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Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.

ABSTRACT: PURPOSE:Chemokines are involved in cancer-related inflammation and malignant progression. In this study, we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas. EXPERIMENTAL DESIGN:We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8-positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitro for cytokine production and ability to modulate T-cell function. RESULTS:We show that monocytic and granulocytic myeloid cell subsets in peripheral blood of patients with cancer with urothelial and renal carcinomas display increased expression of chemokine receptor CCR8. Upregulated expression of CCR8 is also detected within human cancer tissues and primarily limited to tumor-associated macrophages. When isolated, CD11b(+)CCR8(+) cell subset produces the highest levels of proinflammatory and proangiogenic factors among intratumoral CD11b myeloid cells. Tumor-infiltrating CD11b(+)CCR8(+) cells selectively display activated Stat3 and are capable of inducing FoxP3 expression in autologous T lymphocytes. Primary human tumors produce substantial amounts of the natural CCR8 ligand CCL1. CONCLUSIONS:This study provides the first evidence that CCR8(+) myeloid cell subset is expanded in patients with cancer. Elevated secretion of CCL1 by tumors and increased presence of CCR8(+) myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion. Obtained results also implicate that blockade of CCR8 signals may provide an attractive strategy for therapeutic intervention in human urothelial and renal cancers.

SUBMITTER: Eruslanov E

PROVIDER: S-EPMC3618575 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.

Eruslanov Evgeniy E Stoffs Taryn T Kim Wan-Ju WJ Daurkin Irina I Gilbert Scott M SM Su Li-Ming LM Vieweg Johannes J Daaka Yehia Y Kusmartsev Sergei S

Clinical cancer research : an official journal of the American Association for Cancer Research 20130130 7

<h4>Purpose</h4>Chemokines are involved in cancer-related inflammation and malignant progression. In this study, we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas.<h4>Experimental design</h4>We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8-positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitr ...[more]

PMID: 23363815

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Project description:BackgroundUpper tract urothelial carcinomas (UT-UC) can invade the pelvicalyceal system making differential diagnosis of the various histologically distinct renal cell carcinoma (RCC) subtypes and UT-UC, difficult. Correct diagnosis is critical for determining appropriate surgery and post-surgical treatments. We aimed to identify microRNA (miRNA) signatures that can accurately distinguish the most prevalent RCC subtypes and UT-UC form the normal kidney.Methods and findingsmiRNA profiling was performed on FFPE tissue sections from RCC and UT-UC and normal kidney and 434 miRNAs were significantly deregulated in cancerous vs. the normal tissue. Hierarchical clustering distinguished UT-UCs from RCCs and classified the various RCC subtypes among them. qRT-PCR validated the deregulated expression profile for the majority of the miRNAs and ROC analysis revealed their capability to discriminate between tumour and normal kidney. An independent cohort of freshly frozen RCC and UT-UC samples was used to validate the deregulated miRNAs with the best discriminatory ability (AUC>0.8, p<0.001). Many of them were located within cytogenetic regions that were previously reported to be significantly aberrated. miRNA targets were predicted using the miRWalk algorithm and ingenuity pathway analysis identified the canonical pathways and curated networks of the deregulated miRNAs. Using the miRWalk algorithm, we further identified the top anti-correlated mRNA/miRNA pairs, between the deregulated miRNAs from our study and the top co-deregulated mRNAs among 5 independent ccRCC GEO datasets. The AB8/13 undifferentiated podocyte cells were used for functional assays using luciferase reporter constructs and the developmental transcription factor TFCP2L1 was proved to be a true target of miR-489, which was the second most upregulated miRNA in ccRCC.ConclusionsWe identified novel miRNAs specific for each RCC subtype and UT-UC, we investigated their putative targets, the networks and pathways in which they participate and we functionally verified the true targets of the top deregulated miRNAs.

Dataset Information

Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.

Publications

Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.

Similar Datasets

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