• anticancer activity
• biosynthesis
• chemical structure
• phytochemicals
• ribosomally synthesized and post-translationally modified peptides

• 2-Year Research Grant of Pusan National University Pusan National University

• NRF2
• cancer
• initiation
• metastasis
• promotion
• transformation

• Humans
• Carcinogenesis/genetics
• Kelch-Like ECH-Associated Protein 1/genetics
• Kelch-Like ECH-Associated Protein 1/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Signal Transduction
• Tumor Microenvironment

• R01 CA226690 NCI NIH HHS
• T32 GM142521 NIGMS NIH HHS

• Cancer progression
• Gastric cancer
• Mitochondria
• Phytochemicals

• Humans
• Berberine/pharmacology
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/metabolism
• Mitochondria
• Signal Transduction
• Apoptosis
• Phytochemicals/therapeutic use
• Reactive Oxygen Species/metabolism
• Cell Line, Tumor

• Humans
• Biomarkers, Tumor
• Tumor Microenvironment
• Carcinogenesis
• Mitosis
• Prognosis
• Kinesins/genetics

• Animals
• Humans
• Chlorocebus aethiops
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasms/genetics
• Carcinogenesis/genetics
• DNA Copy Number Variations/genetics
• Chromosome Aberrations
• Neoplasms, Second Primary/genetics
• DNA
• Gene Expression Regulation, Neoplastic
• Gene Expression Profiling

• U.S. Food and Drug Administration
• College of Veterinary Medicine, North Carolina State University

Recently, cancer research has described the presence of the cholinergic machinery, specifically muscarinic receptors, in a wide variety of cancers due to their activation and signaling pathways associated with tumor progression and metastasis, providing a wide overview of their contribution to different cancer formation and development for new antitumor targets. This review focused on determining the molecular signatures associated with muscarinic receptors in breast and other cancers and the need for pharmacological, molecular, biochemical, technological, and clinical approaches to improve new therapeutic targets.

Cancer has been considered the pathology of the century and factors such as the environment may play an important etiological role. The ability of muscarinic agonists to stimulate growth and muscarinic receptor antagonists to inhibit tumor growth has been demonstrated for breast, melanoma, lung, gastric, colon, pancreatic, ovarian, prostate, and brain cancer. This work aimed to study the correlation between epidermal growth factor receptors and cholinergic muscarinic receptors, the survival differences adjusted by the stage clinical factor, and the association between gene expression and immune infiltration level in breast, lung, stomach, colon, liver, prostate, and glioblastoma human cancers. Thus, targeting cholinergic muscarinic receptors appears to be an attractive therapeutic alternative due to the complex signaling pathways involved.

• Analogies
• Biological-physical interfaces
• Colloids
• Complexity
• Nanoparticle behaviour

• Colloids
• Nanoparticles
• Nanotechnology

• University College London (UCL)

Surgery is the primary curative treatment for patients with nonmetastasized colorectal cancer (CRC). Rate of complications, morbidity, mortality, and overall survival of patients with CRC are factors associated with speed of recovery following surgery. Wuda granule (WD) is a traditional Chinese medicine (TCM) prescription used to promote rapid recovery after surgery. However, the specific mechanism of action of WD has not been characterized. Our study included 60 patients with clear histopathological evidence of colon or rectal cancer who underwent CRC laparoscopic surgery and 30 healthy individuals. Serum biochemistry and clinical evaluation of gastrointestinal function showed that WD could improve the nutritional status and gastrointestinal function and reduce the level of inflammation of patients with CRC following laparoscopic surgery. In addition, we used UPLC/Q-TOF-MS/MS-based metabolomics analysis to determine the mechanism of WD-related rapid recovery following laparoscopic surgery in patients with CRC. Twenty metabolites associated with arachidonic acid, alanine, aspartate and glutamate, α-linolenic acid, pyruvate, histidine, and glycerophospholipids were identified. The results suggested that the therapeutic mechanism of laparoscopic surgery combined with WD may be related to regulation of nutritional status, inflammation, immune function, energy, and gastrointestinal function in patients with CRC. This study also highlighted the ability of TCM compounds to interact with multiple targets to induce synergistic effects. This study may result in further studies of WD as a therapeutic agent to promote recovery following surgical resection of CRC tumors.

Chlorotoxin (CTX) is a minute 4 kDa protein made up of 36 amino acid residues, commonly known for its binding affinity to chloride channels and matrix metalloproteinase-2 (MMP-2) of glioma tumors of the spine and brain. This property and the possibility of conjugating this peptide to nanoparticles have enabled its diverse use in various biotechnological and biomedical applications for cancer treatment, such as in tumor imaging and radiotherapy. Because of the fascinating biological properties CTX possesses, elucidating its mechanism of action may hold promise for the development of new and effective therapeutic drugs, as well as more sensitive and highly specific cancer-screening kits. This article therefore reviews the currently known applications of CTX and suggests diverse ways in which it can be applied for the design of improved drugs and diagnostic tools for cancer.

• Cancer
• Chlorotoxin
• Diagnostics
• Matrix metalloproteinase-2
• Therapeutics
• Tumor

• Colorectal cancer
• Diet
• Gut microbiota
• Immune response
• Inflammation

• Colorectal Neoplasms/diet therapy
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/microbiology
• Colorectal Neoplasms/prevention & control
• Dysbiosis/immunology
• Dysbiosis/microbiology
• Gastrointestinal Microbiome/immunology
• Humans
• Immunomodulation/immunology
• Prebiotics/administration & dosage
• Probiotics/administration & dosage
• Synbiotics/administration & dosage
• Treatment Outcome

MicroRNAs (miRs) are expected to serve as prognostic tools for cancer. However, many miRs have been reported as prognostic markers of recurrence or metastasis in oral squamous cell carcinoma patients. We aimed to determine the prognostic markers in early-stage tongue squamous cell carcinoma (TSCC). Based on previous studies, we hypothesized that miR-10a, 10b, 196a-5p, 196a-3p, and 196b were prognostic markers and we retrospectively performed miR expression analyses using formalin-fixed paraffin-embedded sections of surgical specimens. Total RNA was isolated from cancer tissues and adjacent normal tissue as control, and samples were collected by laser-capture microdissection. After cDNA synthesis, reverse transcription-quantitative polymerase chain reaction was performed. Statistical analyses for patient clinicopathological characteristics, recurrence/metastasis, and survival rates were performed to discern their relationships with miR expression levels, and the 2^−ΔΔCq method was used. miR-196a-5p levels were significantly upregulated in early-stage TSCC, particularly in the lymph node metastasis (LNM) group. The LNM-free survival rate in the low miR-196a-5p ΔΔCq value regulation group was found to be lower than that in the high ΔΔCq value regulation group (P=0.0079). Receiver operating characteristic analysis of ΔΔCq values revealed that miR-196a-5p had a P-value=0.0025, area under the curve=0.740, and a cut-off value=−0.875 for distinguishing LNM. To our knowledge, this is the first study to examine LNM-related miRs in early-stage TSCC as well as miRs and ‘delayed LNM’ in head and neck cancer. miR-196a-5p upregulation may predict delayed LNM. Our data serve as a foundation for future studies to evaluate miR levels and facilitate the prediction of delayed LNM during early-stage TSCC, which prevent metastasis when combined with close follow-up and aggressive adjuvant therapy or elective neck dissection. Moreover, our data will serve as a foundation for future studies to evaluate whether miR-196a-5p can serve as a therapeutic marker for preventing metastasis.

• lymph node metastasis
• miR-196a
• microRNA
• oral cavity
• prognostic marker
• regional recurrence
• squamous cell carcinoma
• tongue

• carcinogenesis
• chaos
• emergence
• entropy
• fractals
• systems biology
• thermodynamics
• translational research

• Arachidonic acid pathway
• Bioactive natural products
• Cancer
• Prevention
• Therapy

• Animals
• Anticarcinogenic Agents/pharmacology
• Anticarcinogenic Agents/therapeutic use
• Antineoplastic Agents, Phytogenic/pharmacology
• Antineoplastic Agents, Phytogenic/therapeutic use
• Arachidonic Acid/metabolism
• Drug Screening Assays, Antitumor
• Humans
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/prevention & control
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use
• Signal Transduction/drug effects

Galectin-7 (Gal-7) is negatively regulated in cervical cancer, and appears to be a link between the apoptotic response triggered by cancer and the anti-tumoral activity of the immune system. Our understanding of how cervical cancer cells and their molecular networks adapt in response to the expression of Gal-7 remains limited.

Meta-analysis of Gal-7 expression was conducted in three cervical cancer cohort studies and TCGA. In silico prediction and bisulfite sequencing were performed to inquire epigenetic alterations. To study the effect of Gal-7 on cervical cancer, we ectopically re-expressed it in the HeLa and SiHa cervical cancer cell lines, and analyzed their transcriptome and SILAC-based proteome. We also examined the tumor and microenvironment host cell transcriptomes after xenotransplantation into immunocompromised mice. Differences between samples were assessed with the Kruskall-Wallis, Dunn’s Multiple Comparison and T tests. Kaplan–Meier and log-rank tests were used to determine overall survival.

Gal-7 was constantly downregulated in our meta-analysis (p < 0.0001). Tumors with combined high Gal-7 and low galectin-1 expression (p = 0.0001) presented significantly better prognoses (p = 0.005). In silico and bisulfite sequencing assays showed de novo methylation in the Gal-7 promoter and first intron. Cells re-expressing Gal-7 showed a high apoptosis ratio (p < 0.05) and their xenografts displayed strong growth retardation (p < 0.001). Multiple gene modules and transcriptional regulators were modulated in response to Gal-7 reconstitution, both in cervical cancer cells and their microenvironments (FDR < 0.05 %). Most of these genes and modules were associated with tissue morphogenesis, metabolism, transport, chemokine activity, and immune response. These functional modules could exert the same effects in vitro and in vivo, even despite different compositions between HeLa and SiHa samples.

Gal-7 re-expression affects the regulation of molecular networks in cervical cancer that are involved in diverse cancer hallmarks, such as metabolism, growth control, invasion and evasion of apoptosis. The effect of Gal-7 extends to the microenvironment, where networks involved in its configuration and in immune surveillance are particularly affected.

The online version of this article (doi:10.1186/s12885-016-2700-8) contains supplementary material, which is available to authorized users.

• Cervical cancer
• Differential network analysis
• Galectin-7
• Microenvironment crosstalk

• adenoma
• chemokines
• hormones
• pituitary gland
• systems biology

Considerable progress has been made to understand the association between lifestyle and diet in cancer initiation and promotion. Because excessive glucose consumption is a key metabolic hallmark of cancer cells, glucose restriction (GR) decreases the proliferation, and promotes the differentiation and transformation of cancer cells to quiescent cells. The immortality of cancerous cells is largely assured by telomerase, which is an interesting target for inhibition by BIBR 1532. In this study, we investigated the effect of GR on telomerase activity and on the efficacy of its inhibition by BIBR 1532.

Breast cancer MDA-MB 231 and MCF-7 cells were cultured in DMEM (Dulbecco’s modified eagle’s media) with 0, 1 or 4.5 g/l of glucose. The telomerase activity was measured via quantitative Real-Time PCR, and the two telomerase subunits were semi-quantified by RT-PCR. Proliferation test and mitochondrial metabolism were assessed via tetrazolium salt reduction and cell counts; apoptosis was assessed via caspase-3 quantification and flow cytometry.

A decrease in the telomerase activity of more than 75% was associated with a significant reduction in the mRNA expression of its catalytic subunit hTERT (Reverse Transcriptase) and a decrease in the mitochondrial metabolism by more than 80% under restricted glucose conditions. In addition, GR increased the effect of BIBR 1532. Glucose deprivation induces apoptosis via BIBR 1532-mediated telomerase inhibition in triple negative breast cancer cells, as assessed by caspase-3 measurements and Annexin analysis.

Taken together, our results suggest that the effect of BIBR 1532 is potentiated by GR to induce triple negative breast cancer cell death.

• BIBR 1532
• Breast cancer
• Cancer
• Glucose restriction
• Telomerase

• Biomarkers, Tumor/immunology
• Humans
• Immunity, Cellular
• Male
• Mast Cells/immunology
• Mast Cells/physiology
• Prognosis
• Prostatic Neoplasms/immunology
• Prostatic Neoplasms/pathology

• Colorectal cancer
• Immunity
• Inflammation
• Metastasis
• Prognosis

• Adaptive Immunity/physiology
• Animals
• Cell Proliferation
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/physiopathology
• Disease Models, Animal
• Disease Progression
• Humans
• Immunity, Innate/physiology
• Neoplasm Metastasis/immunology
• Neoplasm Metastasis/physiopathology
• Prognosis
• Tumor Microenvironment/immunology
• Tumor Microenvironment/physiology

• Animals
• Antibodies, Monoclonal/pharmacology
• Antineoplastic Agents/pharmacology
• Camptothecin/analogs & derivatives
• Camptothecin/pharmacology
• Drug Design
• Female
• Fibrin/antagonists & inhibitors
• Immunotoxins/pharmacokinetics
• Immunotoxins/pharmacology
• Immunotoxins/therapeutic use
• Irinotecan
• Mice
• Neoplasms, Experimental/drug therapy

In human somatic tumorigenesis, mutations are thought to arise sporadically in individual cells surrounded by unaffected cells. This contrasts with most current transgenic models where mutations are induced synchronously in entire cell populations. Here we have modeled sporadic oncogene activation using a transgenic mouse in which c-MYC is focally activated in prostate luminal epithelial cells. Focal c-MYC expression resulted in mild pathology, but prostate-specific deletion of a single allele of the Pten tumor suppressor gene cooperated with c-MYC to induce high grade prostatic intraepithelial neoplasia (HGPIN)/cancer lesions. These lesions were in all cases associated with loss of Pten protein expression from the wild type allele. In the prostates of mice with concurrent homozygous deletion of Pten and focal c-MYC activation, double mutant (i.e. c-MYC+;Pten-null) cells were of higher grade and proliferated faster than single mutant (Pten-null) cells within the same glands. Consequently, double mutant cells outcompeted single mutant cells despite the presence of increased rates of apoptosis in the former. The p53 pathway was activated in Pten-deficient prostate cells and tissues, but c-MYC expression shifted the p53 response from senescence to apoptosis by repressing the p53 target gene p21^Cip1. We conclude that c-MYC overexpression and Pten deficiency cooperate to promote prostate tumorigenesis, but a p53-dependent apoptotic response may present a barrier to further progression. Our results highlight the utility of inducing mutations focally to model the competitive interactions between cell populations with distinct genetic alterations during tumorigenesis.

In most human cancers, mutations are thought to arise in a single cell or few cells surrounded by their unaffected neighbors. Expansion of mutant cells can then allow the accumulation of additional mutations. The cell–cell interactions that may occur between mutant and unaffected cells or between cells with distinct mutations during tumorigenesis have not been well studied due to the lack of suitable in vivo models. To help fill this gap, we generated and characterized transgenic mice in which the oncogene c-MYC is activated focally in prostate epithelial cells. We have also analyzed mice in which prostate epithelial cells with two mutations (c-MYC overexpression and loss of Pten tumor suppressor) are found next to cells with a single mutation (loss of Pten). Although loss of Pten in the prostate is tumorigenic, it also activates a cellular senescence response which restrains further tumor progression. We found that concurrent c-MYC expression suppressed the senescence response in Pten-null cells in favor of apoptosis. c-MYC+;Pten-null cells proliferated faster than Pten-null cells in the same glands, with the net result that c-MYC+;Pten-null cells outcompete Pten-null cells. Our results demonstrate the utility of accurate models to mimic the heterogeneous and incremental nature of human prostate carcinogenesis.

• Animals
• Apoptosis
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Transgenic
• Mutation
• PTEN Phosphohydrolase/genetics
• PTEN Phosphohydrolase/metabolism
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/physiopathology
• Protein Binding
• Proto-Oncogene Proteins c-myc/genetics
• Proto-Oncogene Proteins c-myc/metabolism

• R01 CA094858 NCI NIH HHS
• R01 CA123484 NCI NIH HHS
• CA094858 NCI NIH HHS
• CA123484 NCI NIH HHS

• Adolescent
• Cerebellar Neoplasms/blood supply
• Cerebellar Neoplasms/therapy
• Child
• Child, Preschool
• Fractals
• Humans
• Infant
• Infant, Newborn
• Medulloblastoma/blood supply
• Medulloblastoma/therapy
• Neovascularization, Pathologic/pathology
• Neovascularization, Pathologic/therapy
• Vascular Endothelial Growth Factor A/antagonists & inhibitors

• Antigens, Neoplasm/analysis
• Antigens, Neoplasm/metabolism
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/therapy
• Genomics
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/therapy