A complex of α6 integrin and E-cadherin drives liver metastasis of colorectal cancer cells through hepatic angiopoietin-like 6.
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 α(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 α(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 α(6) integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC.
Department of Oncology, University of Turin, Candiolo, Italy. serena.marchio@ircc.it
Serena
S
Marchiò
Marco
M
Soster
Sabrina
S
Cardaci
Andrea
A
Muratore
Alice
A
Bartolini
Vanessa
V
Barone
Dario
D
Ribero
Maria
M
Monti
Paola
P
Bovino
Jessica
J
Sun
Raffaella
R
Giavazzi
Sofia
S
Asioli
Paola
P
Cassoni
Lorenzo
L
Capussotti
Piero
P
Pucci
Antonella
A
Bugatti
Marco
M
Rusnati
Renata
R
Pasqualini
Wadih
W
Arap
Federico
F
Bussolino
D020816:Amino Acid Motifs; D000091308:Angiopoietin-Like Protein 6; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D039503:Integrin alpha6 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000098:blood supply / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011485:Protein Binding
C477601:ANGPTL6 protein, human; D000091308:Angiopoietin-Like Protein 6; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D015820:Cadherins; D039503:Integrin alpha6