Bone Marrow-Derived Mesenchymal Stem Cell Homing to Breast Cancer but Not Colon and Renal Cancer and VEGF-C and VEGF-R3 Play the Key Role in Tumor Homing Effect in the Syngeneic Mice (Balb/c) Model,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3418-3418
Author(s):  
Su-Peng Yeh ◽  
Wen-Jyi Lo ◽  
Chang-Fang Chiu
Keyword(s):  
Breast Cancer ◽  
Renal Cancer ◽  
Tumor Tissue ◽  
Luciferase Activity ◽  
Normal Tissues ◽  
Tumor Bearing ◽  
Tumor Homing ◽  
Specific Ligand

Abstract Abstract 3418 Background Mesenchymal stem cells (MSCs) have the unique ability of homing to tumor tissue. Most of prior studies used xenograft models to demonstrate hMSC homing to human cancer on the immunodeficient mice. This model is far away from clinically relevant condition. It was also unknown whether MSCs target specific or all the tumor types in immunocompotent host as well as the mechanism driving MSCs home to tumor site. Methods Migration assay was done to access the in vitro migration effect of D1 cells (BM-MSCs derived from balb/c mice) in response to 4T1, CT26, and Rag cells (breast cancer, colon cancer, and renal cancer cell line derived from balb/c mice). Firefly luciferase (Luc) stably expressed D1 (D1-Luc) was selected and maintained. 4T1 and CT26 cells were inoculated into 6 weeks balb/c mice. D1-Luc cells were then injected into normal or tumor-bearing balb/c through tail vein at different tumor stage (small tumors and big tumors). Besides, 4T1 and CT26 cells were inoculated into bilateral sides of balb/c mice. After tumor formation, D1-Luc cells were injected locally into one side to see whether the D1-Luc can migrate to the contralateral tumor or not. The in vivo tumor homing was accessed by IVIS (xenogen). Finally, 4T1 and CT26 tumors were excised from the mice to analyze gene expression profile (GEP). Chemokines/cytokines highly expressed on 4T1 but not CT26 were selected for blocking study in vitro and in vivo. Results Both in vitro and in vivo studies showed D1 homing to 4T1 (breast) tumor only but not CT26 (colon) and Rag (renal) tumor. In case of 4T1, D1-Luc homed to all (100%) the tumor-bearing mice though tail vein injection. Besides, D1-Luc cells also home to both big and small 4T1 tumor simultaneously. When D1-Luc injected locally to one side of 4T1-bearing mice, the luciferase activity can be detected at the contralateral 4T1 tumor one hour after injection. In case of CT26, luciferase activity can not be detected on the contralateral CT26 tumor up to 7 days after injection. The GEP study showed VEGF-C, CCL24, CXCL 1/2/7 were highly expressed in 4T1 but not CT26. Blocking the VEGF-C receptor of D1 alone by using neutralizing antibody was sufficient to suppress D1 cells migration toward 4T1 tumor both in vitro and in vivo. The expression of VEGF-C is 100-fold higher in tumor tissue comparing to normal tissues (lung, liver, spleen, and kidney) by using RT-PCR. Conclusions MSCs home to specific tumor only and specific ligand-receptor relationship between MSCs and cancer cells determines the specificity. In this immunocompetent, syngeneic mice model, BM-MSCs homes to breast cancer but not normal tissue via VEGF-C and VEGF-C receptor axis. Our model also provides a good platform to the future development of MSC-based cell therapy. Before starting such a trial in human, it is essential to identify a specific ligand that is highly expressed on tumor (maybe very specific type of tumor) but not normal tissues and the MSCs should have corresponding receptor. This work was supported in part by the research grant from Taiwan National Science Council (NSC-96-3111-B-039-001), and Department of Health, China Medical University Hospital Cancer Research of Excellence (DOH-100-TD-C-111-005). Disclosures: No relevant conflicts of interest to declare.

scholarly journals When cholesterol meets histamine, it gives rise to dendrogenin A: a tumour suppressor metabolite1

2016 ◽  
Vol 44 (2) ◽  
pp. 631-637 ◽  
Author(s):  
Marc Poirot ◽  
Sandrine Silvente-Poirot
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Metabolic Pathway ◽  
Protective Role ◽  
Tumour Suppressor ◽  
Human Tissues ◽  
Normal Tissues ◽  
Steroidal Alkaloid

Dendrogenin A (DDA) is the first steroidal alkaloid (SA) to be identified in human tissues to date and arises from the stereoselective enzymatic conjugation of 5,6α-epoxycholesterol (5,6α-EC) with histamine (HA). DDA induces the re-differentiation of cancer cells in vitro and in vivo and prevents breast cancer (BC) and melanoma development in mice, evidencing its protective role against oncogenesis. In addition, DDA production is lower in BCs compared with normal tissues, suggesting a deregulation of its biosynthesis during carcinogenesis. The discovery of DDA reveals the existence of a new metabolic pathway in mammals which lies at the crossroads of cholesterol and HA metabolism and which leads to the production of this metabolic tumour suppressor.

scholarly journals THER-15. DEVELOPING TUMOR-HOMING CYTOTOXIC HUMAN INDUCED NEURAL STEM CELL THERAPY FOR BRAIN METASTASES

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i13-i14
Author(s):  
Alison Mercer-Smith ◽  
Wulin Jiang ◽  
Juli Bago ◽  
Simon Khagi ◽  
Carey Anders ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Drug Carrier ◽  
Human Fibroblasts ◽  
Genetically Engineered ◽  
In Vivo Studies ◽  
Tumor Homing ◽  
The Brain

Abstract INTRODUCTION: Non-small cell lung cancer (NSCLC) and breast cancer are the most common cancers that metastasize to the brain. New therapies are needed to seek out and eradicate metastases. Genetically engineered neural stem cells (NSCs) have shown unique tumor-homing capacity, allowing them to deliver cytotoxic proteins directly to tumors. An ideal NSC drug carrier would be readily available and autologous. We have transdifferentiated human fibroblasts into induced NSCs (hiNSCs) that home to tumors and engineered the hiNSCs to release the cytotoxic protein TRAIL. Here we used intracerebroventricular (ICV) injections to deliver hiNSCs to metastatic foci. METHODS: We performed an in vitro efficacy co-culture assay, used in vivo studies to determine the migration, persistence, and efficacy of therapeutic hiNSCs against H460 NSCLC and triple-negative breast cancer MB231-Br tumors in the brain. Following the establishment of tumors in the brains of nude mice, hiNSCs were injected directly into the tumor or the ventricle contralateral to the site of tumor. The migration and persistence of hiNSCs was investigated by following the bioluminescence of the hiNSCs. The therapeutic efficacy of the hiNSCs was determined by following the bioluminescece of the tumor. RESULTS/CONCLUSION: Co-culture results demonstrated that hiNSC therapy reduced the viability of H460 and MB231-Br up to 75% and 99.8% respectively compared to non-treated controls. ICV-administered hiNSC serial imaging show that cells persisted for more than one week. Fluorescent analysis of tissue sections showed that hiNSCs co-localized with lateral and a contralateral tumors within 7 days. Using H460 and MB231-Br models, kinetic tracking of intracranial tumor volumes showed intratumoral or ICV-injected therapeutic hiNSCs reduced the growth rate of brain tumors by 31-fold and 3-fold, respectively. This work demonstrates for the first time that we can effectively deliver personalized cytotoxic tumor-homing cells through the ventricles to target brain metastases.

A Uracil Auxotroph Toxoplasma gondii Exerting Immunomodulation to Inhibit Breast Cancer Growth and Metastasis

2021 ◽  
Author(s):  
Li-Qing Xu ◽  
Li-Jie Yao ◽  
Dan Jiang ◽  
Min Chen ◽  
Wen-Zhong Liao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Lung Metastasis ◽  
Tumor Bearing ◽  
Uracil Auxotroph ◽  
Ifn Γ

Abstract Background: Breast cancer is the most common cause of cancer-related death among women, and patients with triple-negative breast cancer (TNBC) have poor prognosis, so it is necessary to develop new effective therapies urgently. Recent studies have demonstrated that uracil auxotroph Toxoplasma gondii vaccine displays antitumor effects. Here, we examined the immunotherapy effects of an attenuated uracil auxotroph strain of T. gondii against 4T1 murine breast cancer.Methods: We constructed a uracil auxotroph strain, the orotidine 5′-monophosphate decarboxylase gene deleted strain of T. gondii (RH-Δompdc) with the CRISPR/Cas9 technology. Its virulence in vitro and in vivo was determined by parasite replication assay, plaque assay, the parasite burden detection in mice peritoneal fluids and the survival analysis of T. gondii infection mice. Its immune modulation ability was evaluated by cytokines detection. Its antitumor effect was evaluated after its in situ inoculation to 4T1 tumors in mouse model, the tumor volume was measured, the 4T1 lung metastasis was detected by H&E and Ki67 antibody staining, and the cytokines levels were measured by ELISA.Results: RH-Δompdc strain could proliferate normally with uracil supplement, however, it was unable to propagate without uracil and in vivo, which implicated that it is avirulent to the hosts. This mutant showed vaccine characteristics that it could induce intense immune responses both in vitro and in vivo by boosting the expression of inflammatory cytokines significantly. RH-Δompdc in situ inoculation to the 4T1 tumors in mice could inhibit the tumor growth, reduce the lung metastasis, promote the survival of the tumor-bearing mice, and also increase the secretion of Th1 cytokines IL-12 and IFN-γ both in serum and in the tumor microenvironment (TME). Conclusion: The uracil auxotroph RH-Δompdc inoculation to the 4T1 tumors stimulated the anti-infection and antitumor immunity in mice, resulted in the inhibition of tumor growth and metastasis, the promotion in survival of the tumor-bearing mice, and the increasing secretion of IL-12 and IFN-γ both in serum and in the TME. Our findings implied that the immunomodulation resulted by RH-Δompdc could be a potential antitumor strategy.

scholarly journals MiR-137 Suppresses Triple-Negative Breast Cancer Stemness and Tumorigenesis by Perturbing BCL11A-DNMT1 Interaction

2018 ◽  
Vol 47 (5) ◽  
pp. 2147-2158 ◽  
Author(s):  
Feiyu Chen ◽  
Na Luo ◽  
Yu Hu ◽  
Xin Li ◽  
Kejing  Zhang
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Lines ◽  
Tumor Development ◽  
Cancer Stemness ◽  
Normal Tissues ◽  
Tumor Tissues

Background/Aims: Triple negative breast cancer (TNBC) is resistant to conventional chemotherapy due to high proportions of cancer stem cells (CSCs). The aim of this study is to unravel the miR-137-mediated regulatory mechanism of B-cell lymphoma/leukemia 11A (BCL11A) in TNBC. Methods: A corhort of 34 TNBC tumor tissues and paired adjacent normal tissues, as well as 25 non-TNBC tumor tissues and paired adjacent normal tissues were collected post-operatively from patients with breast cancer. Q-PCR was performed to determine the mRNA levels of miR-137 and BCL11A in breast tissues and cell lines. Bioinformatics analysis and dual luciferase reporter assay were used to verify the direct interaction between miR-137 and BCL11A. After up-/down-regulation of BCL11A, miR-137, or DNMT1 via lentiviral transduction in TNBC cell lines SUM149 and MDA-MB-231 cells, Q-PCR and Western blot assays were used to detect the expression levels of BCL11A, DNA methyltransferases 1 (DNMT1), and Islet-1 (ISL1). Mammosphere assay was conducted to assess tumorosphere formation ability of cells, coupled with flow cytometry to determine the percentage of breast cancer stem cells. Co-immunoprecipitation assay was used to determine the interaction between BCL11A and DNMT1. Xenograft tumorigenesis assay was performed to monitor tumor formation in vivo. Results: BCL11A was highly expressed in TNBC, whereas miR-137 was significantly lower in both TNBC tissues and cell lines. miR-137 suppressed BCL11A expression at both mRNA and protein levels by directly targeting its 3’UTR. In both SUM149 and MDA-MB-231 cells, overexpression of miR-137 or knockdown of BCL11A reduced the number of tumoroshperes and the percentage of cancer stem cells in vitro, and inhibited tumor development in vivo. Furthermore, BCL11A interacted with DNMT1 in TNBC cells. Silencing of either BCL11A or DNMT1 impaired cancer stemness and tumorigenesis of TNBC via suppressing ISL1 expression both in vitro, and in vivo. Conclusions: By perturbing BCL11A-DNMT1 interaction, miR-137 impairs cancer stemness and suppresses tumor development in TNBC.

scholarly journals MicroRNA-101 Inhibits Growth, Proliferation and Migration and Induces Apoptosis of Breast Cancer Cells by Targeting Sex-Determining Region Y-Box 2

2017 ◽  
Vol 43 (2) ◽  
pp. 717-732 ◽  
Author(s):  
Jingjie Wang ◽  
Huijuan Zeng ◽  
Hanjun Li ◽  
Tao Chen ◽  
Lulu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Tnm Classification ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Sox2 Expression ◽  
Normal Tissues ◽  
And Migration

Background: Increasing evidence has demonstrated that microRNAs play a critical role in breast cancer (BC) progression. microRNA-101 (miR-101) has been considered a tumor suppressive miRNA in different cancer types. This study aimed to investigate miR-101 expression in BC tissues and to investigate its roles in BC progression that are mediated by Sex-determining region Y-box 2 (SOX2), a critical oncogene in various cancers. Methods: qRT-PCR and immunohistochemistry were performed to detect miR-101 and SOX2 expression in BC tissues and paired normal tissues or BC cell lines. MTT, transwell migration, wound healing, colony formation, flow cytometric and xenograft assays were performed to determine the influence of miR-101 and SOX2 on the malignant behaviors of BC cells in vitro and in vivo. Results: miR-101 was significantly downregulated in BC tissues and cell lines. miR-101 overexpression inhibited the malignant behaviors of BC cells, both in vitro and in vivo. miR-101 downregulation had the converse effect. A miR-101 binding site was identified by luciferase reporter assay in the 3’UTR of SOX2. SOX2 was upregulated in BC tissues and cell lines, and its upregulation was associated with lymph node metastasis, pathological grade and TNM classification. SOX2 knockdown mimicked the effects of miR-101 overexpression on the malignant behaviors of BC cells, while SOX2 overexpression mitigated the miR-101-induced inhibition of these effects. Conclusions: Our study revealed that miR-101 plays a critical role in suppressing tumor progression by directly targeting SOX2.

scholarly journals Enhanced Anti-Tumor Effect of Folate-Targeted FA-AMA-hyd-DOX Conjugate in a Xenograft Model of Human Breast Cancer

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7110
Author(s):  
Tian-tian Liao ◽  
Jiang-fan Han ◽  
Fei-yue Zhang ◽  
Ren Na ◽  
Wei-liang Ye
Keyword(s):  
Breast Cancer ◽  
Nude Mice ◽  
Folate Receptor ◽  
Xenograft Model ◽  
Maximum Tolerated Dose ◽  
Therapeutic Drug ◽  
Antitumor Effects ◽  
Tumor Bearing

Folate-aminocaproic acid-doxorubicin (FA-AMA-hyd-DOX) was firstly synthesized by our group. It was indicated that FA-AMA-hyd-DOX was pH-responsive, and had strong cytotoxicity on a folate receptor overexpressing cell line (KB cells) in vitro. The aim of our study was to further explore the potential use of FA-AMA-hyd-DOX as a new therapeutic drug for breast cancer. The cellular uptake and the antiproliferative activity of the FA-AMA-hyd-DOX in MDA-MB-231 cells were measured. Compared with DOX, FA-AMA-hyd-DOX exhibited higher targeting ability and cytotoxicity to FR-positive tumor cells. Subsequently, the tissue distribution of FA-AMA-hyd-DOX was studied, and the result confirmed that DOX modified by FA can effectively increase the selectivity of drugs in vivo. After determining the maximum tolerated dose (MTD) of FA-AMA-hyd-DOX in MDA-MB-231 tumor-bearing nude mice, the antitumor effects and the in vivo safety of FA-AMA-hyd-DOX were systematically evaluated. The data showed that FA-AMA-hyd-DOX could effectively increase the dose of DOX tolerated by tumor-bearing nude mice and significantly inhibit MDA-MB-231 tumor growth in vivo. Furthermore, FA-AMA-hyd-DOX treatment resulted in almost no obvious damage to the mice. All the positive data suggest that FA-targeted FA-AMA-hyd-DOX is a promising tumor-targeted compound for breast cancer therapy.

scholarly journals A uracil auxotroph Toxoplasma gondii exerting immunomodulation to inhibit breast cancer growth and metastasis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Li-Qing Xu ◽  
Li-Jie Yao ◽  
Dan Jiang ◽  
Li-Juan Zhou ◽  
Min Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Lung Metastasis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tumor Bearing ◽  
Uracil Auxotroph

Abstract Background Breast cancer is the most common cause of cancer-related death among women, and prognosis is especially poor for patients with triple-negative breast cancer (TNBC); therefore, there is an urgent need for new effective therapies. Recent studies have demonstrated that the uracil auxotroph Toxoplasma gondii vaccine displays anti-tumor effects. Here, we examined the immunotherapy effects of an attenuated uracil auxotroph strain of T. gondii against 4T1 murine breast cancer. Methods We constructed a uracil auxotroph T. gondii RH strain via orotidine 5′-monophosphate decarboxylase gene deletion (RH-Δompdc) with CRISPR/Cas9 technology. The strain’s virulence in the T. gondii-infected mice was determined in vitro and in vivo by parasite replication assay, plaque assay, parasite burden detection in mice peritoneal fluids and survival analysis. The immunomodulation ability of the strain was evaluated by cytokine detection. Its anti-tumor effect was evaluated after its in situ inoculation into 4T1 tumors in a mouse model; the tumor volume was measured, and the 4T1 lung metastasis was detected by hematoxylin and eosin and Ki67 antibody staining, and the cytokine levels were measured by an enzyme-linked immunosorbent assay. Results The RH-Δompdc strain proliferated normally when supplemented with uracil, but it was unable to propagate without the addition of uracil and in vivo, which suggested that it was avirulent to the hosts. This mutant showed vaccine characteristics that could induce intense immune responses both in vitro and in vivo by significantly boosting the expression of inflammatory cytokines. Inoculation of RH-Δompdc in situ into the 4T1 tumor inhibited tumor growth, reduced lung metastasis, promoted the survival of the tumor-bearing mice and increased the secretion of Th1 cytokines, including interleukin-12 (IL-12) and interferon-γ (INF-δ), in both the serum and tumor microenvironment (TME). Conclusion Inoculation of the uracil auxotroph RH-Δompdc directly into the 4T1 tumor stimulated anti-infection and anti-tumor immunity in mice, and resulted in inhibition of tumor growth and metastasis, promotion of the survival of the tumor-bearing mice and increased secretion of IL-12 and IFN-γ in both the serum and TME. Our findings suggest that the immunomodulation caused by RH-Δompdc could be a potential anti-tumor strategy. Graphical abstract

Clinical Evaluation of Radio-Labelled Bleomycin for Tumor Detection

1978 ◽  
Vol 17 (06) ◽  
pp. 238-248
Author(s):  
H. Beekhuis ◽  
M.A.P.C. van de Poll ◽  
A. Versluis ◽  
H. Jurjens ◽  
M.G. Woldring ◽  
...  
Keyword(s):  
Clinical Evaluation ◽  
Acidic Solution ◽  
Tumor Detection ◽  
Neutral Solution ◽  
Normal Tissues ◽  
Patients With Cancer ◽  
Tumor Bearing

Investigations with bleomycin labelled with radionuclides other than 57Co in patients with cancer and in tumor-bearing animals are described. In patients 57Co-bleo appears to be a better tumor-seeking radiopharmaceutical than 111In-bleo, 99mTc-bleo or 197Hg-bleo. This can be explained by a higher stability in vivo and a better tumor-seeking property of 57Co-bleo and less disturbing activity in the cardiac pool and in bone and other normal tissues when assessing the scintigram.Results with 111In-bleo labelled in acidic solution are not essentially different from those with 111In-bleo labelled in neutral solution.Results of 197Hg-bleo are almost identical with those of 197HgCl2 regarding the tumor-seeking effect as well as the distribution in normal tissues and organs. Probably the complex of 197Hg to bleomycin is not stable in vivo. The superiority of 57Co-bleo over 99mTc-bleo, 197Hg-bleo and also over 67Cu-bleo is confirmed by experiments on tumor bearing animals.We may conclude that the indication for use of bleomycin as a tumor-seeking pharmaceutical labelled with 111In, 99mTc, 197Hg or 67Cu seems to be very limited.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

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