Abstract 2135: Complex roles of discoidin domain receptors (DDRs) in tumor growth and experimental metastasis: role of collagen I in DDR-mediated tumor growth

AbstractMalignant pleural mesothelioma (MPM) is an aggressive neoplasm originating from the pleura. Non-epithelioid (biphasic and sarcomatoid) MPM are particularly resistant to therapy. We investigated the role of the GITR-GITRL pathway in mediating the resistance to therapy. We found that GITR and GITRL expressions were higher in the sarcomatoid cell line (CRL5946) than in non-sarcomatoid cell lines (CRL5915 and CRL5820), and that cisplatin and Cs-137 irradiation increased GITR and GITRL expressions on tumor cells. Transcriptome analysis demonstrated that the GITR-GITRL pathway was promoting tumor growth and inhibiting cell apoptosis. Furthermore, GITR+ and GITRL+ cells demonstrated increased spheroid formation in vitro and in vivo. Using patient derived xenografts (PDXs), we demonstrated that anti-GITR neutralizing antibodies attenuated tumor growth in sarcomatoid PDX mice. Tumor immunostaining demonstrated higher levels of GITR and GITRL expressions in non-epithelioid compared to epithelioid tumors. Among 73 patients uniformly treated with accelerated radiation therapy followed by surgery, the intensity of GITR expression after radiation negatively correlated with survival in non-epithelioid MPM patients. In conclusion, the GITR-GITRL pathway is an important mechanism of autocrine proliferation in sarcomatoid mesothelioma, associated with tumor stemness and resistance to therapy. Blocking the GITR-GITRL pathway could be a new therapeutic target for non-epithelioid mesothelioma.

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KLF7/VPS35 axis contributes to hepatocellular carcinoma progression through CCDC85C-activated β-catenin pathway

Cell & Bioscience ◽

10.1186/s13578-021-00585-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yarong Guo ◽

Bao Chai ◽

Junmei Jia ◽

Mudan Yang ◽

Yanjun Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Tumor Growth ◽

Luciferase Reporter ◽

Aberrant Expression ◽

Proliferation And Invasion ◽

Hcc Cells

Abstract Objective Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. Methods CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Immunohistochemical staining and qRT-PCR analysis were performed in human HCC sampels to study the clinical significance of KLF7, VPS35 and β-catenin. Results Firstly, KLF7 was highly expressed in human HCC samples and correlated with patients’ differentiation and metastasis status. KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of β-catenin signaling pathway, confirmed using β-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Lastly, there was a positive correlation among KLF7, VPS35 and active-β-catenin in human HCC patients. Conclusion We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated β-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.

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Kras-driven intratumoral heterogeneity triggers infiltration of M2 polarized macrophages via the circHIPK3/PTK2 immunosuppressive circuit

Scientific Reports ◽

10.1038/s41598-021-94671-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Theodora Katopodi ◽

Savvas Petanidis ◽

Kalliopi Domvri ◽

Paul Zarogoulidis ◽

Doxakis Anestakis ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Lung Tumor ◽

Quantitative Polymerase Chain Reaction ◽

Macrophage Polarization ◽

Metastatic Potential ◽

Intratumoral Heterogeneity ◽

M2 Macrophage

AbstractIntratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1−/CD11b−, Gr1−/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1−/CD11b−, Gr1−/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

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Investigating New Therapeutic Strategies Targeting Hyperinsulinemia's Mitogenic Effects in a Female Mouse Breast Cancer Model

Endocrinology ◽

10.1210/en.2012-2263 ◽

2013 ◽

Vol 154 (5) ◽

pp. 1701-1710 ◽

Cited By ~ 21

Author(s):

Ran Rostoker ◽

Keren Bitton-Worms ◽

Avishay Caspi ◽

Zila Shen-Orr ◽

Derek LeRoith

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Breast Tumor ◽

Experimental Studies ◽

Tumor Development ◽

Treated Group ◽

Tumor Growth Rate ◽

Breast Cancer Patients ◽

Mitogenic Effect

Abstract Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR, we treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961-treated mice had significantly larger tumors compared to the vehicle-treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.

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Evolving role of GTP cyclohydrolase 1 inhibition in mitigating cancer pain besides its role in attenuating tumor growth

International Journal of Cancer ◽

10.1002/ijc.27867 ◽

2012 ◽

Vol 132 (8) ◽

pp. 1969-1969

Author(s):

S. Kapoor

Keyword(s):

Tumor Growth ◽

Cancer Pain ◽

Gtp Cyclohydrolase

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Thymoquinone Inhibits Tumor Growth and Induces Apoptosis in a Breast Cancer Xenograft Mouse Model: The Role of p38 MAPK and ROS

PLoS ONE ◽

10.1371/journal.pone.0075356 ◽

2013 ◽

Vol 8 (10) ◽

pp. e75356 ◽

Cited By ~ 90

Author(s):

Chern Chiuh Woo ◽

Annie Hsu ◽

Alan Prem Kumar ◽

Gautam Sethi ◽

Kwong Huat Benny Tan

Keyword(s):

Breast Cancer ◽

Mouse Model ◽

Tumor Growth ◽

P38 Mapk ◽

Xenograft Mouse Model ◽

Breast Cancer Xenograft

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Abstract 237: Sex-specific Regulation Of Collagen I And III Expression By 17β-estradiol In Rat Cardiac Fibroblasts: Role Of Estrogen Receptors

Circulation Research ◽

10.1161/res.113.suppl_1.a237 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Elke Dworatzek ◽

Shokoufeh Mahmoodzadeh ◽

Sandra Kunze ◽

Vera Regitz-Zagrosek

Keyword(s):

Sex Differences ◽

Western Blot ◽

Estrogen Receptors ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Collagen I ◽

Female Rats ◽

17Β Estradiol ◽

Specific Regulation

Clinical and animal studies showed in female pressure-overloaded hearts less cardiac fibrosis and collagen I and III gene expression compared to males, suggesting an inhibitory effect of 17β-Estradiol (E2) on collagens. Therefore we investigated the role of E2 and estrogen receptors (ER) on collagen I and III expression in isolated rat cardiac fibroblasts from both sexes. Cardiac fibroblasts were isolated from adult male and female Wistar rats, and treated with E2 (10-8M), vehicle, ERα and ERβ-agonist (10-7M) and/or pre-treated with ICI 182,780 (10-5M) for 24h. Cellular localization of ER in cardiac fibroblasts with/without E2 was detected by immunofluorescence staining, and expression of both ER was determined by western blot. Expression of collagen I and III was determined by qRT-PCR and western blot. E2-treatment led to a nuclear translocation of ERα and ERβ in cardiac fibroblasts, suggesting the functional activity of ER as transcription factors. Furthermore in cardiac fibroblasts from female rats E2 led to a significant down-regulation of collagen I and III gene and protein expression. In contrast there was a significant increase of collagen I and III levels in fibroblasts isolated from male rat hearts by E2. E2-effect could be inhibited by ICI 182, 780 indicating the involvement of ER. In cardiac fibroblasts from female rats, ERα-agonist treatment led to a significant down-regulation of collagen I and III mRNA level, but ERβ-agonist had no effects. In contrast, ERβ-agonist treatment of cardiac fibroblasts from males increased collagen I and III mRNA, but no changes with ERα agonist-treatment were detected. ERα protein levels displayed no sex differences at basal level. After E2-treatment ERα protein was up-regulated in male cells, but decreased in cardiac fibroblasts from females. ERβ protein was higher in female cells compared to males, but the expression was not regulated by E2 in both sexes. Sex-specific regulation of collagen I and III expression by E2 in cardiac fibroblasts might be responsible for sex-differences in cardiac fibrosis. This might be due to sexually dimorphic ER expression and regulation. Understanding how E2 and ER mediate sex-differences in cardiac remodeling may help to design sex-specific pharmacological interventions.

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The Role Of Thrombocytes In Tumor Growth And Metastasis

Онкогинекология ◽

10.52313/22278710_2018_4_12 ◽

2018 ◽

pp. 12-20

Author(s):

S.P. Sviridova ◽

Sh.R. Kashiya ◽

O.A. Obukhova ◽

M.V. Rubanskaya ◽

A.V. Sotnikov

Keyword(s):

Tumor Growth ◽

Tumor Growth And Metastasis

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