Focus on the role of the CXCL12/CXCR4 chemokine axis in head and neck squamous cell carcinoma (original) (raw)
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European Archives of Oto-Rhino-Laryngology, 2016
Expression of the CXCL12/CXCR4 chemokine axis has been related with the appearance of metastatic recurrence survival, including regional and distant recurrence, in patients with head and neck squamous cell carcinoma (HNSCC). RT-PCR was used to determine mRNA expression levels of CXCL12 and CXCR4 in biopsy tumor samples in 111 patients with HNSCC. Five-year regional recurrence-free survival for patients with low CXCR4 expression (n = 39, 31.5 %) was 97.4 %, for patients with high CXCR4/high CXCL12 expression (n = 22, 19.8 %) it was 94.7 %, and for patients with high CXCR4/low CXCL12 expression (n = 50, 45.0 %) it was 63.3 %. We found significant differences in the regional recurrence-free survival according to CXCR4/CXCL12 expression values (P = 0.001). HNSCC patients with high CXCR4 and low CXCL12 expression values had a significantly higher risk of regional recurrence and could benefit from a more intense treatment of lymph node areas in the neck. Keywords CXCL12 Á CXCR4 Á Regional recurrence Á Biomarker Á Head and neck squamous cell carcinoma Electronic supplementary material The online version of this article (
Oncogenesis, 2016
Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), has been successfully used to treat some patients with colorectal cancer and those with head and neck squamous cell carcinoma (HNSCC). For the effective treatment, it is essential to first identify cetuximab-responsive patients. The level of EGFR expression and/or the presence of mutations in signalling molecules downstream of the EGFR pathway have been reported to be determining factors for cetuximab responsiveness in colorectal cancer patients; however, limited data have been reported for HNSCC patients. We previously reported that the chemokine CXCL14 exhibits tumour-suppressive effects against xenografted HNSCC cells, which may be classified into two groups, CXCL14-expressing and non-expressing cells under serum-starved culture conditions. Here we employed CXCL14-expressing HSC-3 cells and CXCL14-non-expressing YCU-H891 cells as representatives of the two groups and compared their responses to ...
The role of CXCR2 chemokine receptors in the oral squamous cell carcinoma
Investigational New Drugs, 2012
This study evaluated the relevance of CXCR2 chemokine receptors in oral squamous cell carcinoma, by means of in vitro and in vivo approaches. The in vitro incubation of the selective and non-peptide CXCR2 receptor antagonist N-(2-hydroxy-4-nitrophenyl)-N9-(2bromophenyl) Urea (SB225002; 25 to 800 nM) produced a time-and concentration-dependent inhibition of SCC158 (rat) and HN30 (human) cell lines viability. Conversely, this antagonist did not significantly affect the viability of the immortalized keratinocyte lineage, HaCaT. Additionally, the incubation of human IL-8 and rat CINC-1 CXCR2 agonists produced a concentration-related increase on HN30 and SCC158 proliferation. The submucosal injection of SCC158 cells (5×10 6 cells) into the tongue of Fischer 344 rats induced tumor development, which displayed typical clinical features. Immunohistochemical analysis of rat tongue biopsies revealed a marked increase of CXCR2 receptor immunoreactivity, which was accompanied by augumented expression of VEGF and caspase-3. Our data suggests an important role for CXCR2 receptors in oral squamous cell carcinoma.
ISRN otolaryngology, 2012
In order to find a suppressor(s) of tumor progression in vivo for head and neck squamous cell carcinoma (HNSCC), we searched for molecules downregulated in HNSCC cells when the cells were treated with epidermal growth factor (EGF), whose receptor is frequently overactivated in HNSCC. The expression of BRAK, which is also known as CXC chemokine ligand 14 (CXCL14), was downregulated significantly by the treatment of HNSCC cells with EGF as observed by cDNA microarray analysis followed by reverse-transcriptase polymerase chain reaction analysis and western blotting. The EGF effect on the expression of CXCL14/BRAK was attenuated by the copresence of inhibitors of the EGF receptor, MEK, and ERK. The rate of tumor formation in vivo of BRAK-expressing vector-transfected tumor cells in athymic nude mice or SCID mice was significantly lower than that of mock vector-transfected ones. In addition tumors formed in vivo by the BRAK-expressing cells were significantly smaller than those of the mo...
Asian Pacific journal of cancer prevention : APJCP, 2017
Background: Squamous cell carcinomas (SCCs) are common head and neck malignancies demonstrating lymph node LN involvement. Recently chemokine receptor overxpression has been reported in many cancers. Of particular interest, CCR7 appears to be a strong mediator of LN metastases, while CXCR4 may mediate distant metastases. Any relations between their expression in primary HNSCCs and metastatic lymph nodes need to be clarified. Aims: To investigate CCR7 andCXCR4 expression in primary HNSCCs of all tumor sizes, clinical stages and histological grades, as well as involved lymph nodes, then make comparisons, also with control normal oral epithelium. Materials and Methods: The sample consisted of 60 formalin-fixed, paraffin-embedded specimens of primary HNSCCs, 77 others of metastasi-positive lymph nodes, and 10 of control normal oral epithelial tissues. Sections were conventionally stained with H&E and immunohistochemically with monoclonal anti-CCR7 and monoclonal anti-CXCR4 antibodies. P...
The Role of the CXCL12/CXCR4/ CXCR7 Chemokine Axis in Cancer
Frontiers in Pharmacology, 2020
Chemokines are a family of small, secreted cytokines which regulate a variety of cell functions. The C-X-C motif chemokine ligand 12 (CXCL12) binds to C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine receptor type 7 (CXCR7). The interaction of CXCL12 and its receptors subsequently induces downstream signaling pathways with broad effects on chemotaxis, cell proliferation, migration, and gene expression. Accumulating evidence suggests that the CXCL12/CXCR4/CXCR7 axis plays a pivotal role in tumor development, survival, angiogenesis, metastasis, and tumor microenvironment. In addition, this chemokine axis promotes chemoresistance in cancer therapy via complex crosstalk with other pathways. Multiple small molecules targeting CXCR4/CXCR7 have been developed and used for preclinical and clinical cancer treatment. In this review, we describe the roles of the CXCL12/CXCR4/CXCR7 axis in cancer progression and summarize strategies to develop novel targeted cancer therapies.
CXCR4-CXCL12 axis and distant metastatic outgrowth in head and neck malignancy
2020
Background: To analyze whether distant metastatic outgrowth in different head and neck malignancies (HNM) underlies the CXCR4-CXCL12 axis as overriding molecular mechanism. Methods: Clinic-pathological data of 1,250 HNM was included. HNM were collected due to different capability to exhibit distant metastasis comprising basal cell, squamous cell, and adenoid-cystic carcinoma as well as melanoma. MMP2/9, TIMP1/2, CXCR4, and CXCL12 immunohistochemistry was done in 190 randomly selected specimens.Results: Immunohistochemistry visualized a significant increase in MMP2/9, TIMP1/2, CXCR4, and CXCL12 protein expression following the clinical occurrence of distant metastasis. CXCR4, CXCL12, and TIMP2-expression significantly increases with number of affected organs by distant metastasis. Cox regression demonstrated CXCR4-overexpression and advanced T-status being independent risk factors of distant metastasis associated death.Conclusion: The CXCR4-CXCL12 axis is associated with the occurren...
Chemokine CXCL14 is a multistep tumor suppressor
Journal of Oral Biosciences, 2016
Background The multistep nature of cancer that involves carcinogenesis, an increase in tumor size, and invasion and/or metastasis is well recognized. These respective steps depend on the 2 mutation of several genes, epigenetic changes in cells, and interactions between cancer cells and other cells in the microenvironment. To identify novel intercellular tumor suppressors, we screened for genes whose expression was down-regulated in oral cancer cells. Highlight The chemokine, CXCL14, was down-regulated in oral carcinoma cells, and its up-regulation suppressed tumor cell growth in vivo, indicating that CXCL14 is a tumor growth suppressor. Moreover, to investigate whether CXCL14 suppresses tumors originating from the other cells in a paracrine or endocrine fashion, we generated CXCL14 transgenic (Tg) mice. The Tg mice exhibited a suppressed rate of carcinogenesis, decreased volume of transplanted tumors, and reduced pulmonary metastasis, as well as an increased survival rate following tumor cell injection, compared with wild-type mice. The CXCL14-expressing Tg mice showed no apparent abnormality when observed up to 2 years of age, and, interestingly, in a normal human population an individual was found to have a blood level of CXCL14 protein 10-fold 3 higher than the average but did not present any apparent abnormalities. Conclusion These data indicate that CXCL14 expressed at high levels does not have severe side effects, and, thus, we propose CXCL14 as a promising molecular target for cancer suppression/prevention.
CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression
Cancer and Metastasis Reviews, 2010
Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein coupled seven-span transmembrane receptors (GPCRs), are major regulators of cell trafficking and adhesion. The chemokine CXCL12 [also called stromal-derived factor-1 (SDF-1)] is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years it was believed that CXCR4 was the only receptor for CXCL12. Yet recent work has demonstrated that CXCL12 also binds to another seventransmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here we review the current concepts regarding the role of CXCL12/CXCR4/CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.