Modulatory effects of heparin and short-length oligosaccharides of heparin on the metastasis and growth of LMD MDA-MB 231 breast cancer cells in vivo.
Expression of the chemokine receptor CXCR4 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express CXCL12. In this study, we determined whether this interaction could be disrupted using short-chain length heparin oligosaccharides. Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I(125) CXCL12. Heparin dodecasaccharides were found to be the minimal chain length required to efficiently bind CXCL12 (71% inhibition; P<0.001). These oligosaccharides also significantly inhibited CXCL12-induced migration of CXCR4-expressing LMD MDA-MB 231 breast cancer cells. In addition, heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product, Tinzaparin. When given subcutaneously in a SCID mouse model of human breast cancer, heparin dodecasaccharides had no effect on the number of lung metastases, but did however inhibit (P<0.05) tumour growth (lesion area) compared to control groups. In contrast, polymeric heparin significantly inhibited both the number (P<0.001) and area of metastases, suggesting a differing mechanism for the action of polymeric and heparin-derived oligosaccharides in the inhibition of tumour growth and metastases.
Mellor
P
P
Breast Cancer Research Group, School of Surgical and Reproductive Sciences, Newcastle University, Newcastle-upon-Tyne, UK.
Harvey
J R
JR
Murphy
K J
KJ
Pye
D
D
O'Boyle
G
G
Lennard
T W J
TW
Kirby
J A
JA
Ali
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007457:Iodine Radioisotopes; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009844:Oligosaccharides / Q000494:pharmacology*; D011108:Polymers / Q000378:metabolism; D011869:Radioligand Assay; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000378:metabolism*; D000078222:Tinzaparin
D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D006495:Heparin, Low-Molecular-Weight; D006497:Heparan Sulfate; D007457:Iodine Radioisotopes; D009844:Oligosaccharides; D011108:Polymers; D019718:Receptors, CXCR4; D000078222:Tinzaparin; C515255:CXCL12 protein, human; C515256:Cxcl12 protein, mouse