scholarly journals SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Yu-qiang Yu ◽  
Veronika Thonn ◽  
Jay V. Patankar ◽  
Oana-Maria Thoma ◽  
Maximilian Waldner ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Colon Tumor ◽  
Colonic Tumor ◽  
Experimental Cancer ◽  
Cancer Models ◽  
Tumor Tissues ◽  
Histone H3k4 ◽  
Induced Apoptosis ◽  
Murine Colon

AbstractSMYD2 is a histone methyltransferase, which methylates both histone H3K4 as well as a number of non-histone proteins. Dysregulation of SMYD2 has been associated with several diseases including cancer. In the present study, we investigated whether and how SMYD2 might contribute to colorectal cancer. Increased expression levels of SMYD2 were detected in human and murine colon tumor tissues compared to tumor-free tissues. SMYD2 deficiency in colonic tumor cells strongly decreased tumor growth in two independent experimental cancer models. On a molecular level, SMYD2 deficiency sensitized colonic tumor cells to TNF-induced apoptosis and necroptosis without affecting cell proliferation. Moreover, we found that SMYD2 targeted RIPK1 and inhibited the phosphorylation of RIPK1. Finally, in a translational approach, pharmacological inhibition of SMYD2 attenuated colonic tumor growth. Collectively, our data show that SMYD2 is crucial for colon tumor growth and inhibits TNF-induced apoptosis and necroptosis.

scholarly journals Thymoquinone reduces mouse colon tumor cell invasion and inhibits tumor growth in murine colon cancer models

2007 ◽  
Vol 12 (1) ◽  
pp. 330-342 ◽  
Author(s):  
Hala Gali-Muhtasib ◽  
Matthias Ocker ◽  
Doerthe Kuester ◽  
Sabine Krueger ◽  
Zeina El-Hajj ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Cell Invasion ◽  
Tumor Cell Invasion ◽  
Colon Tumor ◽  
Mouse Colon ◽  
Cancer Models ◽  
Colon Tumor Cell ◽  
Murine Colon

scholarly journals Thymic stromal lymphopoietin (TSLP) inhibits human colon tumor growth by promoting apoptosis of tumor cells

Oncotarget ◽  
2016 ◽  
Vol 7 (13) ◽  
pp. 16840-16854 ◽  
Author(s):  
Wenjie Yue ◽  
Yuli Lin ◽  
Xuguang Yang ◽  
Bingji Li ◽  
Jie Liu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Human Colon ◽  
Thymic Stromal Lymphopoietin ◽  
Colon Tumor

Suppression of in vivo tumor growth by the transfection of the interleukin-5 gene into colon tumor cells

1995 ◽  
Vol 41 (6) ◽  
pp. 325-330 ◽  
Author(s):  
Yoshihiro Masuda ◽  
Seiji Mita ◽  
Kiyoshi Sakamoto ◽  
Takatoshi Ishiko Michio Ogawa
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Colon Tumor ◽  
Interleukin 5

scholarly journals Expression of CCRL2 Inhibits Tumor Growth by Concentrating Chemerin and Inhibiting Neoangiogenesis

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5000
Author(s):  
Diana Al Delbany ◽  
Virginie Robert ◽  
Ingrid Dubois-Vedrenne ◽  
Annalisa Del Prete ◽  
Maxime Vernimmen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Chemokine Receptors ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Cancer Models ◽  
The Family ◽  
G Protein Coupled ◽  
Mouse Cancer Models ◽  
Receptor Family

CCRL2 belongs to the G protein-coupled receptor family and is one of the three chemerin receptors. It is considered as a non-signaling receptor, presenting chemerin to cells expressing the functional chemerin receptor ChemR23/CMKLR1 and possibly GPR1. In the present work, we investigate the role played by CCRL2 in mouse cancer models. Loss of function of Ccrl2 accelerated the development of papillomas in a chemical model of skin carcinogenesis (DMBA/TPA), whereas the growth of B16 and LLC tumor cell grafts was delayed. Delayed tumor growth was also observed when B16 and LLC cells overexpress CCRL2, while knockout of Ccrl2 in tumor cells reversed the consequences of Ccrl2 knockout in the host. The phenotypes associated with CCRL2 gain or loss of function were largely abrogated by knocking out the chemerin or Cmklr1 genes. Cells harboring CCRL2 could concentrate bioactive chemerin and promote the activation of CMKLR1-expressing cells. A reduction of neoangiogenesis was observed in tumor grafts expressing CCRL2, mimicking the phenotype of chemerin-expressing tumors. This study demonstrates that CCRL2 shares functional similarities with the family of atypical chemokine receptors (ACKRs). Its expression by tumor cells can significantly tune the effects of the chemerin/CMKLR1 system and act as a negative regulator of tumorigenesis.

scholarly journals Osteopontin Blockade Immunotherapy Increases Cytotoxic T Lymphocyte Lytic Activity and Suppresses Colon Tumor Progression

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1006
Author(s):  
John D. Klement ◽  
Dakota B. Poschel ◽  
Chunwan Lu ◽  
Alyssa D. Merting ◽  
Dafeng Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoid Cells ◽  
Colon Tumor ◽  
Tumor Bearing

Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer. We report here that OPN is primarily expressed in tumor cells, myeloid cells, and innate lymphoid cells in human colorectal carcinoma. Spp1 knock out mice exhibit a high incidence and fast growth rate of carcinogen-induced tumors. Knocking out Spp1 in colon tumor cells increased tumor-specific CTL cytotoxicity in vitro and resulted in decreased tumor growth in vivo. The OPN protein level is elevated in the peripheral blood of tumor-bearing mice. We developed four OPN neutralization monoclonal antibodies based on their efficacy in blocking OPN inhibition of T cell activation. OPN clones 100D3 and 103D6 increased the efficacy of tumor-specific CTLs in killing colon tumor cells in vitro and suppressed colon tumor growth in tumor-bearing mice in vivo. Our data indicate that OPN blockade immunotherapy with 100D3 and 103D6 has great potential to be further developed for colorectal cancer immunotherapy and for rendering a colorectal cancer response to anti-PD-1 immunotherapy.

Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6

Blood ◽  
2010 ◽  
Vol 115 (11) ◽  
pp. 2264-2273 ◽  
Author(s):  
Sonja Loges ◽  
Thomas Schmidt ◽  
Marc Tjwa ◽  
Katie van Geyte ◽  
Dirk Lievens ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Growth ◽  
Tyrosine Kinases ◽  
Tumor Biology ◽  
Specific Gene ◽  
Wild Type ◽  
Experimental Cancer ◽  
Cancer Models ◽  
Amplification Loop ◽  
Endothelial Growth Factor

AbstractThe transforming and tumor growth–promoting properties of Axl, a member of the Tyro3, Axl, and Mer (TAM) family of receptor tyrosine kinases (TAMRs), are well recognized. In contrast, little is known about the role of the TAMR ligand growth arrest–specific gene 6 (Gas6) in tumor biology. By using Gas6-deficient (Gas6−/−) mice, we show that bone marrow–derived Gas6 promotes growth and metastasis in different experimental cancer models, including one resistant to vascular endothelial growth factor inhibitors. Mechanistic studies reveal that circulating leukocytes produce minimal Gas6. However, once infiltrated in the tumor, leukocytes up-regulate Gas6, which is mitogenic for tumor cells. Consistent herewith, impaired tumor growth in Gas6−/− mice is rescued by transplantation of wild-type bone marrow and, conversely, mimicked by transplantation of Gas6−/− bone marrow into wild-type hosts. These findings highlight a novel role for Gas6 in a positive amplification loop, whereby tumors promote their growth by educating infiltrating leukocytes to up-regulate the production of the mitogen Gas6. Hence, inhibition of Gas6 might offer novel opportunities for the treatment of cancer.

scholarly journals The CCR2/MCP-1 Chemokine Pathway and Lung Adenocarcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3723
Author(s):  
Payal Mittal ◽  
Liqing Wang ◽  
Tatiana Akimova ◽  
Craig A. Leach ◽  
Jose C. Clemente ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Suppressor Cells ◽  
Treg Cells ◽  
Cancer Models ◽  
Inflammatory Site ◽  
Ccr2 Antagonist

Host anti-tumor immunity can be hindered by various mechanisms present within the tumor microenvironment, including the actions of myeloid-derived suppressor cells (MDSCs). We investigated the role of the CCR2/MCP-1 pathway in MDSC-associated tumor progression in murine lung cancer models. Phenotypic profiling revealed maximal expression of CCR2 by tumor-resident MDSCs, and MCP-1 by transplanted TC1 tumor cells, respectively. Use of CCR2-knockout (CCR2-KO) mice showed dependence of tumor growth on CCR2 signaling. Tumors in CCR2-KO mice had fewer CCR2low MDSCs, CD4 T cells and Tregs than WT mice, and increased infiltration by CD8 T cells producing IFN-γ and granzyme-B. Effects were MDSC specific, since WT and CCR2-KO conventional T (Tcon) cells had comparable proliferation and production of inflammatory cytokines, and suppressive functions of WT and CCR2-KO Foxp3+ Treg cells were also similar. We used a thioglycolate-induced peritonitis model to demonstrate a role for CCR2/MCP-1 in trafficking of CCR2+ cells to an inflammatory site, and showed the ability of a CCR2 antagonist to inhibit such trafficking. Use of this CCR2 antagonist promoted anti-tumor immunity and limited tumor growth. In summary, tumor cells are the prime source of MCP-1 that promotes MDSC recruitment, and our genetic and pharmacologic data demonstrate that CCR2 targeting may be an important component of cancer immunotherapy.

scholarly journals Human amniotic epithelial cells exert anti-cancer effects through secretion of immunomodulatory exosomes

2021 ◽  
Author(s):  
Mohammad Bolouri ◽  
Roya Ghods ◽  
sedighe vafaei ◽  
Reza Falak ◽  
Amir-Hassan Zarnani
Keyword(s):  
Colon Cancer ◽  
Tumor Cells ◽  
Tumor Development ◽  
Inhibitory Effects ◽  
Anti Cancer ◽  
Human Amniotic Epithelial Cells ◽  
4T1 Cells ◽  
Induced Apoptosis ◽  
Murine Colon ◽  
Reactive Antibody

We identified here mechanism by which hAEC exert their anti-cancer effects. We showed that vaccination with live hAEC conferred effective protection against murine colon cancer and melanoma but not against breast cancer in orthotopic cancer cell inoculation model. hAEC induced strong cross-reactive antibody response to CT26 cells, but not against B16F10 and 4T1 cells. Neither heterotopic injection of tumor cells in AEC-vaccinated mice nor vaccination with hAEC lysate conferred protection against melanoma or colon cancer. Nanosized AEC-derived exosomes (ADE) induced apoptosis in CT26 cells and inhibited their proliferation. Co-administration of ADE with tumor cells substantially inhibited tumor development and increased CTL responses in vaccinated mice. Our results clearly showed that it is ADE but not the cross-reactive immune responses against tumor cells that mediate inhibitory effects of hAEC on cancer development. Our results highlighted the potential anti-cancer effects of exosomes derived from hAEC.

scholarly journals Kynurenine analog 3-HAA is a ligand for transcription factor YY1

2020 ◽  
Author(s):  
Zhaopeng Shi ◽  
Guifang Gan ◽  
Xiang Xu ◽  
Jieying Zhang ◽  
Yuan Yuan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Formation ◽  
Aryl Hydrocarbon ◽  
Ido Inhibitors ◽  
Induced Apoptosis ◽  
Transcription Factor Yy1

Abstract Kynurenine, a metabolite of tryptophan, promotes immune tolerance in development and tumor evasion by binding to the aryl hydrocarbon receptor (AHR). However, the IDO inhibitors, blocking kynurenine generation, fail in stage III of clinical trials in several tumors for unknown reasons. Here, we report that 3-hydroxyanthranilic acid (3-HAA) synergizes with IDO inhibitors by dramatically increasing the suppression of IDO inhibitors on HCC xenograft growth. The content of 3-HAA, a catabolite of kynurenine, is lower in tumor cells by downregulating its synthetic enzyme KMO/KYNU and/or upregulating its catalytic enzyme HAAO. Overexpression of KMO suppresses tumor formation and tumor growth by increasing endogenous 3-HAA while adding exogenous 3-HAA also inhibits tumor growth. Moreover, we found that 3-HAA directly binds transcription factor YY1 rather than AHR and increasing the PKCζ phosphorylation of YY1 at the Thr 398 in response to 3-HAA; YY1 phosphorylation at T398 increases the YY1 binding to chromatin. 3-HAA-induced Thr398 phosphorylation of YY1 upregulates the expression of dual-specificity phosphatase 6 (DUSP6), etc. DUSP6 overexpression induces apoptosis of hepatocellular carcinoma (HCC) cells and suppresses the HCC growth in vitro and in vivo. The T398 phosphorylation of YY1 is critical for the 3-HAA-induced apoptosis in tumors. These findings demonstrate that kynurenine analog 3-HAA is a functional metabolite associating YY1 as an endogenous ligand, downregulation of 3-HAA is necessary for the rapid growth of tumor cells, suggesting its promising approach in HCC therapy.

scholarly journals Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 361
Author(s):  
Alyssa D. Merting ◽  
Dakota B. Poschel ◽  
Chunwan Lu ◽  
John D. Klement ◽  
Dafeng Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Codon Usage ◽  
Tumor Cells ◽  
Liver Toxicity ◽  
Human Colon ◽  
Tumor Xenograft ◽  
Colon Tumor ◽  
Human Colorectal Cancer

A hallmark of human colorectal cancer is lost expression of FAS, the death receptor for FASL of cytotoxic T lymphocytes (CTLs). However, it is unknown whether restoring FAS expression alone is sufficient to suppress csolorectal-cancer development. The FAS promoter is hypermethylated and inversely correlated with FAS mRNA level in human colorectal carcinomas. Analysis of single-cell RNA-Seq datasets revealed that FAS is highly expressed in epithelial cells and immune cells but down-regulated in colon-tumor cells in human colorectal-cancer patients. Codon usage-optimized mouse and human FAS cDNA was designed, synthesized, and encapsulated into cationic lipid to formulate nanoparticle DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Overexpression of codon usage-optimized FAS in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS+ tumor cells in vitro, suppressed colon tumor growth, and increased the survival of tumor-bearing mice in vivo. Overexpression of codon-optimized FAS-induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. DOTAP-Chol-mFAS therapy exhibited no significant liver toxicity. Our data determined that tumor-selective delivery of FAS DNA nanoparticles is sufficient for suppression of human colon tumor growth in vivo.

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