CX3CL1 involves in breast cancer metastasizing to the spine via the Src/FAK signaling pathway

Liang, Yun; Lee, Yi; Liu, Peng; Jiang, Libo; Wang, Houlei; Hu, Annan; Sun, Chi; Dong, Jian

doi:10.7150/jca.26497

Cited by 52 publications

(55 citation statements)

References 34 publications

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“…High levels of CX3CL1 in cells can attract those cancer cells expressing its receptor CX3CR1 and trigger them to invade the tissue and form metastases as seen e.g. in breast cancer spinal metastases [49]. In our study, we showed that CX3CL1 is selectively elevated in the serum of breast cancer patients with cerebral metastases.…”

Section: Patient Serum and Recombinant Chemokines Lead To Reduced Barsupporting

confidence: 58%

Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood–brain barrier model

Curtaz

Schmitt

Herbert

et al. 2020

Fluids Barriers CNS

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Background: The most threatening metastases in breast cancer are brain metastases, which correlate with a very poor overall survival, but also a limited quality of life. A key event for the metastatic progression of breast cancer into the brain is the migration of cancer cells across the blood-brain barrier (BBB). Methods: We adapted and validated the CD34 + cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) to analyse the effects of patient serum on BBB properties. We collected serum samples from healthy donors, breast cancer patients with primary cancer, and breast cancer patients with, bone, visceral or cerebral metastases. We analysed cytokine levels in these sera utilizing immunoassays and correlated them with clinical data. We used paracellular permeability measurements, immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. Results: The BLECs cultured together with brain pericytes in transwells developed a tight monolayer with a correct localization of claudin-5 at the tight junctions (TJ). Several BBB marker proteins such as the TJ proteins claudin-5 and occludin, the glucose transporter GLUT-1 or the efflux pumps PG-P and BCRP were upregulated in these cultures. This was accompanied by a reduced paracellular permeability for fluorescein (400 Da). We then used this model for the treatment with the patient sera. Only the sera of breast cancer patients with cerebral metastases had significantly increased levels of the cytokines fractalkine (CX3CL1) and BCA-1 (CXCL13). The increased levels of fractalkine were associated with the estrogen/progesterone receptor status of the tumour. The treatment of BLECs with these sera selectively increased the expression of CXCL13 and TJ protein occludin. In addition, the permeability of fluorescein was increased after serum treatment. Conclusion: We demonstrate that the CD34 + cell-derived human in vitro BBB model can be used as a tool to study the molecular mechanisms underlying cerebrovascular pathologies. We showed that serum from patients with

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Section: Patient Serum and Recombinant Chemokines Lead To Reduced Barsupporting

confidence: 58%

Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood–brain barrier model

Curtaz

Schmitt

Herbert

et al. 2020

Fluids Barriers CNS

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“…At the sites of cell-substratum focal adhesions, FAK can combine withSrc to form a dual-kinase complex [20], which coordinate cell behavior through regulating downstream pathways and molecules, including AKT, p38 and ERK kinase [21,22]. Autophosphorylation of Src/FAK complexes is a critical event in cancer progression and metastasis [23]. Src/FAK pathway kinases in solid tumors have been viewed as an attractive target in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

HCRP-1 regulates cell migration, invasion and angiogenesis via Src/ FAK signaling in human prostate cancer

Chen¹,

Wu²,

Teng³

et al. 2020

Int. J. Biol. Sci.

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Prostate cancer (PCa) is the third leading malignancy engendering mortality among men globally. The present study aimed at determining the expression of hepatocellular carcinoma-related protein-1 (HCRP-1) in PCa, to explore its potential role in prostate tumorigenesis in vitro and in vivo. We evaluated HCRP-1 protein with immunohistochemistry (IHC) technology and found HCRP-1 expression was significantly low in PCa tissues (PCTs); In addition, the decreased HCRP-1 was significantly associated with TNM (tumor node metastasis) stage, advanced histology grade and gleason score. Transwell, tube formation, Western blot and co-immunoprecipitation (Co-IP) assays were utilized to determine the role of down-regulating HCRP-1 in PCa cell migration, invasion and angiogenesis. Meanwhile, we found HCRP-1 depletion induced Src and focal adhesion kinase (FAK) phosphorylation, which could be reversed by Src inhibitor PP2 or FAK inhibitor. Furthermore, down-regulated HCRP-1 evidently induced lung metastasis of PCa cells in xenograft mode. Taken together, our study indicates HCRP-1 plays an important role in PCa metastasis. HCRP-1 may serve as a potential therapeutic target for PCa.

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“…The escaping of circulating tumor cells from the micro-vasculature of primary sites and extravasating into distant sites are the most important steps of the metastatic cascade. Our previous study showed that the vertebral marrow sinusoids were full of CX3CL1, which plays an important role in the process of spine metastases derived from CX3CR1-expressing cancer cells (Liang et al, 2018;Liu et al, 2018). During the above process, CX3CL1 chemo-attracted tumor cells and functioned as an adhesion molecule to arrest circulating cancer cells in the vertebra (Fong et al, 1998;Yao et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Src is one of the most widely studied members of the SFKs. Our previous studies found that CX3CL1 quickly activated Src signaling in several tumor cells (Liang et al, 2018;Liu et al, 2018). Interestingly, another study reported that Src regulated cytoskeleton remodeling in Schwann cell morphology and motility (Melfi et al, 2017).…”

Section: Introductionmentioning

confidence: 95%

CX3CL1 Induces Vertebral Microvascular Barrier Dysfunction via the Src/P115-RhoGEF/ROCK Signaling Pathway

Lee

Liang

Zhao

et al. 2020

Front. Cell. Neurosci.

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Trans-endothelial migration (TEM) of cancer cells is a critical step in metastasis. Micro-vascular barrier disruptions of distant organs play important roles in tumor cells TEM. The spine is a preferred site for multiple cancer cell metastases. Our previous study found that vertebral spongy bone was rich in CX3CL1 and that CX3CL1 can attract fractalkine receptor-expressing tumor cells to the spine. In the present study, we determined whether CX3CL1 was involved in vertebral micro-vascular barrier disruption and promoted tumor cell TEM after circulating tumor cells were arrested in the vertebral micro-vasculature. We examined the role of CX3CL1 in the barrier function of vertebral micro-vascular endothelial cells (VMECs) and explored the molecular mechanisms of CX3CL1-induced VMEC barrier disruption. Our results demonstrated that CX3CL1 led to F-actin formation and ZO-1 disruption in VMECs and induced the vertebral micro-vascular barrier disruption. Importantly, we found that the activation of the Src/P115-RhoGEF/ROCK signaling pathway plays an important role in CX3CL1-induced VMEC stress fiber formation, ZO-1 disruption and then vertebral micro-vascular barrier hyper-permeability. Inhibiting Src/P115-RhoGEF/ROCK signaling in VMECs effectively blocked CX3CL1-induced vertebral vascular endothelial dysfunction and subsequent tumor cell TEM. The results of this study and our previous study indicate that in addition to its chemotaxis, CX3CL1 plays a critical role in regulating vertebral micro-vascular barrier function and tumor cell TEM. CX3CL1 induced VMECs stress fiber formation, ZO-1 disruption and then vascular endothelial hyperpermeability via activation of the Src/P115-RhoGEF/ROCK signaling pathway. The inhibition of the Src/P115-RhoGEF/ROCK signaling pathway in VMECs effectively blocked tumor cells TEMs in vertebral spongy bone and maybe a potential therapeutic strategy for spine metastases in the future.

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CX3CL1 involves in breast cancer metastasizing to the spine via the Src/FAK signaling pathway

Cited by 52 publications

References 34 publications

Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood–brain barrier model

Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood–brain barrier model

HCRP-1 regulates cell migration, invasion and angiogenesis via Src/ FAK signaling in human prostate cancer

CX3CL1 Induces Vertebral Microvascular Barrier Dysfunction via the Src/P115-RhoGEF/ROCK Signaling Pathway

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