Lung-derived factors mediate breast cancer cell migration through CD44 receptor-ligand interactions in a novel ex vivo system for analysis of organ-specific soluble proteins.
Breast cancer preferentially metastasizes to lung, lymph node, liver, bone, and brain. However, it is unclear whether properties of cancer cells, properties of organ microenvironments, or a combination of both is responsible for this observed organ tropism. We hypothesized that breast cancer cells exhibit distinctive migration/growth patterns in organ microenvironments that mirror common clinical sites of breast cancer metastasis and that receptor-ligand interactions between breast cancer cells and soluble organ-derived factors mediate this behavior. Using an ex vivo model system composed of organ-conditioned media (CM), human breast cancer cells (MDA-MB-231,MDA-MB-468, SUM149, and SUM159) displayed cell line-specific and organ-specific patterns of migration/proliferation that corresponded to their in vivo metastatic behavior. Notably, exposure to lung-CM increased migration of all cell lines and increased proliferation in two of four lines (P < .05). Several cluster of differentiation (CD) 44 ligands including osteopontin (OPN) and L-selectin (SELL) were identified in lung-CM by protein arrays. Immunodepletion of SELL decreased migration of MDA-MB-231 cells, whereas depletion of OPN decreased both migration and proliferation. Pretreatment of cells with a CD44-blocking antibody abrogated migration effects (P < .05). "Stemlike" breast cancer cells with high aldehyde dehydrogenase and CD44 (ALDH(hi)CD44(+)) responded in a distinct chemotactic manner toward organ-CM, preferentially migrating toward lung-CM through CD44 receptor-ligand interactions (P < .05). In contrast, organ-specific changes in migration were not observed for ALDH(low)CD44(-) cells. Our data suggest that interactions between CD44(+) breast cancer cells and soluble factors present in the lung microenvironment may play an important role in determining organotropic metastatic behavior.
London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada; Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Jenny E
JE
Chu
London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada.
Ying
Y
Xia
London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada.
Benjamin
B
Chin-Yee
London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada.
David
D
Goodale
London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada; Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Alysha K
AK
Croker
London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada; Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada. Electronic address: alison.allan@lhsc.on.ca.
Alison L
AL
Allan
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D019041:L-Selectin / Q000502:physiology; D008024:Ligands; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D053495:Osteopontin / Q000502:physiology
C497483:CD44 protein, human; D017077:Culture Media, Conditioned; D018960:Hyaluronan Receptors; D008024:Ligands; D053495:Osteopontin; D019041:L-Selectin