scholarly journals HEYL Regulates Neoangiogenesis Through Overexpression in Both Breast Tumor Epithelium and Endothelium

2021 ◽  
Vol 10 ◽  
Author(s):  
Liangfeng Han ◽  
Preethi Korangath ◽  
Nguyen K. Nguyen ◽  
Adam Diehl ◽  
Soonweng Cho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Neutralizing Antibodies ◽  
Breast Cancer Cells ◽  
Vascular Endothelial Cells ◽  
Downstream Target ◽  
Mammary Tumor Cells

Blocking tumor angiogenesis is an appealing therapeutic strategy, but to date, success has been elusive. We previously identified HEYL, a downstream target of Notch signaling, as an overexpressed gene in both breast cancer cells and as a tumor endothelial marker, suggesting that HEYL overexpression in both compartments may contribute to neoangiogenesis. Carcinomas arising in double transgenic Her2-neu/HeyL mice showed higher tumor vessel density and significantly faster growth than tumors in parental Her2/neu mice. Providing mechanistic insight, microarray-based mRNA profiling of HS578T-tet-off-HEYL human breast cancer cells revealed upregulation of several angiogenic factors including CXCL1/2/3 upon HEYL expression, which was validated by RT-qPCR and protein array analysis. Upregulation of the cytokines CXCL1/2/3 occurred through direct binding of HEYL to their promoter sequences. We found that vessel growth and migration of human vascular endothelial cells (HUVECs) was promoted by conditioned medium from HS578T-tet-off-HEYL carcinoma cells, but was blocked by neutralizing antibodies against CXCL1/2/3. Supporting these findings, suppressing HEYL expression using shRNA in MDA-MB-231 cells significantly reduced tumor growth. In addition, suppressing the action of proangiogenic cytokines induced by HEYL using a small molecule inhibitor of the CXCl1/2/3 receptor, CXCR2, in combination with the anti-VEGF monoclonal antibody, bevacizumab, significantly reduced tumor growth of MDA-MB-231 xenografts. Thus, HEYL expression in tumor epithelium has a profound effect on the vascular microenvironment in promoting neoangiogenesis. Furthermore, we show that lack of HEYL expression in endothelial cells leads to defects in neoangiogenesis, both under normal physiological conditions and in cancer. Thus, HeyL-/- mice showed impaired vessel outgrowth in the neonatal retina, while the growth of mammary tumor cells E0771 was retarded in syngeneic HeyL-/- mice compared to wild type C57/Bl6 mice. Blocking HEYL’s angiogenesis-promoting function in both tumor cells and tumor-associated endothelium may enhance efficacy of therapy targeting the tumor vasculature in breast cancer.

YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis Through Activating Yap Signaling in Vascular Endothelial Cells

2020 ◽  
Author(s):  
Yu Yan ◽  
Qiang Song ◽  
Li Yao ◽  
Liang Zhao ◽  
Hui Cai
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Tumor Angiogenesis ◽  
Breast Cancer Cells ◽  
Vascular Endothelial Cells ◽  
Tissue Growth ◽  
Vascular Endothelial ◽  
Potential Marker

Abstract Background:The YAP signaling pathway is altered and implicated as oncogenic in human mammary cancers.However, roles of YAP signaling that regulate the breast tumor angiogenesis have remained elusive. Tumor angiogenesis is coordinated by the activation of both cancer cells and vascular endothelial cells. Whether the YAP signalingpathway can regulate the intercellular interaction between cancer cells and endothelial cellsis essentially unknown.Results: We showed here that conditioned media from YAP overexpressed breast cancer cells (CM-YAP+) could promote angiogenesis, accompanied byincreased tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs). Down regulation of YAP in HUVECs reversed CM-YAP+ induced angiogenesis.CM-YAP+ time-dependently activated YAP inHUVECs by dephosphorylating YAP and increasing nuclear translocation.We also identified that both G13-RhoA and PI3K/Akt signaling pathway were necessary for CM-YAP+ induced activation of YAP.Besides, connective tissue growth factor (CTGF) and angiopoietin-2 (ANG-2)actedas down-stream of YAP in HUVECs to promote angiogenesis.In addition, subcutaneous tumors nude mice model demonstrated that tumors overexpressed YAP revealed moreneovascularization in vivo.Conclusions: YAP-YAP interaction between breastcancer cells and endothelial cellscould promote tumor angiogenesis, supporting that YAP is a potential marker and target fordeveloping novel therapeutic strategies against breast cancer.

Pleiotrophin Is Highly Produced by Solid Tumors and Transdifferentiates Human Monocytes Into Endothelial Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3050-3050
Author(s):  
Eric Wirtschafter ◽  
Emily Wong ◽  
Mingjie Li ◽  
Eric Sanchez ◽  
Cathy S Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Blood Vessel ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Human Monocytes ◽  
Rt Pcr

Abstract Abstract 3050 Poster Board II-1026 We have previously shown that tumor cells from multiple myeloma (MM) patients express pleiotrophin (PTN). This protein is elevated in the serum of MM patients and we have shown that, in combination with M-CSF, it induces the transdifferentiation of monocytes into endothelial cells both in vitro and in vivo (Chen et al. Blood 2009). In this study, we determined the level of PTN expression in a variety of solid tumor types including breast, ovarian, prostate, and pancreatic cancers, and examined whether PTN produced by tumor cells from these different types of solid tumors could also induce transdifferentiation of human monocytes into endothelial cells both in vitro and in vivo. Our results showed that breast, ovarian, prostate, and pancreatic cancers all produce high levels of PTN as determined by RT-PCR, Western blot analysis, immunohistochemical staining, and measurement of the level of this growth factor secreted into the medium derived from cultured tumor cells whereas normal peripheral blood mononuclear cells (PBMCs) showed no expression of this protein. Next, monocytes derived from CD14-selected PBMCs or the THP-1 cell line were exposed to breast, ovarian, prostate, and pancreatic cancer cells on collagen I-coated Transwell plates with M-CSF. Following culture of these cells for 5-14 days, both fresh CD14+ cells and THP-1 cells changed their morphology into endothelial-like cells and expressed the endothelial genes and proteins Flk-1 and Tie-2 as determined with RT-PCR and Western blot analysis, respectively. These endothelial cell-inducing effects on monocytes were blocked with anti-PTN antibodies. Next, we determined whether human monocytes could be incorporated into blood vessels and express endothelial cell markers in vivo within solid tumors that express PTN. Human breast cancer cells (MDA-MB-231) alone, THP-1 monocytes transduced with the green fluorescent protein (GFP) gene, or the combination of both cell types were injected subcutaneously into severe combined immunodeficient (SCID) mice. Mice were sacrificed 8 weeks later and the tumor tissue was fixed and cut into frozen sections. Breast cancer cells or GFP+ THP-1 monocytes alone did not demonstrate the presence of GFP-marked cells within tumor blood vessels. When breast cancer cells and GFP+ THP-1 cells were injected together, GFP-marked cells were found within tumor blood vessels; and, moreover, double staining of serial sections of the breast cancer with anti-Tie-2 and CD31 antibodies showed a similar distribution pattern of staining as the blood vessel cells showing the presence of GFP. We also examined endothelial gene expression in these samples using RT-PCR. The results showed that the THP-1 monocytes alone or breast cancer cells alone did not express endothelial genes whereas THP-1 monocytes mixed with breast cancer cells showed endothelial gene (FLK-1, Tie-2) expression. These data show that solid tumors through expression of PTN support new blood vessel formation by the transdifferentiation of monocytes into endothelial cells and provide a new potential target for inhibiting early blood vessel formation within tumors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effects of FSTL1 on the proliferation and motility of breast cancer cells and vascular endothelial cells

2017 ◽  
Vol 8 (6) ◽  
pp. 606-612 ◽  
Author(s):  
Yang Yang ◽  
Tianhao Mu ◽  
Te Li ◽  
Songbo Xie ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial

scholarly journals Elevated Expression of DecR1 Impairs ErbB2/Neu-Induced Mammary Tumor Development

2007 ◽  
Vol 27 (18) ◽  
pp. 6361-6371 ◽  
Author(s):  
Josie Ursini-Siegel ◽  
Ashish B. Rajput ◽  
Huiling Lu ◽  
Virginie Sanguin-Gendreau ◽  
Dongmei Zuo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Fatty Acid Synthesis ◽  
Breast Cancer Cells ◽  
De Novo ◽  
Acid Synthesis ◽  
Mammary Tumor Cells

ABSTRACT Tumor cells utilize glucose as a primary energy source and require ongoing lipid biosynthesis for growth. Expression of DecR1, an auxiliary enzyme in the fatty acid β-oxidation pathway, is significantly diminished in numerous spontaneous mammary tumor models and in primary human breast cancer. Moreover, ectopic expression of DecR1 in ErbB2/Neu-induced mammary tumor cells is sufficient to reduce levels of ErbB2/Neu expression and impair mammary tumor outgrowth. This correlates with a decreased proliferative index and reduced rates of de novo fatty acid synthesis in DecR1-expressing breast cancer cells. Although DecR1 expression does not affect glucose uptake in ErbB2/Neu-transformed cells, sustained expression of DecR1 protects mammary tumor cells from apoptotic cell death following glucose withdrawal. Moreover, expression of catalytically impaired DecR1 mutants in Neu-transformed breast cancer cells restored Neu expression levels and increased mammary tumorigenesis in vivo. These results argue that DecR1 is sufficient to limit breast cancer cell proliferation through its ability to limit the extent of oncogene expression and reduce steady-state levels of de novo fatty acid synthesis. Furthermore, DecR1-mediated suppression of tumorigenesis can be uncoupled from its effects on Neu expression. Thus, while downregulation of Neu expression may contribute to DecR1-mediated tumor suppression in certain cell types, this is not an obligate event in all Neu-transformed breast cancer cells.

Recent Advances on Therapeutic Peptides for Breast Cancer Treatment

2020 ◽  
Vol 21 ◽  
Author(s):  
Samad Beheshtirouy ◽  
Farhad Mirzaei ◽  
Shirin Eyvazi ◽  
Vahideh Tarhriz
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Specific Binding ◽  
High Specificity ◽  
The Novel ◽  
Anti Cancer ◽  
Therapeutic Peptides ◽  
Low Toxicity

: Breast cancer is a heterogeneous malignancy which is the second cause of mortality among women in the world. Increasing the resistance to anti-cancer drugs in breast cancer cells persuades researchers to search the novel therapies approaches for the treatment of the malignancy. Among the novel methods, therapeutic peptides which target and disrupt tumor cells have been of great interest. Therapeutic peptides are short amino acids monomer chains with high specificity to bind and modulate a protein interaction of interest. Several advantages of peptides such as specific binding on tumor cells surface, low molecular weight and low toxicity on normal cells make the peptides as an appealing therapeutic agents against solid tumors, particularly breast cancer. Also, National Institutes of Health (NIH) describes therapeutic peptides as suitable candidate for the treatment of drug-resistant breast cancer. In this review, we attempt to review the different therapeutic peptides against breast cancer cells which can be used in treatment and diagnosis of the malignancy. Meanwhile, we presented an overview of peptide vaccines which have been developed for the treatment of breast cancer.

750 Malat1 lncRNA controls metastatic reactivation of dormant breast cancer by immune evasion

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A799-A799
Author(s):  
Dhiraj Kumar ◽  
Sreeharsha Gurrapu ◽  
Hyunho Han ◽  
Yan Wang ◽  
Seongyeon Bae ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Single Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Breast Cancer Cells ◽  
Metastatic Potential ◽  
Rna Seq

BackgroundLong non-coding RNAs (lncRNAs) are involved in various biological processes and diseases. Malat1 (metastasis-associated lung adenocarcinoma transcript 1), also known as Neat2, is one of the most abundant and highly conserved nuclear lncRNAs. Several studies have shown that the expression of lncRNA Malat1 is associated with metastasis and serving as a predictive marker for various tumor progression. Metastatic relapse often develops years after primary tumor removal as a result of disseminated tumor cells undergoing a period of latency in the target organ.1–4 However, the correlation of tumor intrinsic lncRNA in regulation of tumor dormancy and immune evasion is largely unknown.MethodsUsing an in vivo screening platform for the isolation of genetic entities involved in either dormancy or reactivation of breast cancer tumor cells, we have identified Malat1 as a positive mediator of metastatic reactivation. To functionally uncover the role of Malat1 in metastatic reactivation, we have developed a knock out (KO) model by using paired gRNA CRISPR-Cas9 deletion approach in metastatic breast and other cancer types, including lung, colon and melanoma. As proof of concept we also used inducible knockdown system under in vivo models. To delineate the immune micro-environment, we have used 10X genomics single cell RNA-seq, ChIRP-seq, multi-color flowcytometry, RNA-FISH and immunofluorescence.ResultsOur results reveal that the deletion of Malat1 abrogates the tumorigenic and metastatic potential of these tumors and supports long-term survival without affecting their ploidy, proliferation, and nuclear speckles formation. In contrast, overexpression of Malat1 leads to metastatic reactivation of dormant breast cancer cells. Moreover, the loss of Malat1 in metastatic cells induces dormancy features and inhibits cancer stemness. Our RNA-seq and ChIRP-seq data indicate that Malat1 KO downregulates several immune evasion and stemness associated genes. Strikingly, Malat1 KO cells exhibit metastatic outgrowth when injected in T cells defective mice. Our single-cell RNA-seq cluster analysis and multi-color flow cytometry data show a greater proportion of T cells and reduce Neutrophils infiltration in KO mice which indicate that the immune microenvironment playing an important role in Malat1-dependent immune evasion. Mechanistically, loss of Malat1 is associated with reduced expression of Serpinb6b, which protects the tumor cells from cytotoxic killing by the T cells. Indeed, overexpression of Serpinb6b rescued the metastatic potential of Malat1 KO cells by protecting against cytotoxic T cells.ConclusionsCollectively, our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system represents a new strategy to inhibit tumor metastatic reactivation.Trial RegistrationN/AEthics ApprovalFor all the animal studies in the present study, the study protocols were approved by the Institutional Animal Care and Use Committee(IACUC) of UT MD Anderson Cancer Center.ConsentN/AReferencesArun G, Diermeier S, Akerman M, et al., Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev 2016 Jan 1;30(1):34–51.Filippo G. Giancotti, mechanisms governing metastatic dormancy and reactivation. Cell 2013 Nov 7;155(4):750–764.Gao H, Chakraborty G, Lee-Lim AP, et al., The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 2012b;150:764–779.Gao H, Chakraborty G, Lee-Lim AP, et al., Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation. Proc Natl Acad Sci U S A 2014 Nov 18; 111(46): 16532–16537.

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