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Analysis of circulating tumor cells in colorectal cancer liver metastasis patients before and after cryosurgery.

ABSTRACT: In this study, we determined the number of peripheral blood circulating tumor cells (CTCs) pre- and post-cryosurgery in patients with colorectal cancer liver metastasis as a reference for understanding the relevance of any changes to the efficacy of cryosurgery. CTC numbers and CTC-related gene expression were measured in the peripheral blood of 55 patients with colorectal liver metastasis at 1 day before and 7 and 30 d after cryoablation using magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) combined with real-time quantitative PCR (RT-qPCR). The number of CTCs decreased significantly with postoperative time (P < 0.01). Delta cycle threshold values for the CTC-related genes CEA, Ep-CAM, CK18 and CK19 increased significantly after cryoablation. Furthermore, the expression of CEA, Ep-CAM, CK18 and CK19 decreased significantly with time after cryoablation (P < 0.01). RT-qPCR and FACS combined with MACS has significant diagnostic and prognostic value for evaluating the efficacy of cryosurgery in patients with advanced colorectal cancer.

SUBMITTER: Shi J

PROVIDER: S-EPMC5036405 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Analysis of circulating tumor cells in colorectal cancer liver metastasis patients before and after cryosurgery.

Shi Jian J Li Yuan Y Liang Shuzhen S Zeng Jianying J Liu Guifeng G Mu Feng F Li Haibo H Chen Jibing J Liu Tongjun T Niu Lizhi L

Cancer biology & therapy 20160714 9

In this study, we determined the number of peripheral blood circulating tumor cells (CTCs) pre- and post-cryosurgery in patients with colorectal cancer liver metastasis as a reference for understanding the relevance of any changes to the efficacy of cryosurgery. CTC numbers and CTC-related gene expression were measured in the peripheral blood of 55 patients with colorectal liver metastasis at 1 day before and 7 and 30 d after cryoablation using magnetic activated cell sorting (MACS) and fluoresc ...[more]

PMID: 27415969

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Project description:The genome?wide copy number analysis of circulating tumor cells (CTCs) provides a promising prognostic biomarker for survival in breast cancer liver metastasis (BCLM) patients. The present study aimed to confirm the prognostic value of the presence of CTCs in BCLM patients. We previously developed an assay for the genome?wide pattern differences in copy number variations (CNVs) as an adjunct test for the routine imaging and histopathologic diagnosis methods to distinguish newly diagnosed liver metastases and recurrent liver metastases. Forty?three breast cancer patients were selected for this study in which 23 newly diagnosed and 20 recurrent liver metastases were diagnosed by histopathology and 18F?FDG PET/CT imaging. CTCs were counted from all patients using the CellSearch system and were confirmed by cytomorphology and three?color immunocytochemistry. Genomic DNA of single CTCs was amplified using multiple annealing and looping based amplification cycles (MALBAC). Then, we compared the CTC numbers of newly diagnosed and recurrent BCLM patients using Illumina platforms. A high CTC frequency (>15 CTCs/7.5 ml blood) was found to be correlated with disease severity and metastatic progression, which suggests the value for CTCs in the diagnosis of BCLM in comparison with pathohistology and PET/CT imaging (P>0.05). Moreover, CTCs isolated from BCLM patients remained an independent prognostic detection factor associated with overall survival (P=0.0041). Comparison between newly diagnosed and recurrent liver metastases revealed different frequencies of CNVs (P>0.05). Notably, the CNV pattern of isolated CTCs of recurrent BCLM patients was similar to recurrent liver metastases (nearly 82% of the gain/loss regions). Functional enrichment analysis identified 25 genes as a CNV signature of BCLM. Among them, were defensin and ??defensin genes, which are significantly associated with anti?angiogenesis and immunomodulation signaling pathways. High CTC frequencies are effective in the evaluation and differentiation between newly diagnosed liver metastases from recurrent liver metastases. Future clinical studies will be necessary to fully determine the prognostic potential of CTC cluster signatures in patients with BCLM.

Project description:BackgroundTumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear.MethodsImmunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial-mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients' prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis.ResultsClinically, CD163+ TAMs infiltrated in invasive front was associated with EMT, mesenchymal CTC ratio, and poor prognosis in patients with CRC. CRC-conditioned macrophages regulated EMT program to enhance CRC cells migration and invasion by secreting IL6. TAMs-derived IL6 activated the JAK2/STAT3 pathway, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-506-3p in CRC cells. miR-506-3p, a key miRNA regulating FoxQ1, was downregulated in CRC cells, resulting in increased FoxQ1 expression, which in turn led to the production of CCL2 that promoted macrophage recruitment. Inhibition of CCL2 or IL6 broke this loop and reduced macrophage migration and mesenchymal CTC-mediated metastasis, respectively.ConclusionsOur data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment.

Dataset Information

Analysis of circulating tumor cells in colorectal cancer liver metastasis patients before and after cryosurgery.

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Analysis of circulating tumor cells in colorectal cancer liver metastasis patients before and after cryosurgery.

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