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PURPOSE: G-CSF enhances colon cancer development. This study defines the prevalence and effects of increased G-CSF signaling in human colon cancers and investigates G-CSF inhibition as an immunotherapeutic strategy against metastatic colon cancer. EXPERIMENTAL DESIGN: Patient samples were used to evaluate G-CSF and G-CSF receptor (G-CSFR) levels by IHC with sera used to measure G-CSF levels. Peripheral blood mononuclear cells were used to assess the rate of G-CSFR+ T cells and IFNγ responses to chronic ex vivo G-CSF. An immunocompetent mouse model of peritoneal metastasis (MC38 cells in C57Bl/6J) was used to determine the effects of G-CSF inhibition (αG-CSF) on survival and the tumor microenvironment (TME) with flow and mass cytometry. RESULTS: In human colon cancer samples, the levels of G-CSF and G-CSFR are higher compared to normal colon tissues from the same patient. High patient serum G-CSF is associated with increases in markers of poor prognosis, (e.g., VEGF, IL6). Circulating T cells from patients express G-CSFR at double the rate of T cells from controls. Prolonged G-CSF exposure decreases T cell IFNγ production. Treatment with αG-CSF shifts both the adaptive and innate compartments of the TME and increases survival (HR, 0.46; P = 0.0237) and tumor T-cell infiltration, activity, and IFNγ response with greater effects in female mice. There is a negative correlation between serum G-CSF levels and tumor-infiltrating T cells in patient samples from women. CONCLUSIONS: These findings support G-CSF as an immunotherapeutic target against colon cancer with greater potential benefit in women.
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Neoplasias del Colon , Factor Estimulante de Colonias de Granulocitos , Humanos , Femenino , Ratones , Animales , Leucocitos Mononucleares , Linfocitos T , Receptores de Factor Estimulante de Colonias de Granulocito/fisiología , Neoplasias del Colon/tratamiento farmacológico , Inmunoterapia , Microambiente TumoralRESUMEN
Women with colorectal cancer (CRC) have survival advantages over men, yet the underlying mechanisms are unclear. T cell infiltration within the CRC tumor microenvironment (TME) correlates strongly with survival. We hypothesized that women with CRC have increased T cell infiltration and differential gene expression in the TME compared to men. Tissue microarrays comprising primary tumor, tumor infiltrated lymph nodes, and uninvolved colon were created from CRC patients. Proportions of CD4 positive (CD4+) and CD8 positive (CD8+) T cells were identified using immunohistochemistry. TME immune- and cancer-related genetic expression from primary and metastatic CRC tumor were also evaluated via the NanoStringIO360 panel and The Cancer Genome Atlas Project database. CD4+ was higher in tumor samples from women compared to men (22.04% vs. 10.26%, p=0.002) and also in lymph node samples (39.54% vs. 8.56%, p=0.001). CD8+ was increased in uninvolved colon from women compared to men (59.40% vs. 43.61%, p=0.015), and in stage I/II tumors compared to III/IV in all patients (37.01% vs. 23.91%, p=0.009). Top CD8+ tertile patients survived longer compared to the bottom (43.9 months vs. 25.3 months, p=0.007). Differential gene expression was observed in pathways related to Treg function, T cell activity, and T cell exhaustion, amongst several others, in women compared to men. Thus, significant sexual dimorphism exists in the TME that could contribute to survival advantages observed in female patients with CRC.
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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.
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Colorectal cancer is the 2nd leading cause of cancer-related deaths in the world. The mechanisms underlying CRC development, progression, and resistance to treatment are complex and not fully understood. The immune response in the tumor microenvironment has been shown to play a significant role in many cancers, including colorectal cancer. Colony-stimulating factor 3 (CSF3) has been associated with changes to the immune environment in colorectal cancer animal models. We hypothesized that CSF3 signaling would correlate with pro-tumor tumor microenvironment changes associated with immune infiltrate and response. We utilized publicly available datasets to guide future mechanistic studies of the role CSF3 and its receptor (CSF3R) play in colorectal cancer development and progression. Here, we use bioinformatics data and mRNA from patients with colon (n = 242) or rectal (n = 92) cancers, obtained from The Cancer Genome Atlas Firehose Legacy dataset. We examined correlations of CSF3 and CSF3R expression with patient demographics, tumor stage and consensus molecular subtype classification. Gene expression correlations, cell type enrichment, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data scores and Gene Ontology were used to analyze expression of receptor and ligand, tumor microenvironment infiltration of immune cells, and alterations in biological pathways. We found that CSF3 and CSF3R expression is highest in consensus molecular subtype 1 and consensus molecular subtype 4. Ligand and receptor expression are also correlated with changes in T cell and macrophage signatures. CSF3R significantly correlates with a large number of genes that are associated with poor colorectal cancer prognosis.
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Neoplasias Colorrectales/patología , Perfilación de la Expresión Génica/métodos , Factor Estimulante de Colonias de Granulocitos/genética , Receptores del Factor Estimulante de Colonias/genética , Regulación hacia Arriba , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Bases de Datos Genéticas , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de Secuencia de ARN , Transducción de Señal , Microambiente TumoralRESUMEN
Purpose: Glial fibrillary acid protein (GFAP) and vimentin are type III intermediate filament proteins, ubiquitously expressed in retinal glial cells. Under retinal stress, both GFAP and vimentin are well-known sensitive markers for retinal gliosis. However, little is known about whether these proteins are released into the vitreous body in response to retinal gliosis or are related to the severity of retinal gliosis seen in proliferative vitreoretinopathy (PVR). Methods: Vitreous fluids were collected from 44 patients who underwent pars plana vitrectomy for macular hole (Group 1; n = 8), epiretinal membrane (Group 2; n = 8), or retinal detachment (RD) with various degrees of PVR (Group 3; n = 28). The severity of PVR was determined by cumulative scores using PVR classification. GFAP, vimentin, and total protein levels from the vitreous samples were measured. Results: Both GFAP and vimentin levels were significantly elevated in vitreous fluid from Group 3 (RD) compared with Groups 1 and 2 (P < 0.01). GFAP levels (ng/mL) were 12.4 ± 9.8, 17.5 ± 17.7, and 572.0 ± 11659.7, and vimentin levels (ng/mL) were 40.8 ± 61.9, 88.6 ± 86.8, and 3952.8 ± 8179.5 in Groups 1, 2, and 3, respectively. Total protein levels were not significantly different among the three groups. Elevated GFAP and vimentin levels in Group 3 were positively correlated with the areas of RD (P < 0.01, r = 0.53 in GFAP and P < 0.05, r = 0.46 in vimentin) and PVR scores (P < 0.05, r = 0.46 in GFAP and P < 0.00001, r = 0.76 in vimentin). Conclusions: Our data suggest that human vitreous GFAP and vimentin are protein biomarkers for PVR, and reactive gliosis may play a part in PVR formation.