Co-opting macrophage traits in cancer progression: a consequence of tumor cell fusion?
Tumor-associated macrophages (TAMs) play multiple roles in tumor initiation and progression. Tumors frequently appear in areas of chronic inflammation. This is likely aided by the mutagenic actions of macrophages. Tumor growth and progression is supported by macrophage-induced neoangiogenesis and stroma production, and macrophages produce tumor-stimulating growth factors. In most cancers a high density of TAMs predicts poor outcome. But not only do cancer cells depend upon macrophages for growth and invasion, they also co-opt macrophage traits. These include a wide diversity of molecules and pathways regulating adhesion, matrix alterations, neoangiogenesis, motility, chemotaxis, immune signaling pathways and even multidrug resistance proteins. Evidence is presented that these traits could be generated through macrophage-tumor cell fusion. Fusion has been reported in numerous animal tumor models and was recently documented in 2 human cases. Fusion could also account for the high degree of aneuploidy and plasticity in cancer, and for immune evasion. One common trait of myeloid-tumor fusion is the high expression of Beta1,6-branched N-glycans, used by macrophages in systemic migration. Beta1,6-branched oligosaccharides have long been associated with metastasis in animal models and were recently found to be common in a wide diversity of human cancers. We suggest that Beta1,6-branched oligosaccharides in human cancer may reflect widespread tumor cell fusion. Viewing the cancer cell as a myeloid hybrid provides new approaches towards understanding and treating this complex disease.
Pawelek
John
J
Department of Dermatology, Yale Cancer Center, Yale University School of Medicine, New Haven, Conn., USA.
Chakraborty
Ashok
A
Lazova
Rossita
R
Yilmaz
Yesim
Y
Cooper
Dennis
D
Brash
Douglas
D
Handerson
Tamara
T
D019046:Bone Marrow Neoplasms / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology; D002459:Cell Fusion; D018450:Disease Progression; D006801:Humans; D006822:Hybrid Cells; D008264:Macrophages / Q000166:cytology*; D008545:Melanoma / Q000473:pathology; D009369:Neoplasms / Q000473:pathology*