Chemokine <scp>C</scp>‐<scp>C</scp> motif receptor 5 and <scp>C</scp>‐<scp>C</scp> motif ligand 5 promote cancer cell migration under hypoxia

Lin, Sensen; Wan, Suigui; Sun, Li; Hu, Jialiang; Fang, Dongdong; Zhao, Renping; Yuan, Shengtao; Zhang, Luyong

doi:10.1111/j.1349-7006.2012.02259.x

Cited by 83 publications

(77 citation statements)

References 29 publications

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“…The study reported that mice expressing CCR5 exhibited enhanced local tumor growth and an impaired response to vaccine therapy compared with CCR5-knockout mice. Lin et al (29) reported that CCR5 and CCL5 were highly expressed in breast cancer lymph node metastasis, and that CCR5-CCL5 interaction promotes cancer cell migration under hypoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

Expression of CC chemokine receptor 5 in clear cell renal cell carcinoma and its clinical significance

et al. 2015

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Abstract. DNA hypomethylation was the initial epigenetic abnormality recognized in human malignancy. In the present study, the GoldenGate high-throughput genotyping assay was adapted to determine the methylation state of 1,505 specific CpG sites in 807 cancer-related genes. The methylation results revealed that CC chemokine receptor 5 (CCR5) was hypomethylated (mean β-value difference, -0.21) in clear cell renal cell carcinoma (CCRCC) tissue. Tissue samples from 61 CCRCC cases were used for immunohistochemical staining, and patients with low CCR5 expression (n=44) were compared with those with high CCR5 expression (n=17). Tumor (T) stage was significantly lower in the low expression group compared with the high expression group (P=0.047). The Fuhrman grade of patients in the low expression group was significantly lower than that of patients in the high expression group (P=0.044). Whilst the node (N) and metastasis (M) stages of the CCR5 low expression group appeared to be lower compared with those of the CCR5 high expression group; this difference was not statistically significant (N stage, P=0.632; M stage, P=0.896). Additionally, patients in the low expression group had lower risks of postoperative tumor recurrence (P=0.110) and mortality from CCRCC (P=0.159) compared with those in the high expression group, however, this was also without statistical significance. The results indicate that CCR5 hypomethylation is associated with cancer tissue to a greater extent than normal tissue. Although the biological function of CCR5 in CCRCC remains to be established, low CCR5 expression is associated with low T stage and low Fuhrman grade in these patients.

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Section: Discussionmentioning

confidence: 99%

Expression of CC chemokine receptor 5 in clear cell renal cell carcinoma and its clinical significance

et al. 2015

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confidence: 99%

“…3 Overexpression of CCR5 increases cell migration, and knockdown of CCR5 attenuates hypoxia-mediated cell migration. 4 A mutant allele of CCR5, CCR5del32, is frequently found in populations of northern European origin and encodes a nonfunctional truncated protein that is not transported to the cell surface. 5 The 32-bp deletion results in a frameshift, whereby the CCR5delta32 allele encodes for a protein with a transdominant negative effect on the wildtype protein.…”

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confidence: 99%

Improved metastasis-free survival in nonadjuvantly treated postmenopausal breast cancer patients with chemokine receptor 5 del32 frameshift mutations

et al. 2014

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The CC-chemokine receptor CCR5 has been associated with cancer progression and metastasis. CCR5 blockers such as Maraviroc are tested in metastatic cancer patients. A mutant allele of CCR5, CCR5-delta32 (CCR5del32), which encodes for a protein with a trans-dominant negative effect on the wildtype protein, is frequently found in populations of northern European origin. We set out to determine if the CCR5del32 genotype is associated with progression of breast cancer. Here, we genotyped 414 breast cancer patients and investigated whether the CCR5 genotype had an association with the likelihood to metastasize within specific subgroups of this cohort. The findings were subsequently confirmed in an independent cohort of 1,017 breast cancer patients. Specifically within the postmenopausal subgroup of the initial cohort (n 5 325) individuals carrying the CCR5del32 genotype exhibited a significantly longer metastasis-free survival (MFS, p 5 0.038). In an independent cohort, CCR5del32 genotype was confirmed to be associated with prolonged MFS only in postmenopausal patients (n 5 579, hazard ratio [HR] 5 0.61, 95% confidence interval [95% CI] 5 0.38-0.99, p 5 0.044), and not in premenopausal patients (n 5 438, HR 5 1.01, 95% CI 5 0.70-1.48, p 5 0.94). Our results indicate that CCR5del32 genotype is associated with good prognosis in postmenopausal breast cancer patients. Considering this result, postmenopausal breast cancer patients who are wildtype for CCR5 genotype might benefit from CCR5 blockers, such as Maraviroc.Despite the improved treatment modalities for early breast cancer, a significant proportion of patients experience disease relapse and ultimately die of metastastic disease owing to intrinsic or acquired resistance to systemic treatment. 1 Adjuvant systemic treatment for early breast cancer consists of chemotherapy, whereas targeted options consist of endocrine treatment in case of estrogen receptor (ER)/progesterone receptor (PR) expression and trastuzumab in case of HER2 overexpression in the primary tumor. Adjuvant systemic treatment decisions are currently further guided by clinical characteristics such as tumor size, differentiation grade and axillary lymph node involvement, which may be supported by multigene tests such as OncoTypeDX, MammaPrint and PAM50. 2 Although these clinical characteristics and gene tests allow for the identification of specific risk groups, they do not necessarily predict adjuvant treatment efficacy. New biomarkers with prognostic potential are therefore highly sought after to delineate which patients should be preferentially treated or not, whereas at the same time identifying new targets for therapy.The CC-chemokine receptor CCR5 and its ligands (CCL5 [RANTES], MIP-1a and MIP-1b) have been reported to be associated with cancer progression and metastasis. 3 Overexpression of CCR5 increases cell migration, and knockdown of CCR5 attenuates hypoxia-mediated cell migration. 4 A mutant allele of CCR5, CCR5del32, is frequently found in populations of northern European origin and encod...

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“…The results revealed that although ER stress upregulated intracellular CCL5 expression, it inhibited CCL5 secretion of MCF-7 cells. According to studies of Wang et al (10) and Lin et al (28), CCL5 promotes tumour cell motility and migration by interacting with a specific receptor chemokine C-C motif receptor 5 (CCR5). Thus, we assume that it is the extracellular CCL5 in the microenvironment of tumour cells that actually stimulates the migration, while the intracellular expression level of CCL5 does not affect the migration ability of cancer cells directly.…”

Section: Discussionmentioning

confidence: 99%

Tunicamycin-induced ER stress regulates chemokine CCL5 expression and secretion via STAT3 followed by decreased transmigration of MCF-7 breast cancer cells

et al. 2014

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Abstract. Chemokine C-C motif ligand 5 (CCL5) is an important marker related to the progression of breast cancer and is upregulated in cancer cells. However, the mechanism of the overexpression of CCL5 in tumours has not yet been clarified. The present study aimed to investigate the role of endoplasmic reticulum (ER) stress in regulating CCL5 expression and its relationship with signal transducer and activator of transcription 3 (STAT3). Meanwhile, the effect of tunicamycin, a classical ER stress inducer, and CCL5 on the transmigration of human breast cancer MCF-7 cells was observed and analysed. Compared with the normal breast epithelial tissues, expression levels of CCL5, STAT3 and CHOP, an indicator of ER stress, were significantly upregulated in breast cancer tissues. In human breast cancer MCF-7 cells, ER stress activator tunicamycin increased the expression of CCL5, STAT3 and CHOP in a time-and concentration-dependent manner. Moreover, tunicamycin-induced CCL5 expression was positively related to upregulation of unphosphorylated STAT3 (U-STAT3) but negatively related to STAT3 phosphorylation at the Tyr705 site. Furthermore, ER stress inhibited CCL5 secretion and transmigration of MCF-7 cells. This study also showed that extracellular rhCCL5 induced transmigration of MCF-7 cells which was partially blocked by the CCR5 monoclonal antibody, while knockdown of endogenous expression of CCL5 did not affect the transmigration of the cells. In conclusion, ER stress induced endogenous expression of CCL5 via elevating U-STAT3 expression; however, ER stress inhibited CCL5 secretion, which in turn, decreased the transmigration of breast cancer MCF-7 cells.

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Chemokine C‐C motif receptor 5 and C‐C motif ligand 5 promote cancer cell migration under hypoxia

Cited by 83 publications

References 29 publications

Expression of CC chemokine receptor 5 in clear cell renal cell carcinoma and its clinical significance

Expression of CC chemokine receptor 5 in clear cell renal cell carcinoma and its clinical significance

Improved metastasis-free survival in nonadjuvantly treated postmenopausal breast cancer patients with chemokine receptor 5 del32 frameshift mutations

Tunicamycin-induced ER stress regulates chemokine CCL5 expression and secretion via STAT3 followed by decreased transmigration of MCF-7 breast cancer cells

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