Role of the integrin-binding protein osteopontin in lymphatic metastasis of breast cancer.
Although a primary route of breast cancer metastasis is believed to be via lymphatics, the molecular factors involved are poorly understood. We hypothesized that one such factor may be the integrin-binding protein osteopontin (OPN), and we investigated this clinically and experimentally. In breast cancer patients undergoing sentinel lymph node biopsy, OPN levels were significantly higher in lymph node metastases than in the primary tumor (P < 0.001). To test the functional contribution of OPN to lymphatic metastasis and to determine whether the RGD (Arg-Gly-Asp) integrin-binding sequence of OPN is important for this process, we transfected wild-type OPN or mutant OPN (lacking the RGD sequence) into MDA-MB-468 human breast cancer cells. In vitro, cells overexpressing OPN demonstrated increased anchorage-independent growth in soft agar (P = 0.001) and increased RGD-dependent adhesion (P = 0.045). Following mammary fat pad injection of nude mice, cells overexpressing OPN showed increased lymphovascular invasion, lymph node metastases, and lung micrometastases at earlier time points (P = 0.024). Loss of the RGD region partially abrogated this effect in the lymphatics (P = 0.038). These novel findings indicate that OPN is a key molecular player involved in lymphatic metastasis of breast cancer, potentially by affecting RGD-mediated adhesive interactions and by enhancing the establishment/persistence of tumor cells in the lymphatics.
Allan
Alison L
AL
Department of Oncology, Schulich School of Medicine and Dentistry, University of Western Ontario, London Regional Cancer Program, 790 Commissioners Road East, London, Ontario N6A 4L6, Canada. alison.allan@lhsc.on.ca
George
Rosamma
R
Vantyghem
Sharon A
SA
Lee
Mark W
MW
Hodgson
Nicole C
NC
Engel
C Jay
CJ
Holliday
Ron L
RL
Girvan
David P
DP
Scott
Leslie A
LA
Postenka
Carl O
CO
Al-Katib
Waleed
W
Stitt
Larry W
LW
Uede
Toshimitsu
T
Chambers
Ann F
AF
Tuck
Alan B
AB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000378:metabolism*; D053495:Osteopontin; D021701:Sentinel Lymph Node Biopsy; D012795:Sialoglycoproteins / Q000378:metabolism*; D014162:Transfection
D016023:Integrins; D009842:Oligopeptides; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; C047981:arginyl-glycyl-aspartic acid