 cm. Oncological results are promising: median OS from diagnosis or treatment up to 27 months. Two groups investigated borderline resectable tumours treated with IRE before resection with margin attenuation, whereas IRE has proved to be effective in pain control. Conclusions: Electroporation is bringing new hopes in LAPC management. The first aim of IRE is to offer a palliative treatment. Further efforts are needed for patient selection, as well as the use of IRE for 'margin accentuation' during surgical resection. Even if promising, IRE needs to be validated in large, randomized, prospective series.

IF:6.16

Long Non-Coding RNA: Dual Effects on Breast Cancer Metastasis and Clinical Applications

期刊: CANCERS, 2019; 11 (11)

As a highly heterogeneous malignancy, breast cancer (BC) has become the most significant threat to female health. Distant metastasis and therapy resistance of BC are responsible for most of the cases of mortality and recurrence. Distant metastasis relies on an array of processes, such as cell proliferation, epithelial-to-mesenchymal transition (EMT), mesenchymal-to-epithelial transition (MET), and angiogenesis. Long non-coding RNA (lncRNA) refers to a class of non-coding RNA with a length of over 200 nucleotides. Currently, a rising number of studies have managed to investigate the association between BC and lncRNA. In this study, we summarized how lncRNA has dual effects in BC metastasis by regulating invasion, migration, and distant metastasis of BC cells. We also emphasize that lncRNA has crucial regulatory effects in the stemness and angiogenesis of BC. Clinically, some lncRNAs can regulate chemotherapy sensitivity in BC patients and may function as novel biomarkers to diagnose or predict prognosis for BC patients. The exact impact on clinical relevance deserves further study. This review can be an approach to understanding the dual effects of lncRNAs in BC, thereby linking lncRNAs to quasi-personalized treatment in the future.

IF:6.16

Coupled Genome-Wide DNA Methylation and Transcription Analysis Identified Rich Biomarkers and Drug Targets in Triple-Negative Breast Cancer

期刊: CANCERS, 2019; 11 (11)

Triple-negative breast cancer (TNBC) has poor clinical prognosis. Lack of TNBC-specific biomarkers prevents active clinical intervention. We reasoned that TNBC must have its specific signature due to the lack of three key receptors to distinguish TNBC from other types of breast cancer. We also reasoned that coupling methylation and gene expression as a single unit may increase the specificity for the detected TNBC signatures. We further reasoned that choosing the proper controls may be critical to increasing the sensitivity to identify TNBC-specific signatures. Furthermore, we also considered that specific drugs could target the detected TNBC-specific signatures. We developed a system to identify potential TNBC signatures. It consisted of (1) coupling methylation and expression changes in TNBC to identify the methylation-regulated signature genes for TNBC; (2) using TPBC (triple-positive breast cancer) as the control to detect TNBC-specific signature genes; (3) searching in the drug database to identify those targeting TNBC signature genes. Using this system, we identified 114 genes with both altered methylation and expression, and 356 existing drugs targeting 10 of the 114 genes. Through docking and molecular dynamics simulation, we determined the structural basis between sapropterin, a drug used in the treatment of tetrahydrobiopterin deficiency, and PTGS2, a TNBC signature gene involved in the conversion of arachidonic acid to prostaglandins. Our study reveals the existence of rich TNBC-specific signatures, and many can be drug target and biomarker candidates for clinical applications.

IF:6.16

DOCK1 Regulates Growth and Motility through the RRP1B-Claudin-1 Pathway in Claudin-Low Breast Cancer Cells

期刊: CANCERS, 2019; 11 (11)

Dedicator of cytokinesis 1 (DOCK1) is a critical regulator of cancer metastasis. Claudins are transmembrane proteins that play a role in epithelial barrier integrity. Due to a loss or low expression of claudins (CLDN), the claudin-low type of triple-negative breast cancer (TNBC) is characterized by a mesenchymal-like phenotype with strong metastatic potential. In order to elucidate the mechanism of DOCK1 in cancer metastasis, we first analyzed the transcriptomic changes using a clinical database of human TNBC and found that the increase in DOCK1 expression was highly correlated with the poor survival rate of TNBC patients. Interference with DOCK1 expression by shRNA resulted in re-expression of claudin-1 in conjunction with significant inhibition of cell viability and motility of claudin-low breast cancer cells. Accordingly, overexpression of claudin-1 suppressed cell viability and migration. Genetic knockdown and pharmacological blockade of Rac1/Rac2 up-regulated claudin-1. DOCK1 knockdown also caused a decrease in DNA methyltransferase (DNMT) expression and an increase in claudin-1 transcript and promoter activity. Furthermore, RRP1B mediated DOCK1 depletion, which up-regulated claudin-1 expression, cell viability, and motility in claudin-low breast cancer cells. This study demonstrated that DOCK1 mediates growth and motility through down-regulated claudin-1 expression via the RRP1B-DNMT-claudin-1 pathway and that claudin-1 serves as an important effector in DOCK1-mediated cancer progression and metastasis in claudin-low breast cancer cells.

IF:6.16

The Role of Post-Neoadjuvant Chemotherapy Tumor Volume for Prognostication and Treatment Guidance in Loco-Regionally Advanced Nasopharyngeal Carcinoma

期刊: CANCERS, 2019; 11 (11)

The value of post-neoadjuvant chemotherapy (NACT) tumor volume for prognostication in loco-regionally advanced nasopharyngeal carcinoma (LA-NPC) is unascertained. Here, we recruited 4109 histologically proven LA-NPC (stage III-IVA) that were treated with radical chemo-intensive-modulated radiotherapy (IMRT). Post-NACT gross primary tumor (GTVp) and lymph node (GTVnd) volumes of each patient were calculated from planning computed tomography (CT). We observed similar linear association between GTVp/GTVnd and overall survival (OS); thresholds of 52 cm(3) for GTVp and 12 cm(3) for GTVnd were consistent for risk discretization for OS, disease-free survival (DFS), distant metastasis-free survival (DMFS), and local relapse-free survival (LRFS). Recursive partitioning analysis (RPA) modelling incorporating T-/N-categories and GTVp/GTVnd yielded four T-N-volume (TNV) risk groupings with disparate OS (p < 0.001). TNV risk stratification outperformed GTVp/GTVnd and eighth edition TNM for predicting OS (AUC 0.643 vs. 0.541-0.591; p < 0.001), DFS (0.629 vs. 0.545-0.580; p < 0.001), and DMFS (0.652 vs. 0.522-0.621; p < 0.001). NACT + concurrent chemoradiotherapy (CCRT) over NACT + IMRT was not superior for low- and low-intermediate-risk groupings (p > 0.05 for both), but superior for intermediate- and high-risk groupings in terms of OS (HR 0.68 (95% CI 0.47-0.99) for intermediate risk, 0.73 (0.55-0.97) for high risk; both p < 0.05). Overall, GTVp/GTVnd represent effective indicators for prognostication and decision-making in LA-NPC after NACT.

IF:6.16

The Diagnostic Efficiency of Ultrasound Computer-Aided Diagnosis in Differentiating Thyroid Nodules: A Systematic Review and Narrative Synthesis

期刊: CANCERS, 2019; 11 (11)

Computer-aided diagnosis (CAD) techniques have emerged to complement qualitative assessment in the diagnosis of benign and malignant thyroid nodules. The aim of this review was to summarize the current evidence on the diagnostic performance of various ultrasound CAD in characterizing thyroid nodules. PUBMED, EMBASE and Cochrane databases were searched for studies published until August 2019. The Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Review 2 (QUADAS-2) tool was used to assess the methodological quality of the studies. Reported diagnostic performance data were analyzed and discussed. Fourteen studies with 2232 patients and 2675 thyroid nodules met the inclusion criteria. The study quality based on QUADAS-2 assessment was moderate. At best performance, grey scale CAD had a sensitivity of 96.7% while Doppler CAD was 90%. Combined techniques of qualitative grey scale features and Doppler CAD assessment resulted in overall increased sensitivity (92%) and optimal specificity (85.1%). The experience of the CAD user, nodule size and the thyroid malignancy risk stratification system used for interpretation were the main potential factors affecting diagnostic performance outcomes. The diagnostic performance of CAD of thyroid ultrasound is comparable to that of qualitative visual assessment; however, combined techniques have the potential for better optimized diagnostic accuracy.

IF:6.16

The Potential Mechanism of Bufadienolide-Like Chemicals on Breast Cancer via Bioinformatics Analysis

期刊: CANCERS, 2019; 11 (1)

Bufadienolide-like chemicals are mostly composed of the active ingredient of Chansu and they have anti-inflammatory, tumor-suppressing, and anti-pain activities; however, their mechanism is unclear. This work used bioinformatics analysis to study this mechanism via gene expression profiles of bufadienolide-like chemicals: (1) Differentially expressed gene identification combined with gene set variation analysis, (2) similar small -molecule detection, (3) tissue-specific co-expression network construction, (4) differentially regulated sub-networks related to breast cancer phenome, (5) differentially regulated sub-networks with potential cardiotoxicity, and (6) hub gene selection and their relation to survival probability. The results indicated that bufadienolide-like chemicals usually had the same target as valproic acid and estradiol, etc. They could disturb the pathways in RNA splicing, the apoptotic process, cell migration, extracellular matrix organization, adherens junction organization, synaptic transmission, Wnt signaling, AK-STAT signaling, BMP signaling pathway, and protein folding. We also investigated the potential cardiotoxicity and found a dysregulated subnetwork related to membrane depolarization during action potential, retinoic acid receptor binding, GABA receptor binding, positive regulation of nuclear division, negative regulation of viral genome replication, and negative regulation of the viral life cycle. These may play important roles in the cardiotoxicity of bufadienolide-like chemicals. The results may highlight the potential anticancer mechanism and cardiotoxicity of Chansu, and could also explain the ability of bufadienolide-like chemicals to be used as hormones and anticancer and vasoprotectives agents.

IF:6.16

Chimeric Antigen Receptor T-cell (CAR T) Therapy for Hematologic and Solid Malignancies: Efficacy and Safety-A Systematic Review with Meta-Analysis

期刊: CANCERS, 2019; 11 (1)

Chimeric antigen receptors T cells (CAR T) had been used for treating various tumor patients in clinic, and owned an incredible efficacy in part of malignancies. However, CAR T therapy remains controversial due to doubts about its efficacy and safety in the clinical treatment of various malignancies. A total of 997 tumor patients from 52 studies were included in this review. Eligible studies were searched and reviewed from the databases of PubMed, Web of Science, Wanfang and Clinicaltrials.gov. Then meta-analysis and subgroup analysis were used to investigate the overall response rate (ORR), complete response rate (CRR), common side effect rate (CSER) and relapse rate (RR) of CAR T therapy for patients in clinical researches, respectively. The results further confirmed that CAR T therapy had a higher response rate for hematologic malignancies. More importantly, CAR T therapy had a higher CSER in patients with hematologic malignancies, and it had a similar RR in patients with different malignancies. Cell cultured without the addition of IL-2 and total administration less than 10(8) cells were recommended. This study offers a reference for future research regarding the application in solid and hematologic malignancies, side effects and relapse, and even the production processes of CAR T cells.

IF:6.16

Involvement of N-glycan in Multiple Receptor Tyrosine Kinases Targeted by Ling-Zhi-8 for Suppressing HCC413 Tumor Progression

期刊: CANCERS, 2019; 11 (1)

The poor prognosis of hepatocellular carcinoma (HCC) is resulted from tumor metastasis. Signaling pathways triggered by deregulated receptor tyrosine kinases (RTKs) were the promising therapeutic targets for prevention of HCC progression. However, RTK-based target therapy using conventional kinase-based inhibitors was often hampered by resistances due to compensatory RTKs signaling. Herein, we report that Ling-Zhi-8 (LZ-8), a medicinal peptide from Ganoderma lucidium, was effective in suppressing cell migration of HCC413, by decreasing the amount and activity of various RTKs. These led to the suppression of downstream signaling including phosphorylated JNK, ERK involved in HCC progression. The capability of LZ-8 in targeting multiple RTKs was ascribed to its simultaneous binding to these RTKs. LZ-8 may bind on the N-linked glycan motif of RTKs that is required for their maturation and function. Notably, pretreatment of the N-glycan trimming enzyme PNGase or inhibitors of the mannosidase (N-glycosylation processing enzyme), kifunensine (KIF) and swainsonine (SWN), prevented LZ-8 binding on the aforementioned RTKs and rescued the downstream signaling and cell migration suppressed by LZ-8. Moreover, pretreatment of KIF prevented LZ-8 triggered suppression of tumor growth of HCC413. Our study suggested that a specific type of N-glycan is the potential target for LZ-8 to bind on multiple RTKs for suppressing HCC progression.

IF:6.16

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