scholarly journals Effect of differences in cancer cells and tumor growth sites on recruiting bone marrow-derived endothelial cells and myofibroblasts in cancer-induced stroma

2005 ◽  
Vol 115 (6) ◽  
pp. 885-892 ◽  
Author(s):  
Takafumi Sangai ◽  
Genichiro Ishii ◽  
Keiji Kodama ◽  
Shin'ichi Miyamoto ◽  
Yasuyuki Aoyagi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Tumor Growth ◽  
Cancer Cells

Membrane Derived Micorvesicles - Underappreciated Components of the Tumor Microenvironment That Modulate Tumor Growth, Vascularization and Metastasis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 473-473
Author(s):  
Marcin Wysoczynski ◽  
Fadhi Hayek ◽  
Janina Ratajczak ◽  
Anna Janowska-Wieczorek ◽  
Mariusz Z. Ratajczak
Keyword(s):  
Lung Cancer ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Cell Surface ◽  
Cancer Cells ◽  
Lipid Raft ◽  
Membrane Lipid ◽  
Target Cells

Abstract Viable eukaryotic cells shed circular membrane fragments called microvesicles (MV) from the cell surface and secrete them from the endosomal compartments. These MV, which are different from apoptotic bodies, are enriched in lipids, proteins and mRNA. We postulate that MV play an important and underappreciated role in cell-cell communication by i) stimulating target cells with ligands that the MV express, ii) fusing with target cells and thus transferring various receptors to their surface, and iii) delivering mRNA, lipids and proteins. Since tumor cells secrete large quantities of MV we hypothesized that the latter are important constituents of the tumor microenvironment and their role in tumor progression merited investigation. First, we observed that human and murine lung cancer cell lines secrete more MV in response to non-apoptotic doses of hypoxia, irradiation and chemotherapy. The MV derived from human cancer cells chemoattracted bone marrow-, lymph node- and lung-derived fibroblasts and endothelial cells and activated in these stromal cells the phosphorylation of MAPKp42/44 and AKT. Furthermore, they also induced in bone marrow- and lung-derived fibroblasts expression of LIF, OSM, IL-11, VEGF and MMP-9. Moreover, conditioned media from marrow fibroblasts exposed to MV induced phosphorylation of STAT-3 proteins and chemoattracted lung cancer cells in a LIF- and OSM-dependent manner and, together with IL-11 and VEGF, activated osteoclasts and endothelial cells. Furthermore, MV from cancer cells embedded in Matrigel implants strongly stimulated angiogenesis. We also found that tumor-derived MV express tissue factor (TF) and activate platelets and as a result of this MV derived from activated platelets transfer several adhesion molecules from platelets to the tumor cell surface. This increases adhesiveness of lung cancer cells in endothelium and their metastatic spread in vivo after injection into syngeneic mice. Finally, we found that formation of MV depends on the formation of membrane lipid rafts. Thus we postulate that tumor- and platelet-derived MV are underappreciated constituents of the tumor microenvironment and play a pivotal role in tumor progression/metastasis and angiogenesis. As MV formation appears to be lipid raft-dependent, we suggest that inhibitors of membrane lipid raft formation (e.g, statins or polyene antibiotics) could decrease MV-dependent tumor spread/growth and we are currently testing this hypothesis in animal models in vivo.

Pleiotrophin Is Highly Produced by Myeloma and Breast Cancer and Transdifferentiates Human Monocytes into Endothelial Cells That Are Incorporated into Tumoral Blood Vessels.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1269-1269
Author(s):  
Haiming Chen ◽  
Richard A. Campbell ◽  
Mingjie Li ◽  
Melinda S. Gordon ◽  
Dror Shalitin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Blood Vessels ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Human Monocytes ◽  
Endothelial Gene Expression

Abstract We have previously shown that multiple myeloma (MM) patients express pleiotrophin (PTN) and it is found at high levels in MM serum as well as PTN is a key factor in the transdifferentiation of monocytes into endothelial cells. We determined the level of PTN expression in myeloma and breast cancer and determined whether PTN produced by these tumor cells could induce endothelial cell expression in human monocytes. Both myeloma and breast cancer cells produced high levels of PTN and secreted this growth factor into the culture medium whereas normal bone marrow showed no expression of this protein. Next, MM cell lines, human bone marrow (BM) from MM patients or control subjects or breast cancer cells were cultured with CD14+ PBMCs using transwell culture plates coated with collagen I. CD14+ monocytes exposed to cells from MM cell lines or fresh BM or breast cancer cells showed expression of endothelial genes (Flk-1, Tie-2, CD144, and vWF) and lost expression of monocyte genes (c-fms). Induction of endothelial gene expression was blocked with an anti-PTN antibody. In contrast, CD14+ cells exposed to normal bone marrow as well as cell lines lacking PTN expression did not show endothelial gene expression. We determined whether human monocytes could be incorporated in vivo as vascular endothelium within human tumors that express PTN. Human myeloma LAGλ-1 cells which highly express and secrete PTN were mixed with THP1 monocytes transduced with the green fluorescent protein (GFP) gene and injected subcutaneously into SCID mice. Mice were sacrificed 6 weeks later and tumor was fixed and frozen sections. MM cells or THP1 monocytes alone did not demonstrate the presence of GFP+ blood vessels. Notably, GFP+ THP1 cells were found in blood vessels within the PTN-expressing LAGλ-1 tumor in animals injected with both cells together. When GFP+h2Kd- blood vessels were stained for anti-human and anti-mouse CD31, 60% of the endothelial cells stained positive for human CD31 and the remaining cells stained positive for mouse CD31 whereas none of these cells stained positive for both mouse and human markers. These results show that the blood vessels containing GFP+ cells do not result from fused cells. In addition, an anti-PTN antibody but not control IgG antibody blocks the incorporation of GFP+ cells into the vasculature of the LAGλ-1 tumors. Staining of serial sections with anti-Tie-2 and CD31 antibodies showed a similar distribution pattern. We further examined endothelial gene expression in these in vivo-generated samples using RT-PCR. The results showed that the THP1 monocytes or LAGλ-1 tumor cells alone did not express endothelial genes whereas THP1 monocytes mixed with PTN-expressing LAGλ-1 showed endothelial gene expression. This endothelial gene expression was blocked by anti-PTN antibody. These data show that hematologic and 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 blood vessel formation in solid and liquid tumors.

Bi-directional interactions of prostate cancer cells and bone marrow endothelial cells in three-dimensional culture

The Prostate ◽  
2005 ◽  
Vol 64 (1) ◽  
pp. 75-82 ◽  
Author(s):  
Jeffrey M. Barrett ◽  
Kathy A. Mangold ◽  
Tamas Jilling ◽  
Karen L. Kaul
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Three Dimensional ◽  
Prostate Cancer Cells ◽  
Three Dimensional Culture

Bioengineered three-dimensional co-culture of cancer cells and endothelial cells: A model system for dual analysis of tumor growth and angiogenesis

2017 ◽  
Vol 114 (8) ◽  
pp. 1865-1877 ◽  
Author(s):  
Geraldine Giap Ying Chiew ◽  
Na Wei ◽  
Samiksha Sultania ◽  
Sierin Lim ◽  
Kathy Qian Luo
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Three Dimensional ◽  
Model System ◽  
Dual Analysis

scholarly journals Bone marrow stromal antigen 2 expressed in cancer cells promotes mammary tumor growth and metastasis

2014 ◽  
Vol 16 (6) ◽  
Author(s):  
Wadie D Mahauad-Fernandez ◽  
Kris A DeMali ◽  
Alicia K Olivier ◽  
Chioma M Okeoma
Keyword(s):  
Bone Marrow ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Mammary Tumor ◽  
Mammary Tumor Growth ◽  
Tumor Growth And Metastasis

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.

Crosstalk between Breast Cancer Cells and Bone Marrow Endothelium Require the Engagement of PI3K/AKT Signaling.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1299-1299
Author(s):  
Joana G. Brandao ◽  
Joao T. Barata ◽  
Raquel Nunes ◽  
Lee M. Nadler ◽  
Angelo A. Cardoso
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Metastatic Breast ◽  
Cell Types ◽  
Akt Pathway ◽  
The Impact

Abstract The presence of breast cancer cells in the patient’s bone marrow (BM) at diagnosis is associated with resistance to treatment, disease relapse and poor prognosis. Identification of the factors implicated in the homing, survival and latency of breast cancer cells in the BM should contribute to the design of more efficient therapeutic strategies for breast cancer. There is evidence that breast cancer can recruit endothelial progenitors from the BM. Also, other epithelial tumors seem to preferentially adhere to BM endothelial cells. Therefore, we hypothesized that BM endothelium may play a significant role in the biology of breast cancer cells residing in the BM. Co-cultures in Matrigel showed that breast cancer cells interact with BM endothelium to form heterotypic multicellular networks. Moreover, breast cancer cells migrate towards BM endothelium assembled as capillary-like structures, but not to structures of BM mesenchymal stem cells or BM stroma. This migration was abrogated by pertussis toxin-mediated blockade of chemokine receptor signaling, suggesting the involvement of endothelium-secreted chemokine(s). We then evaluated the impact of breast cancer cells in the survival and proliferation of BM endothelium. All breast cancer lines tested (n=4) promoted the proliferation of BM-derived endothelial cells. This effect is mediated through the engagement of the PI3K/Akt pathway (phosphorylation of Akt at Ser437 and Thr308, and activation of its downstream substrates GSK3β, PRAS-40 and FKHRL1) since its specific blockade abrogated the stimulatory effects of breast cancer on BM endothelium. We next determined whether, reciprocally, BM endothelium impacts on breast cancer cell survival. These experiments were performed in serum-free media to enhance dependency of breast cancer cells from microenvironmental stimuli. In all cases tested, BM endothelium promoted survival/proliferation of breast cancer cells. This stimulation was accompanied by the engagement of the PI3K/Akt pathway in breast cancer cells and, in three of the four lines, the phosphorylation of Erk1/2. These effects were also observed for breast cancer cells that showed constitutive activation of Akt (MCF-7 and ZR-75-1 cells). Specific blockade of PI3K/Akt abrogated the BM endothelium-promoted survival of breast cancer cells, thus demonstrating the critical role of this pathway. These studies show that crosstalk between BM endothelial cells and breast cancer cells may impact on the survival of both cell types. These findings provide new light on the mechanisms that may facilitate the development of a tumor-permissive BM microenvironment in breast cancer, and the creation of breast cancer-supporting BM niches. Importantly, this study implicates BM endothelium as a therapeutic target in breast cancer and suggest that blockade of PI3K/Akt may impact the outcome of patients with metastatic breast cancer.

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