scholarly journals 4006 Methionine Dependence in Cancer: From Metabolic Phenotype to Therapy

2020 ◽  
Vol 4 (s1) ◽  
pp. 12-12
Author(s):  
Isabelle Miousse
Keyword(s):  
Weight Loss ◽  
Animal Models ◽  
Cancer Cells ◽  
Cell Lines ◽  
Drug Targets ◽  
Metabolic Phenotype ◽  
Methionine Restriction ◽  
Methionine Dependence ◽  
Methionine Stress

OBJECTIVES/GOALS: Methionine dependence was described 45 years ago as an increased reliance on an exogenous supply of the essential amino acid methionine in most cancer cells compared to normal cells. Methionine depletion, using either synthetic diets or the enzyme methioninase, potentiates the effects of chemotherapy and radiotherapy in tumor-bearing animal models. Two main obstacles prevent methionine dependence from integrating the clinical treatment of cancer. The first is the weight loss associated with methionine depletion therapy, increasing the risk of cachexia in patients. The second is the stubborn absence of a mechanism to explain the inability of cancer cells to adapt to low methionine levels. METHODS/STUDY POPULATION: To address these two obstacles, we are using an immunocompetent murine model of metastatic melanoma to compare the effects of complete methionine deprivation with a moderate, 75-80% methionine restriction similar to the one used to increase lifespan in animal models. In an effort to identify a mechanism of action, we also performed a proteomic screen of two melanoma cell lines divergent for methionine dependence under methionine stress. RESULTS/ANTICIPATED RESULTS: We recently showed that methionine restriction is sufficient to provide gains in treating local and metastatic lesions in vivo, without weight loss. We observed few differences in pathway activation between the two cell lines in response to methionine stress, despite proliferation being cut by half in the methionine dependent cell line. We expect that subcellular translocation events may provide further information on the molecular bases of methionine dependence. DISCUSSION/SIGNIFICANCE OF IMPACT: A moderate restriction in methionine is sufficient to recapitulate the benefits of methionine depletion in cancer, without weight loss. The mechanism behind this effect remains unknown. This work contributes towards the integration of methionine dependence into clinical practice and the discovery of novel drug targets.

scholarly journals Landscape of Chimeric RNAs in Non-Cancerous Cells

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 466
Author(s):  
Chen Chen ◽  
Samuel Haddox ◽  
Yue Tang ◽  
Fujun Qin ◽  
Hui Li
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Drug Targets ◽  
Neoplastic Cell ◽  
Multiple Cancer ◽  
Chimeric Rnas ◽  
Healthy Donors ◽  
Cancer Types ◽  
Chimeric Rna ◽  
Cancerous Cells

Gene fusions and their products (RNA and protein) have been traditionally recognized as unique features of cancer cells and are used as ideal biomarkers and drug targets for multiple cancer types. However, recent studies have demonstrated that chimeric RNAs generated by intergenic alternative splicing can also be found in normal cells and tissues. In this study, we aim to identify chimeric RNAs in different non-neoplastic cell lines and investigate the landscape and expression of these novel candidate chimeric RNAs. To do so, we used HEK-293T, HUVEC, and LO2 cell lines as models, performed paired-end RNA sequencing, and conducted analyses for chimeric RNA profiles. Several filtering criteria were applied, and the landscape of chimeric RNAs was characterized at multiple levels and from various angles. Further, we experimentally validated 17 chimeric RNAs from different classifications. Finally, we examined a number of validated chimeric RNAs in different cancer and non-cancer cells, including blood from healthy donors, and demonstrated their ubiquitous expression pattern.

scholarly journals The In Vivo Selection Method in Breast Cancer Metastasis

2021 ◽  
Vol 22 (4) ◽  
pp. 1886
Author(s):  
Jun Nakayama ◽  
Yuxuan Han ◽  
Yuka Kuroiwa ◽  
Kazushi Azuma ◽  
Yusuke Yamamoto ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Metastasis ◽  
Metastatic Cancer ◽  
Expression Patterns ◽  
Selection Method ◽  
Gene Signatures ◽  
In Vivo Selection ◽  
Metastatic Cancer Cells

Metastasis is a complex event in cancer progression and causes most deaths from cancer. Repeated transplantation of metastatic cancer cells derived from transplanted murine organs can be used to select the population of highly metastatic cancer cells; this method is called as in vivo selection. The in vivo selection method and highly metastatic cancer cell lines have contributed to reveal the molecular mechanisms of cancer metastasis. Here, we present an overview of the methodology for the in vivo selection method. Recent comparative analysis of the transplantation methods for metastasis have revealed the divergence of metastasis gene signatures. Even cancer cells that metastasize to the same organ show various metastatic cascades and gene expression patterns by changing the transplantation method for the in vivo selection. These findings suggest that the selection of metastasis models for the study of metastasis gene signatures has the potential to influence research results. The study of novel gene signatures that are identified from novel highly metastatic cell lines and patient-derived xenografts (PDXs) will be helpful for understanding the novel mechanisms of metastasis.

scholarly journals Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Pradip Shahi Thakuri ◽  
Megha Gupta ◽  
Sunil Singh ◽  
Ramila Joshi ◽  
Eric Glasgow ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Protein Kinases ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Tnbc Cell

Abstract Background Cell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs. Methods We used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis. Results Fisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells. Conclusions We established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.

scholarly journals Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Denisa Baci ◽  
Antonino Bruno ◽  
Caterina Cascini ◽  
Matteo Gallazzi ◽  
Lorenzo Mortara ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Dietary Supplements ◽  
Cell Lines ◽  
Angiogenic Factors ◽  
Migration And Invasion ◽  
Prostate Cancer Cells

Abstract Background Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible “repurposed agent’ for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.

Characterization of stem cell–like cancer cells in immune-competent mice

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3906-3912 ◽  
Author(s):  
Jorg A. Kruger ◽  
Charles D. Kaplan ◽  
Yunping Luo ◽  
He Zhou ◽  
Dorothy Markowitz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Side Population ◽  
Carcinoma Cell Lines ◽  
Tumorigenic Potential ◽  
4T1 Cells

AbstractRecently, the cancer stem cell hypothesis has gained significant recognition as the descriptor of tumorigenesis. Although previous studies relied on transplanting human or rat tumor cells into immunecompromised mice, our study used the Hoechst 33342 dye–based side population (SP) technique to isolate and transplant stem cell–like cancer cells (SCLCCs) from the 4T1 and NXS2 murine carcinoma cell lines into the immune-competent microenvironment of syngeneic mice. 4T1 cells displayed an SP of 2% with a Sca-1highc-Kit–CD45– phenotype, whereas NXS2 cells contained an SP of 0.2% with a Sca-1highCD24highc-Kit–CD45–GD high2 phenotype. Reverse transcription–polymerase chain reaction (RT-PCR) further revealed up-regulation in SP cells of ABCG2, Sca-1, Wnt-1, and TGF-β2. Additionally, 4T1 and NXS2 SP cells exhibited increased resistance to chemotherapy, and 4T1 SP cells also showed an increased ability to efflux doxorubicin, which correlated with a selective increase in the percentage of SP cells found in the tumors of doxorubicin-treated mice. Most importantly, SP cells showed a markedly higher repopulation and tumorigenic potential in vivo, which correlated with an increased number of cells in the SP compartment of SP-derived tumors. Taken together, these results show that we successfully characterized SCLCCs from 2 murine carcinoma cell lines in the immune-competent microenvironment of syngeneic mice.

TAMI-73. GLIOBLASTOMA CELL POPULATIONS WITH DISTINCT ONCOGENIC PROGRAMS RELEASE PODOPLANIN AS PROCOAGULANT EXTRACELLULAR VESICLES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi213-vi213
Author(s):  
Nadim Tawil ◽  
Rayhaan Bassawon ◽  
Brian Meehan ◽  
Laura Montermini ◽  
Ali Nehme ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Extracellular Vesicles ◽  
Glioblastoma Cell ◽  
Activation Markers ◽  
Increased Risk ◽  
Gradient Fractionation ◽  
D Dimer

Abstract BACKGROUND Vascular anomalies, including thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of dysregulated cancer cell genome and epigenome. Up-regulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk of venous thromboembolism in glioblastoma patients. Thus, regulation of this platelet activating protein by transforming events and release from cancer cells is of considerable interest. AIMS I. Investigate the pattern of PDPN expression and characterize PDPN-expressing cellular populations in GBM. II. Evaluate the contribution of oncogenic drivers to PDPN expression in GBM models. III. Investigate the potential involvement of extracellular vesicles (EVs) as a mechanism for systemic dissemination of PDPN and tissue factor (TF). IV. Examine the role of PDPN in intratumoral and systemic thrombosis. METHODS Bioinformatics (single-cell and bulk transcriptome data mining), GBM cell lines and stem cell lines, xenograft models in mice, ELISA assays for PDPN and TF, platelet (PF4) and clotting activation markers (D-dimer), EV electron microscopy, density gradient fractionation, and nano-flow cytometry. RESULTS PDPN is expressed by distinct glioblastoma cell subpopulations (mesenchymal) and downregulated by oncogenic mutations of EGFR and IDH1 genes, via changes in chromatin modifications (EZH2) and DNA methylation, respectively. GBM cells exteriorize PDPN and/or TF as cargo of exosome-like EVs shed both in vitro and in vivo. Injection of glioma PDPN-EVs activates platelets. Increase of platelet activation (PF4) or coagulation markers (D-dimer) occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Co-expression of PDPN and TF by GBM cells cooperatively increases tumor microthrombosis. CONCLUSION Distinct cellular subsets drive multiple facets of GBM-associated thrombosis and may represent targets for diagnosis and intervention. We suggest that the preponderance of PDPN expression as a risk factor in glioblastoma and the involvement of platelets may merit investigating anti-platelets for potential inclusion in thrombosis management in GBM.

scholarly journals Tumorigenicity and Validity of Fluorescence Labelled Mesenchymal and Epithelial Human Oral Cancer Cell Lines in Nude Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Wei Xin Cai ◽  
Li Wu Zheng ◽  
Li Ma ◽  
Hong Zhang Huang ◽  
Ru Qing Yu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Nude Mice ◽  
Tongue Cancer ◽  
Cancer Cell Lines ◽  
Fluorescent Imaging ◽  
Cell Phenotype ◽  
Human Tongue

Tumorigenicity and metastatic activity can be visually monitored in cancer cells that were labelled with stable fluorescence. The aim was to establish and validate local and distant spread of subcutaneously previously injected fluorescence transduced human tongue cancer cell lines of epithelial and mesenchymal phenotype in nude mice. A total of 32 four-week-old male athymic Balb/c nude mice were randomly allocated into 4 groups (n=8). A single dose of 0.3 mL PBS containing 1 × 107 of four different cancer cell-lines (UM1, UM1-GFP, UM2, and UM2-RFP) was injected subcutaneously into the right side of their posterolateral back. Validity assessment of the labelled cancer cells’ tumorigenicity was assessed by physical examination, imaging, and histology four weeks after the injection. The tumor take rate of cancer cells was similar in animals injected with either parental or transduced cancer cells. Transduced cancer cells in mice were easily detectable in vivo and after cryosection using fluorescent imaging. UM1 cells showed increased tumor take rate and mean tumor volume, presenting with disorganized histopathological patterns. Fluorescence labelled epithelial and mesenchymal human tongue cancer cell lines do not change in tumorigenicity or cell phenotype after injection in vivo.

scholarly journals Selectively Targeting Breast Cancer Stem Cells by 8-Quinolinol and Niclosamide

2021 ◽  
Author(s):  
Patricia Cámara-Sánchez ◽  
Zamira V. Díaz-Riascos ◽  
Natalia García-Aranda ◽  
Petra Gener ◽  
Joaquin Seras-Franzoso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Subtype ◽  
Anchorage Independent Growth ◽  
Tnbc Cell

Abstract Background Cancer maintenance, metastatic dissemination and drug-resistance are sustained by cancer stem cells (CSCs). Triple negative breast cancer (TNBC) is the breast cancer subtype with the highest numbers of CSCs and poorest prognosis. Here, we aimed to identify potential drugs targeting CSCs to be further employed in combination with standard chemotherapy in TNBC treatment. Methods The anti-CSC efficacy of up to 17 small-drugs was tested in TNBC cell lines using cell viability assays on differentiated cancer cells and CSCs. Then, the effect of 2 selected drugs (8-quinolinol -8Q- and niclosamide -NCS-) in the cancer stemness hallmarks were evaluated using mammosphere growth, cell invasion, migration and anchorage-independent growth assays. Changes in the expression of stemness genes upon 8Q or NCS treatment were also evaluated. Moreover, the potential synergism of 8Q and NCS with PTX on the CSC proliferation and on stemness-related signaling pathways was evaluated using TNBC cell lines, CSC-reporter sublines, and CSCenriched mammospheres. Finally, the efficacy of the NCS in combination with PTX was analyzed in vivo using an orthotopic mice model of MDA-MB-231 cells. Results Among all tested drug candidates, 8Q and NCS showed remarkable specific anti-CSC activity in terms of CSC viability, migration, invasion and anchorage independent growth reduction in vitro. Moreover, specific 8Q/PTX and NCS/PTX ratios at which both drugs displayed a synergistic effect in different TNBC cell lines were identified. The solely use of PTX increased the relative presence of CSCs in TNBC cells, whereas the combination with 8Q and NCS counteracted this pro-CSC activity of PTX whilst significantly reducing cell viability. In vivo, the combination of NCS with PTX reduced tumor growth, and limited the dissemination of the disease by reducing the circulating tumor cells and the incidence of lung metastasis. Conclusions The combination of 8Q and NCS with PTX at established ratios inhibits both, the proliferation of differentiated cancer cells and the viability of CSCs, opening a way to more efficacious TNBC treatments.

scholarly journals Animal model of intrahepatic metastasis of hepatocellular carcinoma: establishment and characteristic

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Xuemei Li ◽  
Jike Hu ◽  
Baohong Gu ◽  
Maswikiti Ewetse Paul ◽  
Bofang Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Animal Models ◽  
Cell Line ◽  
Cell Lines ◽  
Intrahepatic Metastasis ◽  
Model Systems ◽  
Large Tumor ◽  
Important Direction ◽  
Disease Study

Abstract One of the most important and striking characteristics of hepatocellular carcinoma (HCC) with intrahepatic metastasis, is that it results in extremely poor prognosis. Animal models have become a fundamental and very useful in research for disease study. However, some limitation has arisen from these model systems. We have therefore established a model of HCC with intrahepatic metastasis and noticed some differential appearances in different HCC cell lines. Luciferase-transfected HCC cell lines MHCC97-H and PLC/PRF/5 were inoculated into SCID mice via spleen. Observation the intrahepatic metastasis by bioluminescence imaging in vivo and comparing of the differential formation of metastatic lesions between different HCC cell lines by incorporating physical anatomy was done. Animal models for HCC intrahepatic metastasis were well established. However, there were some clearly noticed differences between MHCC97-H and PLC/PRF/5 cell lines. The group of MHCC97-H cell line readily metastasis in the liver, whereas group PLC/PRF/5 cell line developed extensive intrahepatic metastasis and formed large tumor in situ in the spleen. MHCC97-H and PLC/PRF/5 cell lines can be used to successfully establish a model of HCC intrahepatic metastasis with distinctive characteristics, which provides an important direction for the study of the mechanism of HCC intrahepatic metastasis, and may hopefully provide a basis for clinical treatment.

scholarly journals ETHNOPHARMACOLOGICAL EVALUATION OF MEDICINAL PLANTS FOR CYTOTOXICITY AGAINST VARIOUS CANCER CELL LINES

2017 ◽  
Vol 9 (5) ◽  
pp. 198 ◽  
Author(s):  
Ruchi Singh Thakur ◽  
Bharti Ahirwar
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Fruit Juice ◽  
Cancer Cell Line ◽  
Cancer Cell Lines ◽  
Phytochemical Analysis ◽  
Phyllanthus Emblica ◽  
Hydroalcoholic Extract

Objective: To evaluate the cytotoxic potential of leaves and seeds of Hibiscus sabdariffa L., fruit juice of Phyllanthus emblica, rhizomes of Dryopteris cochleata and flowers of Caesalpinia decapetala (Roth) Alston along with the chemical profiling of the most toxic extract through Gas-mass spectroscopy-MS technique.Methods: The hydroalcoholic extract of the selected crude drugs was prepared by maceration method and the extracts were undergone through phytochemical analysis. The cytotoxic activity of the hydroalcoholic extract was performed against four cancer cell lines i.e. liver (HepG2), breast (MCF7), prostate (PC-3) and leukemia (HL60) using sulphorhodamine B assay. The hydroalcoholic extract of Caesalpinia decapetala flowers was profiled through using gas mass spectroscopy.Results: The results confirmed that Phyllanthus emblica inhibited HL60 cancer cells at the dose of 35.6 µg/ml and show dose-dependent growth inhibition. The flowers of Caesalpinia decapetala inhibited nearly fifty percent of HL60 cancer cells at very low dose i. e 10 µg/ml. The analysis of Caesalpinia decapetala flowers shows the presence of diterpenoid furanolactones, bufadienolides, polycyclic enones, and androsterone.Conclusion: The fruit juice of Phyllanthus emblica and flowers of Caesalpinia decapetala showed good inhibitory activity against HL60 cancer cell line. The use of Phyllanthus emblica in herbal medicine is justified. The data obtained impelled to further assess the in vivo efficacy of Caesalpinia decapetala flowers for anticancer activity.

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