Regulated Expression of CCL21 in the Prostate Tumor Microenvironment Inhibits Tumor Growth and Metastasis in an Orthotopic Model of Prostate Cancer

Yousefieh, Nazita; Hahto, Suzanne M.; Stephens, Amber L.; Ciavarra, Richard P.

doi:10.1007/s12307-009-0021-z

Cited by 21 publications

(23 citation statements)

References 27 publications

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“…Besides, CCL21 plays roles in the regulation of ERK pathway in human non-small cell lung cancer cells (26). CCL21 is downregulated in many cancers and associated with lymph node metastasis, poor prognosis (27), apoptosis (26), cell cycle (28) and tumor growth (29). SPARCL1 belongs to SPARC family that contains ten protein members (30).…”

Section: Resultsmentioning

confidence: 99%

Bioinformatic analysis of chemokine (C-C motif) ligand 21 and SPARC-like protein 1 revealing their associations with drug resistance in ovarian cancer

Yin

Liu

et al. 2013

International Journal of Oncology

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Chemokine (C-C motif) ligand 21 (CCL21) and SPARC-like protein 1 (SPARCL1/MAST9/hevin/SC-1) are associated with various biological behavior in the development of cancers. Although the expression of CCL21 and SPARCL1 is downregulated in many solid tumors, their roles in ovarian cancer and their associations with drug resistance have rarely been studied. We performed a comprehensive bioinformatic analysis consisting of motif analysis, literature co-occurrence, gene/protein-gene/protein interaction network, protein-small molecule interaction network, and microRNAs enrichments which revealed that CCL21 and SPARCL1 directly or indirectly interact with a number of genes, proteins, small molecules and pathways associated with drug resistance in ovarian and other cancers. These results suggested that CCL21 and SPARCL1 may contribute to drug resistance in ovarian cancer. This study provided important information for further investigation of drug resistance-related functions of CCL21 and SPARCL1 in ovarian cancer.

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Section: Resultsmentioning

confidence: 99%

Bioinformatic analysis of chemokine (C-C motif) ligand 21 and SPARC-like protein 1 revealing their associations with drug resistance in ovarian cancer

Yin

Liu

et al. 2013

International Journal of Oncology

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“…Furthermore, aberrantly increased CCR7 expression has been reported in breast (18,25), gastric (22,26,27), colorectal (28–30), non-small cell lung (31,32), cervical (33), SCC of the head and neck (34), prostate (35,36), melanoma (37) and esophageal, oral and oropharyngeal SCC cancer (38–41) and is generally associated with lymph node metastasis and worse prognosis. In addition, a previous study conducted at our institution in which the CCR7 expression levels in 115 patients with UBC and 10 patients with benign prostatic hyperplasia (BPH) were compared found a significantly higher frequency of detectable CCR7 expression in the UBC group than in the BPH group and the clinical feasibility of CCR7 expression level as an independent predictive biomarker in the diagnosis of lymph node metastasis (42).…”

Section: Discussionmentioning

confidence: 99%

CCL21/CCR7 interaction promotes cellular migration and invasion via modulation of the MEK/ERK1/2 signaling pathway and correlates with lymphatic metastatic spread and poor prognosis in urinary bladder cancer

Xiong

Huang

et al. 2017

International Journal of Oncology

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Lymph node metastasis in patients with urinary bladder cancer (UBC) is always associated with poor prognosis and is the determinant for tumor staging and the development of treatment regimens; however, its underlying mechanisms remain to be studied. Immunohistochemical staining of tumor sections from 62 UBC patients was performed using CCR7, D2-40 and CD34 antibodies. We showed that increased CCR7 expression was significantly associated with positive lymph node status (P=0.008), pT3-T4 tumor stage (P=0.015), tumor grade (P=0.010) and worse overall survival (OS, P<0.001) and that both CCR7 expression and lymph node metastasis were independent prognostic factors for OS (P=0.031 and P=0.001, respectively) based on multivariate analysis. We found that there was a significant association between MLVD and lymph node status (P=0.006), but this relation was not observed for MVD. Furthermore, we showed that increased CCR7 expression correlated significantly with higher MLVD (P=0.014) and MVD (P=0.002). Wound-healing and Matrigel Transwell assays indicated that activation of CCR7 with CCL21 significantly enhanced the invasion and migration abilities of UM-UC-3 cells, and this enhanced effect was significantly abrogated by CCR7 knockdown using siRNA. Western blot analysis revealed that the phospho-ERK1/2 level was markedly increased when UM-UC-3 cells were treated with CCL21 and significantly decreased when the CCR7 gene was silenced. MEK/ERK1/2 inhibition with PD98059 significantly suppressed the migration and invasion abilities of UM-UC-3 cells and also significantly abrogated the effects of CCL21/CCR7 on cell migration and invasion. Based on these results, we conclude that activation of the CCL21/CCR7 chemoaxis promotes lymph node metastasis of UBC in at least two ways. Firstly, although CCR7 is a promoting factor that induces both lymphangiogenesis and angiogenesis, it may promote lymph node metastasis through its lymphangiogenic effect rather than through its angiogenic effect. Secondly, the CCL21/CCR7 chemoaxis promotes the migration and invasion of UBC cells via the MEK/ERK1/2 signaling pathway rather than the PI3K/AKT pathway.

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“…Interestingly, expression of CCL19 and CCL21 induces tumor regression in different mouse models (14,15,30,31). Moreover, stronger expression of VCAM-1 and Mad-CAM-1 has been associated to increased survival in colorectal carcinoma (32).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Chemokines and Adhesion Molecules Associated with T cell Presence in Tertiary Lymphoid Structures in Human Lung Cancer

et al. 2011

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De novo formation of tertiary lymphoid structures (TLS) has been described in lung cancers. Intratumoral TLS seem to be functional and are associated with a long-term survival for lung cancer patients, suggesting that they represent an activation site for tumor-specific T cells. Here, we characterized T-cell recruitment to TLS in human lung cancer to identify the adhesion molecules and chemoattractants orchestrating this migration. We found that most TLS T cells were CD62Lþ and mainly of CD4þ memory phenotype, but naive T cells were highly enriched in these structures as compared with the rest of the tumor. A specific gene expression signature associated with T cell presence was identified in TLS, which included chemokines (CCL19, CCL21, CXCL13, CCL17, CCL22, and IL16), adhesion molecules (ICAM-2, ICAM-3, VCAM-1, and MAdCAM-1) and integrins (alphaL, alpha4, and alphaD). The presence of the corresponding receptors on TLS T cells was confirmed. Intratumoral PNAdþ high endothelial venules also were exclusively associated with TLS and colocalized with CD62Lþ lymphocytes. Together, these data bring new insights into the T-cell recruitment to intratumoral TLS and suggest that blood T cell enter into TLS via high endothelial venules, which represent a new gateway for T cells to the tumor. Findings identify the molecules that mediate migration of tumor-specific T cells into TLS where T cell priming occurs, suggesting new strategies to enhance the efficacy of cancer immunotherapies.

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Regulated Expression of CCL21 in the Prostate Tumor Microenvironment Inhibits Tumor Growth and Metastasis in an Orthotopic Model of Prostate Cancer

Cited by 21 publications

References 27 publications

Bioinformatic analysis of chemokine (C-C motif) ligand 21 and SPARC-like protein 1 revealing their associations with drug resistance in ovarian cancer

Bioinformatic analysis of chemokine (C-C motif) ligand 21 and SPARC-like protein 1 revealing their associations with drug resistance in ovarian cancer

CCL21/CCR7 interaction promotes cellular migration and invasion via modulation of the MEK/ERK1/2 signaling pathway and correlates with lymphatic metastatic spread and poor prognosis in urinary bladder cancer

Characterization of Chemokines and Adhesion Molecules Associated with T cell Presence in Tertiary Lymphoid Structures in Human Lung Cancer

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