• Angiopoietin-like protein 2
• Colony-stimulating factor 3
• Colony-stimulating factor 3 receptor
• Gastric cancer
• Heterogeneous nuclear ribonucleoprotein H1
• Human leukocyte antigen-G
• Immunosuppressive receptor
• Leukocyte immunoglobulin-like receptor B2

• Clinicopathological significance
• G-CSF
• Immunohistochemistry
• Prognostic marker
• Upper tract urothelial carcinoma

• Humans
• Granulocyte Colony-Stimulating Factor/metabolism
• Granulocyte Colony-Stimulating Factor/biosynthesis
• Female
• Male
• Stromal Cells/pathology
• Stromal Cells/metabolism
• Aged
• Middle Aged
• Prognosis
• Carcinoma, Transitional Cell/pathology
• Carcinoma, Transitional Cell/metabolism
• Carcinoma, Transitional Cell/mortality
• Biomarkers, Tumor/metabolism
• Aged, 80 and over
• Urologic Neoplasms/pathology
• Urologic Neoplasms/metabolism
• Adult
• Urothelium/pathology
• Urothelium/metabolism

• Hiroshima University

• Distant metastasis
• NSCLC
• Postoperative recurrence
• Risk factor
• rhG-CSF

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/surgery
• Male
• Female
• Lung Neoplasms/drug therapy
• Lung Neoplasms/surgery
• Middle Aged
• Granulocyte Colony-Stimulating Factor/therapeutic use
• Retrospective Studies
• Neoplasm Recurrence, Local/prevention & control
• Recombinant Proteins/therapeutic use
• Aged
• Risk Factors
• Adult

• colorectal cancer
• complete blood count
• inflammation-related biomarkers

• Humans
• Colorectal Neoplasms/blood
• Colorectal Neoplasms/diagnosis
• Male
• Female
• Middle Aged
• Blood Cell Count/methods
• Aged
• Inflammation/blood
• Adult
• Adenoma/blood
• Adenoma/diagnosis
• Adenoma/pathology
• Platelet Count
• C-Reactive Protein/analysis
• Leukocyte Count
• Biomarkers/blood
• ROC Curve
• Eosinophils
• Biomarkers, Tumor/blood

• Gastric precancerous lesions (PLGC)
• Helicobacter pylori (Hp)
• Molecular targets
• Regulatory mechanisms

• Humans
• Stomach Neoplasms/pathology
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/metabolism
• Precancerous Conditions/pathology
• Precancerous Conditions/drug therapy
• Animals
• Autophagy/drug effects
• Gastric Mucosa/pathology
• Gastric Mucosa/drug effects
• Gastric Mucosa/metabolism
• Apoptosis/drug effects
• Tumor Microenvironment/drug effects
• Molecular Targeted Therapy
• Bile Acids and Salts/metabolism
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology

• Granulocyte colony-stimulating factor
• Granulocyte-macrophage colony-stimulating factor
• Head and neck neoplasms
• Interleukin-3
• Macrophage colony-stimulating factor

• Humans
• Colony-Stimulating Factors
• Interleukin-3
• Granulocyte Colony-Stimulating Factor/therapeutic use
• Cytokines
• Granulocytes
• Head and Neck Neoplasms/drug therapy
• Tumor Microenvironment

• P30 CA042014 NCI NIH HHS

• Granulocyte Colony-Stimulating Factor
• Granulocyte-Macrophage Colony-Stimulating Factor
• Immune Evasion
• Myeloid-Derived Suppressor Cell
• Neutrophils
• Programmed Death-Ligand 1

• 2017R1A5A2015385 National Research Foundation of Korea
• 2022R1A2C2010148 National Research Foundation of Korea
• Ministry of Science and ICT
• Korea Health Industry Development Institute
• HR20C0025 Ministry of Health and Welfare

Disseminated carcinomatosis of the bone marrow (DCBM) is a widespread metastasis with a hematologic disorder that is mainly caused by gastric cancer. Although it commonly occurs as a manifestation of recurrence long after curative treatment, the precise mechanism of relapse from dormant status remains unclear. Granulocyte colony-stimulating factor (G-CSF) can promote cancer progression and invasion in various cancers. However, the potential of G-CSF to trigger recurrence from a cured malignancy has not been reported.

A 55-year-old Japanese woman was diagnosed with Ewing sarcoma localized on the fifth lumbar vertebrae 6 years after curative gastrectomy for T1 gastric cancer. After palliative surgery to release nerve compression, pathological diagnosis of the resected specimen was followed by curative radiation and chemotherapy. During treatment, G-CSF was administered 32 times for severe neutropenia prophylaxis. Eight months after completing definitive treatment, she complained of severe back pain and was diagnosed as multiple bone metastases with DCBM from gastric cancer. Despite palliative chemotherapy, she died of disseminated intravascular coagulation 13 d after the diagnosis. Immunohistochemical examination of the autopsied bone marrow confirmed a diffuse positive staining for the G-CSF receptor (G-CSFR) in the relapsed gastric cancer cell cytoplasm, whereas the primary lesion cancer cells showed negative staining for G-CSFR. In this case, G-CSF administration may have been the key trigger for the disseminated relapse of a dormant gastric cancer.

When administering G-CSF to cancer survivors, recurrence of a preceding cancer should be monitored even after curative treatment.

• Disseminated bone marrow carcinomatosis
• Gastric cancer
• Granulocyte colony-stimulating factor
• Cancer survivor
• Immunostaining
• Case report

Granulocyte colony-stimulating factor receptor (GCSFR) is a critical regulator of granulopoiesis. Studies have shown significant upregulation of GCSFR in a variety of cancers and cell types and have recognized GCSFR as a cytokine receptor capable of influencing both myeloid and non-myeloid immune cells, supporting pro-tumoral actions. This systematic review aims to summarize the available literature examining the mechanisms that control GCSFR signaling, regulation, and surface expression with emphasis on how these mechanisms may be dysregulated in cancer. Experiments with different cancer cell lines from breast cancer, bladder cancer, glioma, and neuroblastoma are used to review the biological function and underlying mechanisms of increased GCSFR expression with emphasis on actions related to tumor proliferation, migration, and metastasis, primarily acting through the JAK/STAT pathway. Evidence is also presented that demonstrates a differential physiological response to aberrant GCSFR signal transduction in different organs. The lifecycle of the receptor is also reviewed to support future work defining how this signaling axis becomes dysregulated in malignancies.

• National Institutes of Health

• Anti-tumor activity
• Cancer therapy
• Pro-tumor activity
• Tumor microenvironment
• Tumor-associated neutrophils

Chemotherapy serves as the first choice in clinic to treat advanced gastric cancer. However, emerging evidence indicated the induction of drug resistance and cancer stem cells occasionally by chemotherapy, which seriously limit the therapeutic effects, but the regulatory mechanism remains unclear. Here we treated two human gastric cancer cell lines SGC7901 and BGC823 with 5-Fluorouracil (5-Fu) or Cisplatin (DDP) in vitro. The survived cells showed significant increase of drug resistance, cell stemness and cytokine GM-CSF expression and secretion. As such, GM-CSF was applied to stimulate gastric cancer cells, followed by the subpopulation of CD133⁺ CSC analysis, sphere formation assay and stemness genes expression analysis. As a result, CSCs showed induction by GM-CSF treatment. A gastric cancer animal model further indicated that the gastric cancer cells significantly promoted tumor growth after GM-CSF treatment in vivo. High-throughput miRNA and mRNA sequencing analyses identified a subset of miRNAs and mRNAs under regulation of both 5-Fu and GM-CSF in gastric cancer cells, including upregulation of miR-877-3p and downregulation of SOCS2. Targeted overexpression or knockdown of miR-877-3p in gastric cancer cells revealed the oncogenic function of miR-877-3p in regulating gastric cancer by suppressing target gene SOCS2. Jak2/Stat3 signaling pathway, as a downstream target of SOCS2, showed activation in vitro and in vivo after treatment with miR-877-3p or GM-CSF. Our findings not only revealed a novel mechanism through which chemotherapy induced CSCs in gastric cancer via GM-CSF-miRNA-Jak2/Stat3 signaling, but also provided an experimental evidence for appropriate dose reduction of adjuvant chemotherapy in treatment of cancer patients.

Gastrointestinal malignant tumor is the fourth most common cancer in the world and the second cause of cancer death. Due to the susceptibility to lymphatic metastasis and liver metastasis, the prognosis of advanced tumor patients is still poor till now. With the development of tumor molecular biology, the tumor microenvironment and the cytokines, which are closely related to the proliferation, infiltration and metastasis, have become a research hotspot in life sciences. Colony stimulating factor-1 (CSF-1), a polypeptide chain cytokine, and its receptor CSF-1R are reported to play important roles in regulating tumor-associated macrophages in tumor microenvironment and participating in the occurrence and development in diversities of cancers. Targeted inhibition of the CSF-1/CSF-1R signal axis has broad application prospects in cancer immunotherapy. Here, we reviewed the biological characters of CSF-1/CSF-1R and their relationship with gastrointestinal malignancies.

• colony stimulating factor-1
• colony stimulating factor-1 receptor
• gastrointestinal malignant tumors
• tumor-associated macrophages

• granulocyte colony-stimulating factor
• granulocyte colony-stimulating factor receptor
• hemangiopericytoma
• leukocytosis
• solitary fibrous tumor

Despite the recent development of chemotherapeutic agents, the prognosis of colorectal cancer (CRC) patients with peritoneal dissemination (PD) remains poor. The tumor immune microenvironment (TIME) has drawn attention as a key contributing factor of tumor progression. Of TIME components, myeloid-derived suppressor cells (MDSCs) are considered to play a responsible role in the immunosuppressive characteristics of the TIME. MDSCs are classified into two major subsets: Monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs). Therefore, we hypothesize that MDSCs would play important roles in the PD-relevant TIME and PD progression. To address this hypothesis, we established PD mouse models. As the PD nodules consisted scarcely of immune cells, we focused on the peritoneal cavity, but not PD nodule, to evaluate the PD-relevant TIME. As a result, intraperitoneal PMN-MDSCs were found to be substantially increased in association with PD progression. Based on these results, we phenotypically and functionally verified the usefulness of CD244 for identifying PMN-MDSCs. In addition, the concentrations of interleukin (IL)-6 and granulocyte-colony stimulating factor (G-CSF) were significantly increased in the peritoneal cavity, both of which were produced by the tumors and thought to contribute to the increases in the PMN-MDSCs. In vivo depletion of the PMN-MDSCs by anti-Ly6G monoclonal antibody (mAb) significantly inhibited the PD progression and reverted CD4⁺ and CD8⁺ T cells in the peritoneal cavity and the peripheral blood. Collectively, these results suggest that the targeted therapy for PMN-MDSCs would provide not only new therapeutic value but also a novel strategy to synergize with T-cell-based immunotherapy for CRC-derived PD.

• CD244
• colon cancer
• myeloid‑derived suppressor cell
• neutrophil
• peritoneal dissemination
• polymorphonuclear myeloid‑derived suppressor cell

Our previous study revealed that Shuanghuang Shengbai granule could cure the myelosuppression induced by cyclophosphamide (CTX) in lung cancer. However, its hematopoietic effects and molecular mechanisms remain not fully understood. Therefore, this study was intended to investigate the effects and the underlying mechanisms of Astragaloside IV (AS) and saponins of rhizoma polygonati (SRP), the two main bioactive ingredients of Shuanghuang Shengbai granule, on CTX-induced myelosuppression. CTX inhibited the proliferation and promoted apoptosis in bone marrow hematopoietic stem cells (BMHSCs), accompanied by the increased expression of miR-142-3p. AS and/or SRP treatment could alleviate CTX-induced cell injury and suppress the expression of miR-142-3p. Over-expression of miR-142-3p partially reversed the therapeutic effect of AS and/or SRP on CTX-induced cell injury in BMHSCs. Further mechanism exploration discovered that HMGB1 was the target gene of miR-142-3p, and miR-142-3p negatively regulated the expression of HMGB1. To further explore the function of AS and/or SRP in vivo, we constructed a lung cancer xenograft combined with CTX-induced myelosuppression mouse model, and we found that AS and SRP remarkably reversed the CTX-induced reduction of white blood cells, bone marrow nucleated cells, and thymus index in vivo and did not affect the chemotherapy effect of lung cancer. Collectively, our results strongly suggested that AS and SRP could improve the hematopoietic function of myelosuppressed lung cancer mice, and their effects may be related to the inhibition of miR-142-3p expression in BMHSCs.

• HMGB1
• astragaioside IV
• mir-142-3p
• myelosuppression
• saponins of rhizoma polygonati

• Colorectal cancer
• G-CSF
• G-CSF receptor
• Immune cells
• Tumor microenvironment

Mammalian Ste20-like kinase 4 (MST4), also known as serine/threonine kinase 26 (STK26), promotes development of several cancers and is found to be highly expressed in the placenta. However, in choriocarcinoma that originated from the placenta, the expression of MST4 was undetermined and its mechanism was unknown. In this study, the expression of MST4 in choriocarcinoma as well as the underlying mechanism was explored.

To detect the expression of MST4 in patient samples and mechanism of mediating EMT by MST4 in choriocarcinoma.

The metastatic lesions of choriocarcinoma (n=17) and volunteer villus (n=17) were collected to determine MST4 expression using immunohistochemistry and H&E staining. We use siRNA and lentiviral vector to knockdown MST4 and use plasmid to overexpress MST4 in choriocarcinoma. Then, we apply real-time polymerase chain reaction (RT-PCR), Western blot assay and immunofluorescence assay to detect target protein expressions. Cell invasion and migration and cell proliferation were detected by transwell assay and wound healing assay and CCK-8 and cell colony formation.

MST4 is lowly expressed in the metastatic lesions of choriocarcinoma patients when compared with normal villus. Knockdown of MST4 activated epithelial–mesenchymal transition (EMT) process, significantly increasing the ability of invasion and migration in choriocarcinoma cell lines (JAR and JEG-3). In contrast, the EMT process was restrained in choriocarcinoma cell lines with overexpressed MST4. Meanwhile, genome-wide gene expression array, Western blot and ELISA revealed that tumor growth factor-beta 1 (TGF-β1) has significantly increased. The EMT process and metastatic prompting biofunction were reversed after using TGF-β1 inhibitor (LY364947) in the choriocarcinoma cell lines with MST4 knockdown.

Our studies demonstrated that MST4 was lowly expressed in patient samples. Additionally, JAR and JEG-3 increase cell invasion and migration ability while there is no influence on cell proliferation with MST4 knockdown. Conversely, the metastatic ability of JAR and JEG-3 was decreased with overexpressed MST4. Moreover, TGF-β1 was a key factor after MST4 knockdown. In conclusion, MST4 affects choriocarcinoma EMT by mediating TGF-β1 expression.

• EMT
• MST4
• TGF-β1
• choriocarcinoma

The prognostic roles of granulocyte-/granulocyte-macrophage colony-stimulating factor (G-/GM-CSF) and its receptors (CSFRs) from the genomic perspective remain controversial. The aim of our study was to evaluate their prognostic value in multiple cancer types by analyzing omics data.

The omics data of G-/GM-CSF and receptors were obtained from the cBioportal database. Cutoff values were determined by X-tile. Overall survival (OS) was assessed by Kaplan–Meier curves. Differentially expressed genes (DEGs) and common regulated genes were analyzed using R software and Venny 2.1.0, while enrichment pathway analyses were performed by Metascape.

A comprehensive mRNA analysis was performed in 8,565 patients across 24 cancer types. The combination subgroup of CSF2 and its receptors with high expression and favorable prognosis was associated with the activation of immune-related pathways, while the subgroup with unfavorable prognosis was associated with the activation of inflammatory and cellular pathways. As for the combination subgroup of CSF3 and its receptor, the high expression and poor prognosis subgroup was accompanied by the activation of inflammation and signaling transduction pathways.

The prognostic value of CSFs and CSFRs are cancer-type dependent. Therefore, personalized risk stratification based on CSF and CSFR pathway should be considered for cancer patients.

• Colony-stimulating factors (CSFs)
• colony-stimulating factor receptors (CSFRs)
• differentially expressed genes
• enrichment pathway
• survival analysis

Gastric cancer is associated with chronic inflammation, but there is still much to understand about the tumor microenvironment and the underlying tumor-promoting mechanisms. The Map kinase-activated protein kinase 2 (MK2) pathway is a regulator of inflammatory cytokine production that we have been studying in gastrointestinal cancers. Here, we set out to determine the significance of this gene in gastric cancer along with its downstream mediators and if there were differences in the primary tumors with and without metastasis.

Human gastric cancer tissues with and without metastasis were examined for MK2 expression and cytokine profile in organ culture supernatants. Advanced statistical methods including a lower triangular correlation matrix, novel rooted correlation network, linear and logistic regression modeling along with Kruskal–Wallis testing with Sidak correction for multiple testing were applied to gain understanding of cytokines/chemokines linked to metastasis.

The MK2 pathway is strongly linked with metastasis and a panel of cytokines. Gene expression was able to classify gastric cancer metastasis 85.7% of the time. A significant association with a panel of cytokines was found, including G-CSF, GM-CSF, Mip-1β, IFN-α, MCP-1, IL-1β, IL-6, and TNF-α. Mip-1β was found to have the strongest association with MK2 and metastasis after Sidak correction for multiple testing.

MK2 gene expression and a novel associated cytokine panel are linked to gastric cancer metastasis. G-CSF is the strongest cytokine to differentiate between metastasis and non-metastasis patients and had the lowest P value, while Mip-1β showed the strongest association with MK2 and metastasis after Sidak correction. MK2 and associated cytokines are potential biomarkers for gastric cancer metastasis. The novel intercorrelation analysis approach is a promising method for understanding the complex nature of cytokine/chemokine regulation and links to disease outcome.

• Chemokines
• Cytokines
• Gastric cancer
• Granulocyte colony-stimulating factor
• Map kinase-activated protein kinase 2

Granulocyte-colony-stimulating factor (G-CSF) is a member of the hematopoietic growth factor family that primarily affects the neutrophil lineage. G-CSF serves as a powerful mobilizer of peripheral blood stem cells and recombinant human G-CSF (rhG-CSF) has been used to treat granulocytopenia and neutropenia after chemotherapy for cancer patients. However, recent studies have found that G-CSF plays an important role in cancer progression. G-CSF expression is increased in different types of cancer cells, such as lung cancer, gastric cancer, colorectal cancer, invasive bladder carcinoma, glioma and breast cancer. However, it is unclear whether treatment with G-CSF has an adverse effect. The current review provides an overview of G-CSF in malignant breast cancer development and the data presented in this review are expected to provide new ideas for cancer therapy.

• Granulocyte colony-stimulating factor a (GCSFa)
• Large yellow croaker (Larimichthys crocea)
• Proliferation
• STAT3 and STAT5
• Signal pathway

• Adaptive Immunity/genetics
• Amino Acid Sequence
• Animals
• Fish Diseases/immunology
• Fish Proteins/chemistry
• Fish Proteins/genetics
• Fish Proteins/immunology
• Gene Expression Profiling/veterinary
• Gene Expression Regulation/immunology
• Granulocyte Colony-Stimulating Factor/chemistry
• Granulocyte Colony-Stimulating Factor/genetics
• Granulocyte Colony-Stimulating Factor/immunology
• Immunity, Innate/genetics
• Perciformes/genetics
• Perciformes/immunology
• Phylogeny
• Sequence Alignment/veterinary

The effectiveness of chemotherapy and radiotherapy to treat lung cancer is limited because of highly metastatic nature. Novel strategies and drugs to attenuate metastatic activity are urgently required. In this study, red fluorescence proteins (RFP)-labeled A549 human lung cancer cells were orthotopically implantation, where they developed primary tumors. Metastasis in brain and intestines were reduced by up to 80% by treatment with 100 mpk 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) compared with that in control mice. PLAG treatment also reduced the migration of the primary tumors. Interestingly, substantial neutrophil infiltration was observed in the tumors in control mice. The neutrophil contribution to A549 cell metastatic activity was examined in in vitro co-culture system. Metastatic activity could be achieved in the A549 cells through epidermal growth factor receptor (EGFR) transactivation mediated by protease activating receptor 2 (PAR2) receptor. Neutrophil elastase secreted from tumor-infiltrating neutrophils stimulated PAR2 and induced EGFR transactivation. However, this transactivation was inhibited by inducing PAR2 degradation following PLAG treatment and metastatic activity was effectively inhibited. PLAG attenuated cancer metastatic activity via modulated PAR2/EGFR transactivation by accelerating PAR2 degradation. These results suggest PLAG as potential therapeutic agent to combat tumor metastasis via regulating the activation signal pathway of PAR2 by tumor infiltrate-neutrophils.

• EGFR transactivation
• PAR2 degradation
• PLAG
• anti-metastasis
• tumor infiltrated-neutrophils (TINs)

• CLEC5A
• Cell apoptosis
• Cell proliferation
• Gastric cancer
• PI3K/AKT/mTOR pathway

A higher incidence of gastric cancer has been found in East Asia compared to the incidence in other regions. Gastric cancer patients have a poor prognosis due to distant metastasis and advanced cancer stages. Tumor escape pathways include the expansion of the immunosuppressive myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We have successfully established an orthotopic immunocompetent gastric cancer model in C57BL/6 mice. The cell line is named M12 and was deposited at the Bioresource Collection and Research Center of Taiwan on Sep. 13, 2016 (Patent No. I604054). The orthotopic animal model of gastric cancer has similar biological characteristics as human gastric cancer. Serine/threonine-protein kinase 24 (STK24) is a member of the germinal center kinase (GCK)-III family. GCKs participate in cancer and immunological disorders. The effects of STK24 in gastric cancer are less well understood. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 technology was used to induce a STK24 genetic knockout at the genomic DNA level in tumor cells. The knockdown of the STK24 gene increased the tumor growth in an orthotopic model of gastric cancer. The STK24 gene silencing in tumors induced the expansion of CD11b⁺Ly6C⁺ cells and F4/80⁺ macrophages in vivo. To our knowledge, we have developed the first orthotopic transplantable model of gastric cancer in syngeneic inbred mice. Our results further indicate that STK24 is important for immune regulation during the tumorigenesis of gastric cancer.

• gastric cancer
• germinal center kinase
• myeloid-derived suppressor cells
• orthotopic model of gastric cancer
• serine/threonine-protein kinase 24
• tumorigenesis

• GRASP overexpression
• methylation subtypes
• prognosis survival related model
• proliferation
• risk score

• Cancer
• Imaging
• Immunotherapy
• Nanobody
• Single Domain Antibody