scholarly journals Macrophage proliferation machinery leads to PDAC progression, but susceptibility to innate immunotherapy.

2021 ◽  
Author(s):  
David G DeNardo ◽  
Chong Zuo ◽  
John M. Baer ◽  
Brett L. Knolhoff ◽  
Jad I. Belle ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Genetically Engineered ◽  
Macrophage Phenotype ◽  
Sequencing Data ◽  
In Vitro Systems ◽  
Regulation Of Cell Cycle ◽  
The Impact

Tumor-associated macrophages (TAMs) are involved in many aspects of cancer progression and correlate with poor clinical outcomes in many cancer types, including pancreatic ductal adenocarcinomas (PDACs). Previous studies have shown that TAMs can populate PDAC tumors not only by monocyte recruitment but also by local proliferation. However, the impact local proliferation might have on macrophage phenotype and cancer progression is unknown. Here, we utilized genetically engineered cancer models, single-cell RNA-sequencing data, and in vitro systems to show that proliferation of TAMs was driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. The p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression, also drive response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy.

scholarly journals Impact of RARα and miR-138 on retinoblastoma etoposide resistance

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 11-26
Author(s):  
Maike Busch ◽  
Natalia Miroschnikov ◽  
Jaroslaw Thomas Dankert ◽  
Marc Wiesehöfer ◽  
Klaus Metz ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Cancer Progression ◽  
Treated Patient ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Gene Assay ◽  
The Impact

BACKGROUND: Retinoblastoma (RB) is the most common childhood eye cancer. Chemotherapeutic drugs such as etoposide used in RB treatment often cause massive side effects and acquired drug resistances. Dysregulated genes and miRNAs have a large impact on cancer progression and development of chemotherapy resistances. OBJECTIVE: This study was designed to investigate the involvement of retinoic acid receptor alpha (RARα) in RB progression and chemoresistance as well as the impact of miR-138, a potential RARα regulating miRNA. METHODS: RARα and miR-138 expression in etoposide resistant RB cell lines and chemotherapy treated patient tumors compared to non-treated tumors was revealed by Real-Time PCR. Overexpression approaches were performed to analyze the effects of RARα on RB cell viability, apoptosis, proliferation and tumorigenesis. Besides, we addressed the effect of miR-138 overexpression on RB cell chemotherapy resistance. RESULTS: A binding between miR-138 and RARα was shown by dual luciferase reporter gene assay. The study presented revealed that RARα is downregulated in etoposide resistant RB cells, while miR-138 is endogenously upregulated. Opposing RARα and miR-138 expression levels were detectable in chemotherapy pre-treated compared to non-treated RB tumor specimen. Overexpression of RARα increases apoptosis levels and reduces tumor cell growth of aggressive etoposide resistant RB cells in vitro and in vivo. Overexpression of miR-138 in chemo-sensitive RB cell lines partly enhances cell viability after etoposide treatment. CONCLUSIONS: Our findings show that RARα acts as a tumor suppressor in retinoblastoma and is downregulated upon etoposide resistance in RB cells. Thus, RARα may contribute to the development and progression of RB chemo-resistance.

scholarly journals Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2078
Author(s):  
Luca Gelsomino ◽  
Giuseppina Daniela Naimo ◽  
Rocco Malivindi ◽  
Giuseppina Augimeri ◽  
Salvatore Panza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Leptin Receptor ◽  
Macrophage Phenotype ◽  
In Vivo Models ◽  
Monocyte Chemoattractant Protein 1 ◽  
Arginase 1 ◽  
The Impact

Aberrant leptin (Ob) signaling, a hallmark of obesity, has been recognized to influence breast cancer (BC) biology within the tumor microenvironment (TME). Here, we evaluated the impact of leptin receptor (ObR) knockdown in affecting BC phenotype and in mediating the interaction between tumor cells and macrophages, the most abundant immune cells within the TME. The stable knockdown of ObR (ObR sh) in ERα-positive and ERα-negative BC cells turned the tumor phenotype into a less aggressive one, as evidenced by in vitro and in vivo models. In xenograft tumors and in co-culture experiments between circulating monocytes and BC cells, the absence of ObR reduced the recruitment of macrophages, and also affected their cytokine mRNA expression profile. This was associated with a decreased expression and secretion of monocyte chemoattractant protein-1 in ObR sh clones. The loss of Ob/ObR signaling modulated the immunosuppressive TME, as shown by a reduced expression of programmed death ligand 1/programmed cell death protein 1/arginase 1. In addition, we observed increased phagocytic activity of macrophages compared to control Sh clones in the presence of ObR sh-derived conditioned medium. Our findings, addressing an innovative role of ObR in modulating immune TME, may open new avenues to improve BC patient health care.

scholarly journals MiR-223 Promotes Tumor Progression via Targeting RhoB in Gastric Cancer

2022 ◽  
Vol 2022 ◽  
pp. 1-10
Author(s):  
You Hu ◽  
Bin Yi ◽  
Xin Chen ◽  
Lu Xu ◽  
Xiaojun Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Tumor Development ◽  
Migration And Invasion ◽  
Cellular Mechanisms ◽  
Borrmann Type ◽  
Potential Biomarker

Gastric cancer (GC) is among the most prevalent causes of cancer-related death globally. MiR-223 has been implicated in a variety of cellular mechanisms linked to cancer progression. However, the miR-223 expressions and its function in GC are unknown. We discovered that miR-223 expression was raised in GC tissues in comparison with nearby normal tissues in this investigation. Additionally, multiplied miR-223 expression was strongly linked with TNM stage ( p = 0.022 ), live metastasis ( p = 0.004 ),lymph node metastasis ( p = 0.004 ),and Borrmann type and was associated with an unfavorable prognostic for patients with GC. Furthermore, suppressing miR-223 significantly increased cell death and prevented cell migration and invasion in vitro. Additionally, miR-223 silencing decreased tumor development in vivo. Additionally, we discovered that miR-223 enhanced GC development by specifically targeting RhoB. In summary, our findings reveal that miR-223 increases tumor progression in GC by targeting RhoB, suggesting that it could serve to be a potential biomarker for the prediction of the disease.

scholarly journals G-CSF and G-CSFR Induce a Pro-Tumorigenic Macrophage Phenotype to Promote Colon and Pancreas Tumor Growth

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2868
Author(s):  
Ioannis Karagiannidis ◽  
Eliane de Santana Van Vilet ◽  
Erika Said Abu Egal ◽  
Brandon Phinney ◽  
Damian Jacenik ◽  
...  
Keyword(s):  
Tumor Progression ◽  
No Production ◽  
Macrophage Phenotype ◽  
Pancreas Tumor ◽  
Inflammatory Phenotype ◽  
The Difference ◽  
And Function ◽  
Stimulating Factor

Tumor-associated macrophages (TAMs) in the gastrointestinal tumor microenvironment (TME) are known to polarize into populations exhibiting pro- or anti-tumoral activity in response to stimuli such as growth factors and cytokines. Our previous work has recognized granulocyte colony-stimulating factor (G-CSF) as a cytokine capable of influencing immune cells of the TME exhibiting pro-tumoral activity. Here, we aimed to focus on how G-CSF regulates TAM phenotype and function and the effects on gastrointestinal (GI) tumor progression. Thus, wildtype (WT) and G-CSFR−/− macrophages were examined for cytokine production, gene expression, and transcription factor activity. Adoptive transfer of WT or G-CSFR−/− macrophages into tumor-bearing mice was performed to study their influence in the progression of colon (MC38) and pancreatic (PK5L1940) tumor mouse models. Finally, the difference in cytotoxic potential between WT and G-CSFR−/− macrophages was examined both in vitro and in vivo. Our results indicate that G-CSF promotes increased IL-10 production and decreased IL-12 production, which was reversed in G-CSFR−/− macrophages for a pro-inflammatory phenotype. Furthermore, G-CSFR−/− macrophages were characterized by higher levels of NOS2 expression and NO production, which led to greater tumor related cytotoxicity both in vitro and in vivo. Our results suggest that in the absence of G-CSFR, macrophage-related tumor cytotoxicity was amplified. These findings, along with our previous reports, pinpoint G-CSF /G-CSFR as a prominent target for possible clinical applications that aim to control the TME and the GI tumor progression.

scholarly journals A versatile ES cell-based melanoma mouse modeling platform

2019 ◽  
Author(s):  
Ilah Bok ◽  
Olga Vera ◽  
Xiaonan Xu ◽  
Neel Jasani ◽  
Koji Nakamura ◽  
...  
Keyword(s):  
Embryonic Stem ◽  
Genetically Engineered ◽  
Conditional Knockout ◽  
Mouse Strains ◽  
Mouse Modeling ◽  
Rapid Modeling ◽  
Development And Validation ◽  
The Impact

AbstractThe cumbersome and time-consuming process of generating new mouse strains and multi-allelic experimental animals often hinders the use of genetically engineered mouse models (GEMM) in cancer research. Here, we describe the development and validation of an embryonic stem cell (ESC)-GEMM platform for rapid modeling of melanoma in mice. Our platform incorporates twelve clinically relevant genotypes composed of combinations of four driver alleles (LSL-BrafV600E, LSL-NrasQ61R, PtenFlox, Cdkn2aFlox) and regulatory alleles to spatiotemporally control the perturbation of genes-of-interest. Our ESCs produce high contribution chimeras, which recapitulate the melanoma phenotypes of conventionally bred mice. Using our ESC-GEMM platform to modulate Pten expression in melanocytes in vivo, we highlight the utility and advantages of gene depletion by CRISPR-Cas9, RNAi, or conditional knockout for melanoma modeling. Moreover, we use complementary genetic methods to demonstrate the impact of Pten restoration on the prevention and maintenance of Pten-deficient melanomas. Finally, we show that chimera-derived melanoma cell lines retain regulatory allele competency and are a powerful resource to complement ESC-GEMM chimera experiments in vitro and in syngeneic grafts in vivo. Thus, when combined with sophisticated genetic tools, our ESC-GEMM platform enables rapid, high-throughput, and versatile studies aimed at addressing outstanding questions in melanoma biology.

Matrixmetalloproteinase Inhibitors: Promising Therapeutic Targets Against Cancer

2021 ◽  
Vol 27 ◽  
Author(s):  
Vibha Rani ◽  
Dhananjay Yadav ◽  
Neha Atale
Keyword(s):  
Clinical Trials ◽  
Tumor Progression ◽  
Cancer Progression ◽  
In Vivo Studies ◽  
Therapeutic Effects ◽  
Mmp Inhibitors ◽  
Cellular Environment ◽  
Wide Range

Background: Cancer is a wide range cellular level disease that occurs when cells go through uncontrolled division and growth. The mechanisms by which the cells undergo metastasis are complex and involve many interactions between the tumor cells and their cellular environment. Matrix metalloproteinases (MMPs) have been found to over-express at various stages of tumor progression and their inhibition using MMP inhibitors has been a subject of potential therapy against cancer. Objective: This review discusses recent research in MMP inhibitors (MMPI) used for preventing tumor progression. Methods: In this review, we explored the role of MMPs in cancer progression and summarized the current developments in MMPIs, their role in cancer suppression in in vitro and in vivo studies and their evaluation in clinical trials from the current research data. Results: MMPIs have shown to be very successful in in vitro models, cell lines and in some in vivo studies. Unfortunately, their efficacy in clinical trials has been found to be hit and miss. Recent studies have shown that the novel delivery approaches of MMP inhibitors may enhance their therapeutic effects towards the prevention of cancer. Conclusion: In this review, we presented different MMP inhibitors, their performance at different stages of models - in vitro, in vivo, small animal models and eventually clinical trials. We provide newer methods of MMPI delivery that may be better targeted to suppress only specific MMPs and avoid toxic side-effects in healthy cells.

scholarly journals Magnetic Compression of Tumor Spheroids Increases Cell Proliferation In Vitro and Cancer Progression In Vivo

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 366
Author(s):  
Gaëtan Mary ◽  
Brice Malgras ◽  
Jose Efrain Perez ◽  
Irène Nagle ◽  
Nathalie Luciani ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Peritoneal Cancer Index ◽  
Colon Cancer Cells ◽  
Tumor Spheroids ◽  
Proliferating Cells ◽  
The Impact

A growing tumor is submitted to ever-evolving mechanical stress. Endoscopic procedures add additional constraints. However, the impact of mechanical forces on cancer progression is still debated. Herein, a set of magnetic methods is proposed to form tumor spheroids and to subject them to remote deformation, mimicking stent-imposed compression. Upon application of a permanent magnet, the magnetic tumor spheroids (formed from colon cancer cells or from glioblastoma cells) are compressed by 50% of their initial diameters. Such significant deformation triggers an increase in the spheroid proliferation for both cell lines, correlated with an increase in the number of proliferating cells toward its center and associated with an overexpression of the matrix metalloproteinase−9 (MMP−9). In vivo peritoneal injection of the spheroids made from colon cancer cells confirmed the increased aggressiveness of the compressed spheroids, with almost a doubling of the peritoneal cancer index (PCI), as compared with non-stimulated spheroids. Moreover, liver metastasis of labeled cells was observed only in animals grafted with stimulated spheroids. Altogether, these results demonstrate that a large compression of tumor spheroids enhances cancer proliferation and metastatic process and could have implications in clinical procedures where tumor compression plays a role.

scholarly journals Cyclocreatine suppresses prostate tumorigenesis through dual effects on SAM and creatine metabolism

2021 ◽  
Author(s):  
Rachana Patel ◽  
Lisa Rodgers ◽  
Catriona A. Ford ◽  
Linda K Rushworth ◽  
Janis Fleming ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
De Novo ◽  
Basal Respiration ◽  
Genetically Engineered ◽  
Prostate Tumorigenesis ◽  
Genetically Engineered Mouse Model ◽  
Creatine Metabolism

ABSTRACTProstate cancer is highly prevalent, being the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of PTEN and SPRY2 (Sprouty 2) tumour suppressors, we identified enhanced creatine metabolism within the phosphagen system in progressive disease. Altered creatine metabolism was validated in in vitro and in vivo prostate cancer models and in clinical cases. Upregulated creatine levels were due to increased uptake through the SLC6A8 creatine transporter and de novo synthesis, resulting in enhanced cellular basal respiration. Treatment with cyclocreatine (a creatine analogue that potently and specifically blocks the phosphagen system) dramatically reduces creatine and phosphocreatine levels. Blockade of creatine biosynthesis by cyclocreatine leads to cellular accumulation of S-adenosyl methionine (SAM), an intermediary of creatine biosynthesis, and suppresses prostate cancer growth in vitro. Furthermore, cyclocreatine treatment impairs cancer progression in our GEMM and in a xenograft liver metastasis model. Hence, by targeting the phosphagen system, cyclocreatine results in anti-tumourigenic effects from both SAM accumulation and suppressed phosphagen system.

scholarly journals Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy

2022 ◽  
Vol 79 (1) ◽  
Author(s):  
Ana Mitrović ◽  
Janja Završnik ◽  
Georgy Mikhaylov ◽  
Damijan Knez ◽  
Urša Pečar Fonović ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Mouse Models ◽  
Cancer Progression ◽  
Cathepsin B ◽  
Cancer Resistance ◽  
Antitumor Therapy ◽  
Cysteine Cathepsins ◽  
Cathepsin X

AbstractNew therapeutic targets that could improve current antitumor therapy and overcome cancer resistance are urgently needed. Promising candidates are lysosomal cysteine cathepsins, proteolytical enzymes involved in various critical steps during cancer progression. Among them, cathepsin X, which acts solely as a carboxypeptidase, has received much attention. Our results indicate that the triazole-based selective reversible inhibitor of cathepsin X named Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) significantly reduces tumor progression, both in vitro in cell-based functional assays and in vivo in two independent tumor mouse models: the FVB/PyMT transgenic and MMTV-PyMT orthotopic breast cancer mouse models. One of the mechanisms by which cathepsin X contributes to cancer progression is the compensation of cathepsin-B activity loss. Our results confirm that cathepsin-B inhibition is compensated by an increase in cathepsin X activity and protein levels. Furthermore, the simultaneous inhibition of both cathepsins B and X with potent, selective, reversible inhibitors exerted a synergistic effect in impairing processes of tumor progression in in vitro cell-based assays of tumor cell migration and spheroid growth. Taken together, our data demonstrate that Z9 impairs tumor progression both in vitro and in vivo and can be used in combination with other peptidase inhibitors as an innovative approach to overcome resistance to antipeptidase therapy.

scholarly journals Role of RAGE and Its Ligands on Inflammatory Responses to Brain Tumors

2021 ◽  
Vol 15 ◽  
Author(s):  
Griffith Kyle Otazu ◽  
Mojtaba Dayyani ◽  
Behnam Badie
Keyword(s):  
Cancer Progression ◽  
Inflammatory Responses ◽  
Checkpoint Inhibitors ◽  
Malignant Gliomas ◽  
Low Grade ◽  
Molecular Pattern ◽  
The Impact

Gliomas, the most common form of brain cancer, can range from relatively slow-growing low-grade to highly aggressive glioblastoma that has a median overall survival of only 15 months despite multimodal standard therapy. Although immunotherapy with checkpoint inhibitors has significantly improved patient survival for some cancers, to date, these agents have not shown consistent efficacy against malignant gliomas. Therefore, there is a pressing need to better understand the impact of host inflammatory responses on the efficacy of emerging immunotherapy approaches for these resistant tumors. RAGE is a multi-ligand pattern recognition receptor that is activated in various inflammatory states such as diabetes, Alzheimer’s disease, cystic fibrosis, and cancer. Low levels of RAGE can be found under normal physiological conditions in neurons, immune cells, activated endothelial, and vascular smooth muscle cells, but it is over-expressed under chronic inflammation due to the accumulation of its ligands. RAGE binds to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA which mediate downstream cellular responses that promote tumor growth, angiogenesis, and invasion. Both in vitro and in vivo studies have shown that inhibition of RAGE signaling can disrupt inflammation and cancer progression and metastasis. Here, we will review our current understanding of the role of RAGE pathway on glioma progression and how it could be exploited to improve the efficacy of immunotherapy approaches.

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