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.

SDF-1α regulation in breast cancer cells contacting bone marrow stroma is critical for normal hematopoiesis

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3245-3252 ◽  
Author(s):  
Anabella L. Moharita ◽  
Marcelo Taborga ◽  
Kelly E. Corcoran ◽  
Margarette Bryan ◽  
Prem S. Patel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Cells ◽  
Connexin 43 ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Contact Inhibition ◽  
Enzyme Linked Immunosorbent Assay ◽  
Hematopoietic Regulation

Abstract Breast cancer cells (BCCs) show preference for the bone marrow (BM). An animal model showed 2 populations of BCCs in the BM with regard to their cycling states. An in vitro model of early BC entry into BM showed normal hematopoiesis. Here, we show a critical role for BCC-derived SDF-1α in hematopoietic regulation. The studies used a coculture of BM stroma and BCCs (cell lines and stage II BCCs). Northern blots and enzyme-linked immunosorbent assay (ELISA) showed gradual decreases in SDF-1α production in BCCs as they contact BM stroma, indicating partial microenvironmental effects caused by stroma on the BCCs. SDF-1 knock-down BCCs and increased exogenous SDF-1α prevented contact inhibition between BCCs and BM stroma. Contact inhibition was restored with low SDF-1α levels. Long-term culture-initiating assays with CD34+/CD38–/Lin– showed normal hematopoiesis provided that SDF-1α levels were reduced in BCCs. Gap junctions (connexin-43 [CX-43]) were formed between BCCs and BM stroma, with concomitant interaction between CD34+/CD38–/Lin– and BM stroma but not with the neighboring BCCs. In summary, SDF-1α levels are reduced in BCCs that contact BM stroma. The low levels of SDF-1α in BCCs regulate interactions between BM stroma and hematopoietic progenitors, consequently facilitating normal hematopoiesis.

scholarly journals S100A4 released from highly bone-metastatic breast cancer cells plays a critical role in osteolysis

Bone Research ◽  
2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Haemin Kim ◽  
Bongjun Kim ◽  
Sang Il Kim ◽  
Hyung Joon Kim ◽  
Brian Y. Ryu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Bone Loss ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Bone Destruction ◽  
Metastatic Breast ◽  
Breast Cancer Patients

Abstract Bone destruction induced by breast cancer metastasis causes severe complications, including death, in breast cancer patients. Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis. Tumor-derived factors play fundamental roles in this form of communication. To identify soluble factors released from cancer cells in bone metastasis, we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells. This subline (mtMDA) showed a markedly elevated ability to secrete S100A4 protein, which directly stimulated osteoclast formation via surface receptor RAGE. Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo. Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts. Furthermore, the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells. In addition, administration of an anti-S100A4 monoclonal antibody (mAb) that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice. Taken together, our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.

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.

scholarly journals Metastatic breast cancer cells induce altered microglial morphology and electrical excitability in vivo

2019 ◽  
Author(s):  
Anna Simon ◽  
Ming Yang ◽  
Joanne L. Marrison ◽  
Andrew D. James ◽  
Peter J. O’Toole ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Inflammatory Response ◽  
Cancer Cells ◽  
Brain Tumours ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Field Potential ◽  
Metastatic Breast ◽  
Optical Window

AbstractBackgroundAn emerging problem in the treatment of breast cancer is the increasing incidence of metastases to the brain. Metastatic brain tumours are incurable and can cause epileptic seizures and cognitive impairment, so better understanding of this niche, and the cellular mechanisms, is urgently required. Microglia are the resident brain macrophage population, becoming “activated” by neuronal injury, eliciting an inflammatory response. Microglia promote proliferation, angiogenesis and invasion in brain tumours and metastases. However, the mechanisms underlying microglial involvement appear complex and better models are required to improve understanding of function.MethodsHere, we sought to address this need by developing a model to study metastatic breast cancer cell-microglial interactions using intravital imaging combined with ex vivo electrophysiology. We implanted an optical window on the parietal bone to facilitate observation of cellular behaviour in situ in the outer cortex of heterozygous Cx3cr1GFP/+ mice. Results: We detected GFP-expressing microglia in Cx3cr1GFP/+ mice up to 350 µm below the window without significant loss of resolution. When DsRed-expressing metastatic MDA-MB-231 breast cancer cells were implanted in Matrigel under the optical window, significant accumulation of activated microglia around invading tumour cells could be observed. This inflammatory response resulted in significant cortical disorganisation and aberrant spontaneously-occurring local field potential spike events around the metastatic site.ConclusionsThese data suggest that peritumoral microglial activation and accumulation may play a critical role in local tissue changes underpinning aberrant cortical activity, which offers a possible mechanism for the disrupted cognitive performance and seizures seen in patients with metastatic breast cancer.

scholarly journals Depletion of mitochondrial protease OMA1 alters proliferative properties and promotes metastatic growth of breast cancer cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Amita Daverey ◽  
Roman M. Levytskyy ◽  
Kimberly M. Stanke ◽  
Martonio Ponte Viana ◽  
Samantha Swenson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Metastatic Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Metastatic Breast ◽  
Protein Homeostasis ◽  
Mesenchymal Transition ◽  
Ductal Hyperplasia

Abstract Metastatic competence of cancer cells is influenced by many factors including metabolic alterations and changes in mitochondrial biogenesis and protein homeostasis. While it is generally accepted that mitochondria play important roles in tumorigenesis, the respective molecular events that regulate aberrant cancer cell proliferation remain to be clarified. Therefore, understanding the mechanisms underlying the role of mitochondria in cancer progression has potential implications in the development of new therapeutic strategies. We show that low expression of mitochondrial quality control protease OMA1 correlates with poor overall survival in breast cancer patients. Silencing OMA1 in vitro in patient-derived metastatic breast cancer cells isolated from the metastatic pleural effusion and atypical ductal hyperplasia mammary tumor specimens (21MT-1 and 21PT) enhances the formation of filopodia, increases cell proliferation (Ki67 expression), and induces epithelial-mesenchymal transition (EMT). Mechanistically, loss of OMA1 results in alterations in the mitochondrial protein homeostasis, as reflected by enhanced expression of canonic mitochondrial unfolded protein response genes. These changes significantly increase migratory properties in metastatic breast cancer cells, indicating that OMA1 plays a critical role in suppressing metastatic competence of breast tumors. Interestingly, these results were not observed in OMA1-depleted non-tumorigenic MCF10A mammary epithelial cells. This newly identified reduced activity/levels of OMA1 provides insights into the mechanisms leading to breast cancer development, promoting malignant progression of cancer cells and unfavorable clinical outcomes, which may represent possible prognostic markers and therapeutic targets for breast cancer treatment.

scholarly journals Loss of miR-101-3p Promotes Transmigration of Metastatic Breast Cancer Cells through the Brain Endothelium by Inducing COX-2/MMP1 Signaling

2020 ◽  
Vol 13 (7) ◽  
pp. 144 ◽  
Author(s):  
Rania Harati ◽  
Mohammad G. Mohammad ◽  
Abdelaziz Tlili ◽  
Raafat A. El-Awady ◽  
Rifat Hamoudi
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Metastatic Breast ◽  
Brain Endothelium ◽  
Cox 2 ◽  
The Brain

Brain metastases represent one of the incurable end stages in breast cancer (BC). Developing effective or preventive treatments is hampered by a lack of knowledge on the molecular mechanisms driving brain metastasis. Transmigration of BC cells through the brain endothelium is a key event in the pathogenesis of brain metastasis. In this study, we identified miR-101-3p as a critical micro-RNA able to reduce transmigration of BC cells through the brain endothelium. Our results revealed that miR-101-3p expression is downregulated in brain metastatic BC cells compared to less invasive variants, and varies inversely compared to the brain metastatic propensity of BC cells. Using a loss-and-gain of function approach, we found that miR-101-3p downregulation increased transmigration of BC cells through the brain endothelium in vitro by inducing COX-2 expression in cancer cells, whereas ectopic restoration of miR-101-3p exerted a metastasis-reducing effect. In regulatory experiments, we found that miR-101-3p mediated its effect by modulating COX-2-MMP1 signaling capable of degrading the inter-endothelial junctions (claudin-5 and VE-cadherin), key components of the brain endothelium. These findings suggest that miR-101-3p plays a critical role in the transmigration of breast cancer cells through the brain endothelium by modulating the COX-2-MMP1 signaling and thus may serve as a therapeutic target that can be exploited to prevent or suppress brain metastasis in human breast cancer.

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