Role of C-X-C chemokine ligand 12/C-X-C chemokine receptor 4 in the progression of hepatocellular carcinoma (original) (raw)
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Insights on the CXCL12-CXCR4 axis in hepatocellular carcinoma carcinogenesis
American journal of translational research, 2014
Chemokines, a group of small chemotactic cytokines, and their G-protein-coupled receptors were originally identified for their ability to mediate various pro- and anti-inflammatory responses. Beyond the influence of chemokines and their cognate receptors in several inflammatory diseases, several malignancies have been shown to be dependent of chemokines for progression, tumor growth, cellular migration and invasion, and angiogenesis; those later facilitating the development of distant metastases. In hepatocellular carcinoma (HCC), chemokines were shown to affect leukocyte recruitment, neovascularization and tumor progression. CXCL12 (stromal-derived factor 1 alpha- SDF-1) is the primary ligand for the seven transmembrane G-protein coupled receptor CXCR4. The CXCR4/CXCL12 axis exerts a variety of functions at different steps of HCC tumor progression, using autocrine and/or paracrine mechanisms to sustain tumor cell growth, to induce angiogenesis and to facilitate tumor escape through...
CXCR4 regulates the early extravasation of metastatic tumor cells in vivo
Neoplasia (New York, N.Y.), 2009
Recent studies have demonstrated that the chemokine receptor CXCR4 plays a crucial role in organ-specific metastasis formation. Although a variety of studies showed the expression of chemokine receptors, in particular, CXCR4, by gastrointestinal tumors, the precise mechanisms of chemokine receptor-mediated homing of cancer cells to specific sites of metastasis remained elusive. Here, we used liver metastatic human HEP-G2 hepatoma and HT-29LMM colon cancer cells expressing functional CXCR4 to dissect the metastatic cascade by intravital fluorescence microscopy. Immunohistochemistry revealed that the CXCR4 ligand CXCL12 is expressed by endothelial cells and likely Kupffer cells lining the liver sinusoids. Tumor cell adhesion and extravasation in vivo was quantitatively analyzed using intravital fluorescence microscopy. Treatment of cells with an anti-CXCR4 antibody did not affect cell adhesion but significantly impaired tumor cell extravasation (HEP-G2; isotype control: 22.3% +/- 4.3%...
… (New York, NY), 2008
Field cancerization involves the lateral spread of premalignant or malignant disease and contributes to the recurrence of head and neck tumors. The overall hypothesis underlying this work is that endothelial cells actively participate in tumor cell invasion by secreting chemokines and creating a chemotactic gradient for tumor cells. Here we demonstrate that conditioned medium from head and neck tumor cells enhance Bcl-2 expression in neovascular endothelial cells. Oral squamous cell carcinoma-3 (OSCC3) and Kaposi's sarcoma (SLK) show enhanced invasiveness when cocultured with pools of human dermal microvascular endothelial cells stably expressing Bcl-2 (HDMEC-Bcl-2), compared to cocultures with empty vector controls (HDMEC-LXSN). Xenografted OSCC3 tumors vascularized with HDMEC-Bcl-2 presented higher local invasion than OSCC3 tumors vascularized with control HDMEC-LXSN. CXCL1 and CXCL8 were upregulated in primary endothelial cells exposed to vascular endothelial growth factor (VEGF), as well as in HDMEC-Bcl-2. Notably, blockade of CXCR2 signaling, but not CXCR1, inhibited OSCC3 and SLK invasion toward endothelial cells. These data demonstrate that CXC chemokines secreted by endothelial cells induce tumor cell invasion and suggest that the process of lateral spread of tumor cells observed in field cancerization is guided by chemotactic signals that originated from endothelial cells.
Oncology Reports
The liver is a common site for the metastatic spread of primary malignancies including colorectal cancer, and liver metastasis is a main cause of death in cancer patients. This is due to the complexity of the interactions taking place in the liver between tumor and stromal cells. In fact, cancer-associated fibroblasts (CAFs) have been shown to support tumor growth through the CXCL12/CXCR4 axis. However, along with cancer cells, myeloid-derived suppressor cells (MDSCs), immature dendritic cells with immunosuppressive potential, also express CXCR4. It has recently been demonstrated that reducing CXCL12 availability in the tumor microenvironment decreases liver metastasis. Therefore, blocking CXCL12 chemokine receptor CXCR4 may be a successful approach to diminish the metastatic spread of colorectal cancer to the liver. However, the subjacent mechanisms by which this chemokine influences the tumor are not fully understood. Thus, in order to uncover the role of CXCR4 during tumor cell/liver fibroblast crosstalk driving liver metastasis, the CXCR4 antagonist AMD3100 was used for in vitro studies and in an in vivo approach using an orthotopic model of liver metastasis in immune competent mice through intrasplenic injection of grafted C26 cells. In vitro blockage of CXCR4 led to an impaired migratory potential of tumor and hepatic stellate cells (HSCs) and a reduced tumor response to CXCL12. In vivo administration of AMD3100 to tumor-bearing mice resulted in attenuated metastatic development in the liver, which was accompanied by an impaired infiltration of αSMA-expressing cells within the tumors. In addition, a reduced CD11 + Ly6G + cell count in the liver was directly correlated with a reduction in MDSC numbers in the blood of AMD3100-treated mice compared to the vehicle-treated mice. Therefore, disruption of the CXCR4/CXCL12 axis by CXCR4 antagonist AMD3100 blocked the contribution of both cancer and stromal cells to the metastatic cascade in the liver.
Emerging targets in cancer management: role of the CXCL12/CXCR4 axis
OncoTargets and Therapy, 2013
The chemokine CXCL12 (SDF-1) and its cell surface receptor CXCR4 were first identified as regulators of lymphocyte trafficking to the bone marrow. Soon after, the CXCL12/CXCR4 axis was proposed to regulate the trafficking of breast cancer cells to sites of metastasis. More recently, it was established that CXCR4 plays a central role in cancer cell proliferation, invasion, and dissemination in the majority of malignant diseases. The stem cell concept of cancer has revolutionized the understanding of tumorigenesis and cancer treatment. A growing body of evidence indicates that a subset of cancer cells, referred to as cancer stem cells (CSCs), plays a critical role in tumor initiation, metastatic colonization, and resistance to therapy. Although the signals generated by the metastatic niche that regulate CSCs are not yet fully understood, accumulating evidence suggests a key role of the CXCL12/CXCR4 axis. In this review we focus on physiological functions of the CXCL12/CXCR4 signaling pathway and its role in cancer and CSCs, and we discuss the potential for targeting this pathway in cancer management.
Experimental Cell Research, 2005
Colorectal cancer (CRC) is characterized by a distinct metastatic pattern resembling chemokine-induced leukocyte trafficking. This prompted us to investigate expression, signal transduction and specific functions of the chemokine receptor CXCR4 in CRC cells and metastases. Using RT-PCR analysis and Western blotting, we demonstrated CXCR4 and CXCL12 expression in CRC and CRC metastases. Cell differentiation increases CXCL12 mRNA levels. Moreover, CXCR4 and its ligand are inversely expressed in CRC cell lines with high CXCR4 and low or not detectable CXCL12 expression. CXCL12 activates ERK-1/2, SAPK/JNK kinases, Akt and matrix metalloproteinase-9. These CXCL12-induced signals mediate reorganization of the actin cytoskeleton resulting in increased cancer cell migration and invasion. Moreover, CXCL12 increases vascular endothelial growth factor (VEGF) expression and cell proliferation but has no effect on CRC apoptosis. Therefore, the CXCL12/CXCR4 system is an important mediator of invasion and metastasis of CXCR4 expressing CRC cells.
HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF- B
Carcinogenesis, 2006
CXCR4 is a chemokine receptor probably involved in the homing of metastatic breast cancer, and its expression is modulated by tumor environmental stimuli such as hepatocyte growth factor (HGF) and hypoxia. Here, we demonstrate that, depending on the stimulus, different transcription factors can cooperate in enhancing CXCR4 transcription in MCF-7 breast cancer cell line. In HGFtreated MCF-7 cells, the DNA binding of Ets1 activated by MAPK1/ERK1/2 transduction pathway as well as the DNA binding of NF-kB played a critical role in CXCR4 transcription and protein induction. Under HGF stimulation, the blockade of these transcription factors by dominant negatives and inhibitors prevented the expression of CXCR4 receptor, the activity of a gene reporter driven by CXCR4 promoter sequence and the chemoinvasion toward the CXCL12 ligand. NF-kB was activated also by hypoxia and contributed, with HIF-1, to the increase in CXCR4 expression. The results suggest that Ets1, specifically activated by HGF, might cooperate with NF-kB activity to enhance the invasive/metastatic phenotype of breast carcinoma cells.
HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kB
2007
CXCR4 is a chemokine receptor probably involved in the homing of metastatic breast cancer, and its expression is modulated by tumor environmental stimuli such as hepatocyte growth factor (HGF) and hypoxia. Here, we demonstrate that, depending on the stimulus, different transcription factors can cooperate in enhancing CXCR4 transcription in MCF-7 breast cancer cell line. In HGFtreated MCF-7 cells, the DNA binding of Ets1 activated by MAPK1/ERK1/2 transduction pathway as well as the DNA binding of NF-kB played a critical role in CXCR4 transcription and protein induction. Under HGF stimulation, the blockade of these transcription factors by dominant negatives and inhibitors prevented the expression of CXCR4 receptor, the activity of a gene reporter driven by CXCR4 promoter sequence and the chemoinvasion toward the CXCL12 ligand. NF-kB was activated also by hypoxia and contributed, with HIF-1, to the increase in CXCR4 expression. The results suggest that Ets1, specifically activated by HGF, might cooperate with NF-kB activity to enhance the invasive/metastatic phenotype of breast carcinoma cells.
Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4
British journal of cancer, 2006
In different tumour entities, expression of the chemokine receptor 4 (CXCR4) has been linked to tumour dissemination and poor prognosis. Therefore, we evaluated, if the expression of CXCR4 exerts similar effects in human hepatocellular carcinoma (HCC). Expression analysis and functional assays were performed in vitro to elucidate the impact of CXCL12 on human hepatoma cells lines. In addition, expression of CXCR4 was evaluated in 39 patients with HCC semiquantitatively and correlated with both, tumour and patients characteristics. Human HCC and hepatoma cell lines displayed variable intensities of CXCR4 expression. Loss of p53 function did not impact on CXCR4 expression. Exposure to CXCL12 mediated a perinuclear translocation of CXCR4 in Huh7/Hep3B cells and increased the invasive potential of Huh7 cells. In HCC patients, CXCR4 expression significantly correlated with progressed local tumours (T-status; P=0.006), lymphatic metastasis (N-status; P=0.005) and distant dissemination (M-...
The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis
Cancer and Metastasis Reviews, 2007
Tumor cells are known to adapt to and utilize existing physiological mechanisms to promote survival and metastasis. The role of the microenvironment in the establishment of a metastatic lesion has become increasingly important as several factors secreted by stromal cells regulate metastatic pattern in a variety of tumor types. Tumor cells interact with osteoblasts, osteoclasts and bone matrix to form a vicious cycle that is essential for successful metastases. Here we review the current concepts regarding the role of an important chemokine/chemokine receptor (SDF-1 or CXCL12/CXCR4) pathway in tumor development and metastasis. CXCL12 secretion by stromal cells is known to attract cancer cells via stimulation of the CXCR4 receptor that is up regulated by tumor cells. CXCL12/CXCR4 activation regulates the pattern of metastatic spread with organs expressing high levels of CXCL12 developing secondary tumors (i.e., the bone marrow compartment). CXCL12 has a wide range of effects in regards to tumor development but the primary role of CXCL12 appears to be the mobilization of hematopoietic stem cells and the establishment of the cancer stem-like cell niche where high levels of CXCL12 recruit a highly tumorigenic population of tumor cells and promotes cell survival, proliferation, angiogenesis, and metastasis. Keywords CXCL12/CXCR4 axis. Tumor cells. Chemokines 1 The chemokine system overview Chemokines are small pro-inflammatory chemoattractant cytokines that bind to G-protein-coupled seven-span transmembrane receptors that are major regulators of cellular trafficking. To date, the human chemokine system includes more than 50 chemokines that have the ability to induce directional chemotasis of cells towards a cytokine. Binding of chemokines to their receptors triggers activation of many downstream signaling pathways including non-receptor tyrosine kinases, MAPK or protein kinase C. Chemokines are classified by their structure into four subclasses based upon the number and position of conserved cysteines. CXC (known as α-chemokines), CC (β-chemokines) and CX 3 C chemokines all have four conserved cysteines, with either zero, one or three amino acids separating the first two cysteines [1]. Functionally, CXC chemokines containing an ELR motif promote angiogenesis, whereas CXC chemokine lacking this sequence are often anti-angiogenic [1]. Most chemokine receptors are able to bind with high affinity to multiple chemokine ligands (CXCR, CCR, XCR, and CX3CR). However, the ligands to which they bind are almost always restricted to a single subclass. Chemokine receptors are present on almost all cell types examined, but were initially identified on leukocytes, where they are to known play a major role in the inflammatory process [2, 3]. Exciting work in cancer biology has extended our understanding of the function of chemokines beyond their role in inflammation. Several chemokines have been implicated as having a critical role in the establishment and progression of a number of malignancies by serving in autocrine or paracrine functions. Moreover, chemokine secretion by tumor cells themselves is known to regulate angiogenesis and, secondarily, tumor growth and metastasis. In addition, there is strong evidence to suggest that chemokines and their receptors mediate the expression of MMPs needed for tumor cell invasion through the