CXCL12–CXCR4 Contributes to the Implication of Bone Marrow in Cancer Metastasis

Shi, Jimin; Wei, Yibing; Xia, Jun; Wang, Siqun; Wu, Jianguo; Chen, Feiyan; Huang, Gangyong; Chen, Jie

doi:10.2217/fon.13.193

Cited by 32 publications

(25 citation statements)

References 91 publications

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“…CXCL12 evokes pain hyperalgesia by sensitizing CXCR4-mediated MAPK pathways in na€ ıve rats Chemokine CXCL12, also known as the stromal cellderived factor-1, is the sole ligand for congenetic receptor CXCR4. Emerging evidence has highlighted that CXCL12/ CXCR4 signaling is responsible for pleiotropic aspects of metastatic cancer progression including homing, survival, proliferation, and angiogenesis in bone marrow microenvironment (Sun et al 2010;Shi et al 2014). It is well known that, after metastasized to bone, the secondary tumors in the advanced stage subsequently result in BCP (Duan et al 2012;Xu et al 2013).…”

Section: R E T R a C T E Dmentioning

confidence: 99%

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Liu

Zhang

et al. 2015

Journal of Neurochemistry

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The activation of MAPK pathways in spinal cord and subsequent production of proinflammatory cytokines in glial cells contribute to the development of spinal central sensitization, the basic mechanism underlying bone cancer pain (BCP). Our previous study showed that spinal CXCL12 from astrocytes mediates BCP generation by binding to CXCR4 in both astrocyters and microglia. Here, we verified that CXCL12/CXCR4 signaling contributed to BCP through a MAPK-mediated mechanism. In na€ ıve rats, a single intrathecal administration of CXCL12 considerably induced pain hyperalgesia and phosphorylation expression of spinal MAPK members (including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase), which could be partially prevented by pre-treatment with CXCR4 inhibitor AMD3100. This CXCL12-induced hyperalgesia was also reduced by MAPK inhibitors. In bone cancer rats, tumor cell inoculation into the tibial cavity caused prominent and persistent pain hyperalgesia, and associated with up-regulation of CXCL12 and CXCR4, activation of glial cells, phosphorylation of MAPKs, and production of proinflammatory cytokines in the spinal cord. These tumor cell inoculation-induced behavioral and neurochemical alterations were all suppressed by blocking CXCL12/CXCR4 signaling or MAPK pathways. Taken together, these results demonstrate that spinal MAPK pathways mediated CXCL12/CXCR4-induced pain hypersensitivity in bone cancer rats, which could be druggable targets for alleviating BCP and glia-derived neuroinflammation. Keywords: astrocytes, bone cancer pain, chemokine, mitogenactivated protein kinase, microglia, neuroinflammation. Bone cancer pain (BCP) caused by primary tumors or bone metastases is the most common source of moderate and severe cancer pain, which not only makes patients less confident to receive therapeutic plan but also discourages tumor-burdened people from desiring to live (Knopp et al. 2011). With effective treatment strategies depending on a better understanding of BCP, intensive studies of underlying pathogenic mechanisms of BCP and development of novel analgesic targets are highly anticipated in the basic and clinical research communities.Following local inoculation of primary or metastatic bone tumor in the bone microenvironment, cellular and neurochemical alterations take place abundantly in the spinal cord, triggering hyperalgesic behaviors (Medhurst et al. 2002). In this complex pathophysiologic process, glial cells (especially astrocytes and microglia) react and release various proinflammatory cytokines, including tumor necrosis factor a (TNF-a), interleukin 1b (IL-1b) and IL-6, which enhance central sensitization and thus evoking pain hypersensitivity (Falk and Dickenson 2014). Indeed, inhibiting functional activation of astrocytes and microglia at the spinal level is sufficient to suppress BCP and these glia-derived mediators Moreover, numerous studies have shown that all three MAPK members are prone to be phosphorylated following the activation of certain GPCRs, especially che...

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Section: R E T R a C T E Dmentioning

confidence: 99%

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Liu

Zhang

et al. 2015

Journal of Neurochemistry

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“…C-X-C motif chemokine 12 (CXCL12) from neighboring stromal cells and other distant organs primarily binds to the chemokine receptor 4 (CXCR4) on tumor cells and subsequently induces intracellular signaling through several divergent pathways, which are involved in the progression and metastasis of several tumor types [6,7]. Lymphotactin receptor (XCR1) is also one of the members of the chemokine receptor family.…”

Section: Introductionmentioning

confidence: 99%

XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

Wang

Han

et al. 2015

Biochemical and Biophysical Research Communications

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“…As reported, Gab1 can be expressed in many human organs and can interact with PIP3, PI3K, Grb2, and SHP2 to exert various biological effects and behaviors [11,12]. At the same time, SDF-1 signaling also plays an important role in tumorigenesis, which promotes some important pathological events [13,14]. Several signaling pathways stimulated by SDF-1 can promote the proliferation, migration, and even apoptosis of CS.…”

Section: Introductionmentioning

confidence: 88%

Gab1 regulates SDF-1-induced progression via inhibition of apoptosis pathway induced by PI3K/AKT/Bcl-2/BAX pathway in human chondrosarcoma

et al. 2015

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In recent decades, the stromal cell-derived factor-l (SDF-1) and Gab1 have been investigated to be involved in oncogenesis. However, it is scarcely reported that SDF-1-Gab1 pathway mediates proliferation and apoptosis in human chondrosarcoma (CS). In this study, we assessed the expression of Gab1 in 90 CS solid tumors by immunohistochemistry, immunoblotting, and qRT-PCR, and then, some in vitro assays were also applied to CS cells treated with SDF-1. We observed that the overexpression of Gab1 was positively correlated with lung metastasis and recurrence, and acts as an independent prognostic factor for CS patients. Gab1 expression was up-regulated in response to SDF-1 stimulation in CS cell line JJ012, SW1353, L3252. Overexpression of Gab1 increased Bcl-2/BAX ratio to promote cell growth via PI3K/AKT. On the other hand, silencing of Gab1 accelerated apoptosis and repressed the growth of CS cells, which further caused the inhibition of G1/S phase transition and decreased invasion capacity in CS cell lines. In vivo assay identified that the knockdown of Gab1 interfered with the tumor mass formation. In conclusion, our data identified overexpression of Gab1 in CS tissues, and Gab1 can be recommended as a novel biomarker for diagnosis and prognosis in patients with CS. Additionally, PI3K/AKT/Bcl-2/BAX axis was involved in Gab1-induced CS progression, indicating Gab1 might act as a new target for the treatment of CS patients.

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CXCL12–CXCR4 Contributes to the Implication of Bone Marrow in Cancer Metastasis

Cited by 32 publications

References 91 publications

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

Gab1 regulates SDF-1-induced progression via inhibition of apoptosis pathway induced by PI3K/AKT/Bcl-2/BAX pathway in human chondrosarcoma

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