scholarly journals Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer

2020 ◽  
Vol 6 (20) ◽  
pp. eaba1590 ◽  
Author(s):  
Xue Dong ◽  
Pei Pan ◽  
Di-Wei Zheng ◽  
Peng Bao ◽  
Xuan Zeng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
In Vivo Studies ◽  
Host Immune System ◽  
Immune Microenvironment ◽  
Phage Display Technology ◽  
Tumor Immune Microenvironment

Mounting evidence suggests that the gut microbiota contribute to colorectal cancer (CRC) tumorigenesis, in which the symbiotic Fusobacterium nucleatum (Fn) selectively increases immunosuppressive myeloid-derived suppressor cells (MDSCs) to hamper the host’s anticancer immune response. Here, a specifically Fn-binding M13 phage was screened by phage display technology. Then, silver nanoparticles (AgNP) were assembled electrostatically on its surface capsid protein (M13@Ag) to achieve specific clearance of Fn and remodel the tumor-immune microenvironment. Both in vitro and in vivo studies showed that of M13@Ag treatment could scavenge Fn in gut and lead to reduction in MDSC amplification in the tumor site. In addition, antigen-presenting cells (APCs) were activated by M13 phages to further awaken the host immune system for CRC suppression. M13@Ag combined with immune checkpoint inhibitors (α-PD1) or chemotherapeutics (FOLFIRI) significantly prolonged overall mouse survival in the orthotopic CRC model.

scholarly journals Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer

2021 ◽  
Vol 9 (1) ◽  
pp. e001895
Author(s):  
Chao Liu ◽  
Ruiqi Liu ◽  
Bojun Wang ◽  
Jie Lian ◽  
Yang Yao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Mrna Levels ◽  
Murine Models ◽  
T Cell Infiltration ◽  
Interleukin 17A ◽  
Tumor Environment

BackgroundImmune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflammatory mediators, mobilize myeloid cells and reshape the tumor environment. In the present study, we aimed to investigate the role of IL-17A in resistance to antitumor immunity and to explore the feasibility of anti-IL-17A combined with anti-PD-1 therapy in MSS CRC murine models.MethodsThe expression of programmed cell death-ligand 1 (PD-L1) and its regulation by miR-15b-5p were investigated in MSS CRC cell lines and tissues. The effects of miR-15b-5p on tumorigenesis and anti-PD-1 treatment sensitivity were verified both in vitro and in colitis-associated cancer (CAC) and APCmin/+ murine models. In vivo efficacy and mechanistic studies were conducted using antibodies targeting IL-17A and PD-1 in mice bearing subcutaneous CT26 and MC38 tumors.ResultsEvaluation of clinical pathological specimens confirmed that PD-L1 mRNA levels are associated with CD8+ T cell infiltration and better prognosis. miR-15b-5p was found to downregulate the expression of PD-L1 at the protein level, inhibit tumorigenesis and enhance anti-PD-1 sensitivity in CAC and APCmin/+ CRC models. IL-17A led to high PD-L1 expression in CRC cells through regulating the P65/NRF1/miR-15b-5p axis. Combined IL-17A and PD-1 blockade had efficacy in CT26 and MC38 tumors, with more cytotoxic T lymphocytes cells and fewer myeloid-derived suppressor cells in tumors.ConclusionsIL-17A increases PD-L1 expression through the p65/NRF1/miR-15b-5p axis and promotes resistance to anti-PD-1 therapy. Blocking IL-17A improved the efficacy of anti-PD-1 therapy in MSS CRC murine models. IL-17A might serve as a therapeutic target to sensitize patients with MSS CRC to ICI therapy.

scholarly journals Development of an LDL Receptor-Targeted Peptide Susceptible to Facilitate the Brain Access of Diagnostic or Therapeutic Agents

Biology ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 161
Author(s):  
Séverine André ◽  
Lionel Larbanoix ◽  
Sébastien Verteneuil ◽  
Dimitri Stanicki ◽  
Denis Nonclercq ◽  
...  
Keyword(s):  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Therapeutic Agents ◽  
In Vivo Studies ◽  
Phage Display Technology ◽  
Brain Penetration ◽  
Wide Range ◽  
The Brain

Blood-brain barrier (BBB) crossing and brain penetration are really challenging for the delivery of therapeutic agents and imaging probes. The development of new crossing strategies is needed, and a wide range of approaches (invasive or not) have been proposed so far. The receptor-mediated transcytosis is an attractive mechanism, allowing the non-invasive penetration of the BBB. Among available targets, the low-density lipoprotein (LDL) receptor (LDLR) shows favorable characteristics mainly because of the lysosome-bypassed pathway of LDL delivery to the brain, allowing an intact discharge of the carried ligand to the brain targets. The phage display technology was employed to identify a dodecapeptide targeted to the extracellular domain of LDLR (ED-LDLR). This peptide was able to bind the ED-LDLR in the presence of natural ligands and dissociated at acidic pH and in the absence of calcium, in a similar manner as the LDL. In vitro, our peptide was endocytosed by endothelial cells through the caveolae-dependent pathway, proper to the LDLR route in BBB, suggesting the prevention of its lysosomal degradation. The in vivo studies performed by magnetic resonance imaging and fluorescent lifetime imaging suggested the brain penetration of this ED-LDLR-targeted peptide.

scholarly journals A Review of the Role of Neurotensin and Its Receptors in Colorectal Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Shengyang Qiu ◽  
Gianluca Pellino ◽  
Francesca Fiorentino ◽  
Shahnawaz Rasheed ◽  
Ara Darzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Animal Studies ◽  
In Vivo Studies ◽  
Signalling Pathways ◽  
Diagnostic Biomarker ◽  
Gi Tract ◽  
Cellular Receptors

Neurotensin (NTS) is a physiologically occurring hormone which affects the function of the gastrointestinal (GI) tract. In recent years, NTS, acting through its cellular receptors (NTSR), has been implicated in the carcinogenesis of several cancers. In colorectal cancer (CRC), a significant body of evidence, from in vitro and in vivo studies, is available which elucidates the molecular biology of NTS/NTSR signalling and the resultant growth of CRC cells. There is growing clinical data from human studies which corroborate the role NTS/NTSR plays in the development of human CRC. Furthermore, blockade and modulation of the NTS/NTSR signalling pathways appears to reduce CRC growth in cell cultures and animal studies. Lastly, NTS/NTSR also shows potential of being utilised as a diagnostic biomarker for cancers as well as targets for functional imaging. We summarise the existing evidence and understanding of the role of NTS and its receptors in CRC.

Adjuvant-induced nonspecific suppressor cells: In vitro and in vivo studies

1980 ◽  
Vol 53 (2) ◽  
pp. 225-235 ◽  
Author(s):  
Nabil Hanna ◽  
Sarah Blanc ◽  
David Nelken
Keyword(s):  
Suppressor Cells ◽  
In Vivo Studies

scholarly journals THE POTENTIAL OF ROBUSTA COFFEE (COFFEA CANEPHORA) AS A COLORECTAL CANCER THERAPY MODALITY: AN IN SILICO STUDY

2021 ◽  
pp. 83-87
Author(s):  
DESSY AGUSTINI ◽  
LEO VERNADESLY ◽  
DELVIANA ◽  
THEODORUS
Keyword(s):  
Colorectal Cancer ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
Binding Energies ◽  
In Vivo Studies ◽  
Discovery Studio ◽  
Robusta Coffee ◽  
In Silico Study

Objectives: This research aims to determine the efficacy of compounds in robusta coffee against colorectal cancer through the inhibition of the T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) receptor. Methods: This in silico study has been conducted in computing platform from June to August 2021. The selected test compounds would go through the Lipinski rule screening through the SwissADME website and the compounds that met these regulations would be docked to the TIGIT protein using AutoDock Tools and AutoDock Vina. The interactions with the highest binding energies were visualized using BIOVIA Discovery Studio 2020. The test compounds then underwent a toxicity profile analysis on the admetSAR 2.0 website. Results: All test compounds complied with the Lipinski rule. The molecular docking results showed the highest binding energy in kahweol and cafestol (−8.1 kcal/mol) compared to OMC (−7.9 kcal/mol), chlorogenic acid (−7.8 kcal/mol), caffeic acid (−6.3 kcal/mol), caffeine (−6.1 kcal/mol), trigonelline (−5.3 kcal/mol), HMF (−5.1 kcal/mol), furfuryl alcohol (−4.4 kcal/mol), and 5-fluorouracil as the comparator drug (−5.3 kcal/mol). Kahweol, cafestol, and 5-fluorouracil revealed the hydrophobic interactions and hydrogen bonds with amino acid residues in TIGIT. Kahweol and cafestol unveiled minimal toxicity prediction Conclusion: Kahweol and cafestol demonstrated the best results in inhibiting the TIGIT protein which played a role in colorectal cancer. In vitro and in vivo studies are needed to strengthen the findings of this research.

scholarly journals Targeting OLFML3 in Colorectal Cancer Suppresses Tumor Growth and Angiogenesis, and Increases the Efficacy of Anti-PD1 Based Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4625
Author(s):  
Jimmy Stalin ◽  
Beat A. Imhof ◽  
Oriana Coquoz ◽  
Rachel Jeitziner ◽  
Philippe Hammel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Molecular Subtype ◽  
Human Cancer ◽  
Tumor Development ◽  
Tumor Grade ◽  
Tissue Expression ◽  
In Vivo Studies

The role of the proangiogenic factor olfactomedin-like 3 (OLFML3) in cancer is unclear. To characterize OLFML3 expression in human cancer and its role during tumor development, we undertook tissue expression studies, gene expression analyses of patient tumor samples, in vivo studies in mouse cancer models, and in vitro coculture experiments. OLFML3 was expressed at high levels, mainly in blood vessels, in multiple human cancers. We focused on colorectal cancer (CRC), as elevated expression of OLFML3 mRNA correlated with shorter relapse-free survival, higher tumor grade, and angiogenic microsatellite stable consensus molecular subtype 4 (CMS4). Treatment of multiple in vivo tumor models with OLFML3-blocking antibodies and deletion of the Olfml3 gene from mice decreased lymphangiogenesis, pericyte coverage, and tumor growth. Antibody-mediated blockade of OLFML3 and deletion of host Olfml3 decreased the recruitment of tumor-promoting tumor-associated macrophages and increased infiltration of the tumor microenvironment by NKT cells. Importantly, targeting OLFML3 increased the antitumor efficacy of anti-PD-1 checkpoint inhibitor therapy. Taken together, the results demonstrate that OLFML3 is a promising candidate therapeutic target for CRC.

scholarly journals SPZ1 promotes deregulation of Bim to boost apoptosis resistance in colorectal cancer

2020 ◽  
Vol 134 (2) ◽  
pp. 155-167
Author(s):  
Xiao-Yu Liu ◽  
Chang-Bo Zheng ◽  
Teng Wang ◽  
Jian Xu ◽  
Meng Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Growth ◽  
Clinical Stage ◽  
In Vivo Studies ◽  
Apoptosis Resistance ◽  
Advanced Clinical Stage ◽  
Helix Loop Helix ◽  
The Stability

Abstract Colorectal cancer (CRC) is the third most common malignancies in adults. Similar to other solid tumors, CRC cells show increased proliferation and suppressed apoptosis during the development and progression of the disease. Previous studies have shown that a novel tumor oncogene, spermatogenic basic helix-loop-helix transcription factor zip 1 (SPZ1), can promote proliferation. However, it is unclear whether SPZ1 plays a role in suppressing apoptosis, and the molecular mechanism behind SPZ1’s suppression of apoptosis in CRC remains unclear. Here, we found that silencing endogenous SPZ1 inhibits cell growth and induces apoptosis, and overexpression of SPZ1 promotes cell growth. These findings were corroborated by in vitro and in vivo studies. Interestingly, SPZ1 overexpressing cells were resistant to 5-fluorouracil, a drug commonly used to treat cancer. Moreover, knocking down SPZ1 led to the activation of caspase through the deregulation of Bim by ERK1/2, we found that CRC tissues had significantly higher SPZ1 and lower Bim expression, and SPZ1HBimL were associated with advanced clinical stage of CRC. Collectively, our findings demonstrate that SPZ1 contributes to tumor progression by limiting apoptosis. SPZ1 reduces apoptosis by altering the stability of Bim, suggesting SPZ1 may serve as a biomarker and therapeutic target for CRC.

scholarly journals Dopamine Pathway Mediated by DRD5 Facilitates Tumor Growth via Enhancing Warburg Effect in Esophageal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaozhe Qian ◽  
Donglei Zhang ◽  
Ziang Cao ◽  
Haitao Ma
Keyword(s):  
Esophageal Cancer ◽  
Tumor Cells ◽  
Lymphatic Metastasis ◽  
Warburg Effect ◽  
Transcriptional Analysis ◽  
Immune Microenvironment ◽  
Tumor Tissues ◽  
Tumor Immune Microenvironment

Esophageal cancer (EC) is among the most malignant cancers globally due to its aggressiveness and poor survival. To set off from the inflammatory tumor immune microenvironment, we analyzed tumor tissues of EC patients with or without lymphatic metastasis to explore the importance of cancer cell derived neurotransmitters. Results have emphasized that the accumulation of dopamine but not other neurotransmitters could be observed in EC tumor tissue of patients, especially those who are bearing lymphatic metastasis. Transcriptional analysis of mentioned tissues was also performed to filter out key enzymes involved in dopamine pathway including tyrosine hydroxylase (TH), DOPA decarboxylase (DCC), monoamine oxidase (MAO), etc. Further analysis on tumor tissues of patients indicated that dopamine receptor D5 was aberrantly upregulated and co-located with TH. Both in vitro and in vivo tests have demonstrated that dopamine could stimulate the proliferation and outgrowth of EC tumor cells via the DRD5 mediated pathway. The exploration of mechanism has unveiled that activation of the dopamine pathway significantly enhanced the uptake of glucose and production of lactate of EC tumor cells. It can also facilitate the extracellular acid rate (ECAR), dedicating that DRD5-mediated activated dopamine pathway could effectively form and trigger Warburg effect, which is modulated by the cross-talk of mTOR and AKT pathway. Our results would unveil the relationship between cancer derived neurotransmitters and inflammatory tumor immune microenvironment, thus provide potential therapeutic targets and novel clinical strategy towards metastatic EC.

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