title: Quantitative changes in tumor-associated M2 macrophages characterize cholangiocarcinoma and their association with metastasis.
abstract: The tumor microenvironment (TME) includes numerous non-neoplastic cells such as leukocytes and fibroblasts that surround the neoplasm and influence its growth. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are documented as key players in facilitating cancer appearance and progression. Alteration of the macrophage (CD68, CD163) and fibroblast (α-SMA, FSP-1) cells in Opisthorchis viverrini (Ov)-induced cholangiocarcinoma (CCA) was here assessed using liver tissues from an established hamster model and from 43 human cases using immunohistochemistry. We further investigated whether M2-activated TAMs influence CCA cell migration ability by wound healing assay and Western blot analysis. Macrophages and fibroblasts change their phenotypes to M2-TAMs (CD68+, CD163+) and CAFs (α-SMA+, FSP-1+), respectively in the early stages of carcinogenesis. Interestingly, a high density of the M2-TAMs CCA in patients is significantly associated with the presence of extrahepatic metastases (p=0.021). Similarly, CD163+ CCA cells are correlated with metastases (p=0.002), and they may be representative of an epithelial-to-mesenchymal transition (EMT) with increased metastatic activity. We further showed that M2-TAM conditioned medium can induce CCA cell migration as well as increase N-cadherin expression (mesenchymal marker). The present work revealed that significant TME changes occur at an early stage of Ov-induced carcinogenesis and that M2-TAMs are key factors contributing to CCA metastasis, possibly via EMT processes.
authors: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand E-mail : watloi@yahoo.com; puangrat@kku.ac.th.
authors: Malinee
authors: M
authors: Thanee
authors: Watcharin
authors: W
authors: Loilome
authors: Anchalee
authors: A
authors: Techasen
authors: Nisana
authors: N
authors: Namwat
authors: Thidarut
authors: T
authors: Boonmars
authors: Chawalit
authors: C
authors: Pairojkul
authors: Puangrat
authors: P
authors: Yongvanit
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D006224:Cricetinae; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000473:pathology*; D009889:Opisthorchiasis / Q000378:metabolism / Q000473:pathology; D009891:Opisthorchis / Q000472:pathogenicity; D059016:Tumor Microenvironment / Q000502:physiology; D020298:U937 Cells
chemical_list: D015820:Cadherins