期刊
EMBO MOLECULAR MEDICINE
卷 4, 期 11, 页码 1156-1175出版社
WILEY
DOI: 10.1002/emmm.201101164
关键词
angiopoietin-like 6; E-cadherin; metastatic colorectal cancer; microenvironment; alpha(6) integrin
资金
- Italian Federation for Cancer Research (FIRC)
- Italian Association for Cancer Research - My First AIRC Grant (AIRC-MFAG)
- Banca d'Alba
- Piedmont Region
- Piedmont Foundation for Cancer Research (FPRC) [5x1000 2008]
- AIRC
- European Union [LSHM-CT-2003-503254]
- Piedmont Region (Converging Technologies, grant PHOENICS)
- Piedmont Region (Industrial Research, grant BANP)
- Cassa di Risparmio di Torino (CRT) Foundation
- Italian Ministry of Health [RBAP11BYNP-Newton]
- Italian Ministry of University and Research (FIRB) [RBRN07BMCT]
- US National Cancer Institute
- Department of Defense
Homing of colorectal cancer (CRC) cells to the liver is a non-random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis-specific peptide ligand (CGIYRLRSC) that binds a complex of E-cadherin and alpha(6) integrin on the surface of CRC cells. We identify angiopoietin-like 6 protein as a peptide-mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin-like 6 and tumoural alpha(6) integrin/E-cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed alpha(6) integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC.
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