Microfluidic platform for studying osteocyte mechanoregulation of breast cancer bone metastasis

2019 ◽  
Vol 11 (4) ◽  
pp. 119-129 ◽  
Author(s):  
Xueting Mei ◽  
Kevin Middleton ◽  
Dongsub Shim ◽  
Qianqian Wan ◽  
Liangcheng Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fluid Flow ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Bone Remodeling ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Intervention Strategy ◽  
Side Channels ◽  
Breast Cancer Bone Metastasis

AbstractBone metastasis is a common, yet serious, complication of breast cancer. Breast cancer cells that extravasate from blood vessels to the bone devastate bone quality by interacting with bone cells and disrupting the bone remodeling balance. Although exercise is often suggested as a cancer intervention strategy and mechanical loading during exercise is known to regulate bone remodeling, its role in preventing bone metastasis remains unknown. We developed a novel in vitro microfluidic tissue model to investigate the role of osteocytes in the mechanical regulation of breast cancer bone metastasis. Metastatic MDA-MB-231 breast cancer cells were cultured inside a 3D microfluidic lumen lined with human umbilical vein endothelial cells (HUVECs), which is adjacent to a channel seeded with osteocyte-like MLO-Y4 cells. Physiologically relevant oscillatory fluid flow (OFF) (1 Pa, 1 Hz) was applied to mechanically stimulate the osteocytes. Hydrogel-filled side channels in-between the two channels allowed real-time, bi-directional cellular signaling and cancer cell extravasation over 3 days. The applied OFF was capable of inducing intracellular calcium responses in osteocytes (82.3% cells responding with a 3.71 fold increase average magnitude). Both extravasation distance and percentage of extravasated side-channels were significantly reduced with mechanically stimulated osteocytes (32.4% and 53.5% of control, respectively) compared to static osteocytes (102.1% and 107.3% of control, respectively). This is the first microfluidic device that has successfully integrated stimulatory bone fluid flow, and demonstrated that mechanically stimulated osteocytes reduced breast cancer extravasation. Future work with this platform will determine the specific mechanisms involved in osteocyte mechanoregulation of breast cancer bone metastasis, as well as other types of cancer metastasis and diseases.

BRMS1L inhibits bone metastasis of breast cancer cells through epigenetic silence of CXCR4.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13002-e13002
Author(s):  
Yinghuan Cen ◽  
Chang Gong ◽  
Jun Li ◽  
Gehao Liang ◽  
Zihao Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Qrt Pcr ◽  
Metastatic Sites

e13002 Background: We previously demonstrated that BRMS1L (breast cancer metastasis suppressor 1 like) suppresses breast cancer metastasis through HDAC1 recruitment and histone H3K9 deacetylation at the promoter of FZD10, a receptor for Wnt signaling. It is still unclear whether BRMS1L regulates organ-specific metastases, such as bone metastasis, the most prevalent metastatic site of breast cancer. Methods: Examination of the expression of BRMS1L in primary tumors, bone metastatic and other metastatic tissues from breast cancer patients was implemented using qRT-PCR and immunohistochemistry staining. To investigate the mechanism by which BRMS1L drives breast cancer bone metastasis, we tested the mRNA expression by qRT-PCR of a set of potential bone related genes (BRGs) based on PubMed database in MDA-MB-231 cells over expressing BRMS1L and MCF-7 cells knocking-down BRMS1L, and detected the expression of CXCR4 in these established cells by western blot. Transwell assays were performed to assess the migration abilities of breast cancer cells towards osteoblasts. ChIP (Chromatin Immuno-Precipitation) were employed to test the interaction between BRMS1L and CXCR4. Results: At both mRNA and protein levels, the expression of BRMS1L was significantly lower in bone metastatic sites than that in primary cancer tissues and other metastatic sites of breast cancer patients. CXCR4 was screened out in a set of BRGs and negatively correlated with the expression of BRMS1L in breast cancer cell lines. BRMS1L inhibited the migration of breast cancer cells towards osteoblasts through CXCL12/CXCR4 axis. In the presence of TSA treatment, breast cancer cell lines showed an increased expression of CXCR4 in a TSA concentration-dependent manner. In addition, ChIP assays verified that BRMS1L directly bound to the promoter region of CXCR4 and inhibited its transcription through promoter histone deacetylation. Conclusions: BRMS1L mediates the migration abilities of breast cancer cells to bone microenvironment via targeting CXCR4 and contributes to bone metastasis of breast cancer cells. Thus, BRMS1L may be a potential biomarker for predicting bone metastasis in breast cancer.

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.

scholarly journals Knockdown of AKT3 Activates HER2 and DDR Kinases in Bone-Seeking Breast Cancer Cells, Promotes Metastasis In Vivo and Attenuates the TGFβ/CTGF Axis

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 430
Author(s):  
Nico Hinz ◽  
Anke Baranowsky ◽  
Michael Horn ◽  
Malte Kriegs ◽  
Freya Sibbertsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Crucial Role ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Combined Treatment ◽  
Breast Cancer Patients ◽  
Breast Cancer Bone Metastasis

Bone metastases frequently occur in breast cancer patients and lack appropriate treatment options. Hence, understanding the molecular mechanisms involved in the multistep process of breast cancer bone metastasis and tumor-induced osteolysis is of paramount interest. The serine/threonine kinase AKT plays a crucial role in breast cancer bone metastasis but the effect of individual AKT isoforms remains unclear. Therefore, AKT isoform-specific knockdowns were generated on the bone-seeking MDA-MB-231 BO subline and the effect on proliferation, migration, invasion, and chemotaxis was analyzed by live-cell imaging. Kinome profiling and Western blot analysis of the TGFβ/CTGF axis were conducted and metastasis was evaluated by intracardiac inoculation of tumor cells into NOD scid gamma (NSG) mice. MDA-MB-231 BO cells exhibited an elevated AKT3 kinase activity in vitro and responded to combined treatment with AKT- and mTOR-inhibitors. Knockdown of AKT3 significantly increased migration, invasion, and chemotaxis in vitro and metastasis to bone but did not significantly enhance osteolysis. Furthermore, knockdown of AKT3 increased the activity and phosphorylation of pro-metastatic HER2 and DDR1/2 but lowered protein levels of CTGF after TGFβ-stimulation, an axis involved in tumor-induced osteolysis. We demonstrated that AKT3 plays a crucial role in bone-seeking breast cancer cells by promoting metastatic potential without facilitating tumor-induced osteolysis.

scholarly journals Curcuminoids Block TGF-β Signaling in Human Breast Cancer Cells and Limit Osteolysis in a Murine Model of Breast Cancer Bone Metastasis

2012 ◽  
Vol 76 (3) ◽  
pp. 316-321 ◽  
Author(s):  
Laura E. Wright ◽  
Jennifer B. Frye ◽  
Ashley L. Lukefahr ◽  
Barbara N. Timmermann ◽  
Khalid S. Mohammad ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Murine Model ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Breast Cancer Bone Metastasis

scholarly journals EZH2 Engages TGFβ Signaling to Promote Breast Cancer Bone Metastasis via Integrin β1-FAK Activation

2021 ◽  
Author(s):  
Lin Zhang ◽  
Jingkun Qu ◽  
Yutao Qi ◽  
Yu-Wen Huang ◽  
Zhifen Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Receptor Type ◽  
Tgfβ Signaling ◽  
Integrin Β1 ◽  
Tgfβ Receptor ◽  
Breast Cancer Bone Metastasis

ABSTRACTBone metastasis is a frequent complication of breast cancer, occurring in about 50-70% of breast cancer patients with late-stage disease. The lack of effective therapy suggests that the precise molecular mechanisms underlying bone metastasis are still unclear. Enhancer of zeste homolog 2 (EZH2) is considered a breast cancer oncogene and its expression is correlated with metastasis of breast cancer, but its function in bone metastasis has not been well explored. Herein we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling, a key pathway in bone metastasis. Knocking down EZH2 decreases bone metastasis incidence and outgrowth in vivo. EZH2 induces cancer cell proliferation and osteoclast maturation, when breast cancer cells are co-cultured with osteoblasts and osteoclasts together in vitro. Mechanistically, EZH2 increases transcription of ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182, thus enhances the binding of TGFβRI to TGFβ receptor type II (TGFβRII), therefore activates Smad2 and increases parathyroid hormone-like hormone (PTHLH) expression. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitor effectively inhibits breast cancer bone metastasis in vivo. Overall, our data signify integrin β1-FAK as a new downstream effector of EZH2 in breast cancer cells, and EZH2-integrin β1-FAK axis cooperates with TGFβ signaling pathway to promote bone metastasis of breast cancer.

scholarly journals Sympathetic activity in breast cancer and metastasis: partners in crime

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Francisco Conceição ◽  
Daniela M. Sousa ◽  
Joana Paredes ◽  
Meriem Lamghari
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Bone Remodeling ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Sympathetic Innervation ◽  
Breast Cancer Progression ◽  
Vicious Cycle ◽  
Native Bone ◽  
Cancer Management

AbstractThe vast majority of patients with advanced breast cancer present skeletal complications that severely compromise their quality of life. Breast cancer cells are characterized by a strong tropism to the bone niche. After engraftment and colonization of bone, breast cancer cells interact with native bone cells to hinder the normal bone remodeling process and establish an osteolytic “metastatic vicious cycle”. The sympathetic nervous system has emerged in recent years as an important modulator of breast cancer progression and metastasis, potentiating and accelerating the onset of the vicious cycle and leading to extensive bone degradation. Furthermore, sympathetic neurotransmitters and their cognate receptors have been shown to promote several hallmarks of breast cancer, such as proliferation, angiogenesis, immune escape, and invasion of the extracellular matrix. In this review, we assembled the current knowledge concerning the complex interactions that take place in the tumor microenvironment, with a special emphasis on sympathetic modulation of breast cancer cells and stromal cells. Notably, the differential action of epinephrine and norepinephrine, through either α- or β-adrenergic receptors, on breast cancer progression prompts careful consideration when designing new therapeutic options. In addition, the contribution of sympathetic innervation to the formation of bone metastatic foci is highlighted. In particular, we address the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature, driving breast cancer cell engraftment in the bone niche. Finally, clinical perspectives and developments on the use of β-adrenergic receptor inhibitors for breast cancer management and treatment are discussed.

scholarly journals Biomechanical regulation of breast cancer metastasis and progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adrianne Spencer ◽  
Andrew D. Sligar ◽  
Daniel Chavarria ◽  
Jason Lee ◽  
Darshil Choksi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Mechanical Load ◽  
Breast Cancer Metastasis ◽  
Proliferation And Metastasis ◽  
Xenograft Models ◽  
Chemotherapeutic Treatment ◽  
Complex Signaling

AbstractPhysical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor.

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