Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis.
Pancreatic ductal adenocarcinoma (PDAC) still ranking 4th in the order of fatal tumor diseases is characterized by a profound tumor stroma with high numbers of tumor-associated macrophages (TAMs). Driven by environmental factors, monocytes differentiate into M1- or M2-macrophages, the latter commonly regarded as being protumorigenic. Because a detailed analysis of TAMs in human PDAC development is still lacking, freshly isolated PDAC-derived TAMs were analyzed for their phenotype and impact on epithelial-mesenchymal-transition (EMT) of benign (H6c7) and malignant (Colo357) pancreatic ductal epithelial cells. TAMs exhibited characteristics of M1-macrophages (expression of HLA-DR, IL-1β, or TNF-α) and M2-macrophages (expression of CD163 and IL-10). In the presence of TAMs, H6c7, and Colo357 cells showed an elongated cell shape along with an increased expression of mesenchymal markers such as vimentin and reduced expression of epithelial E-cadherin. Similar to TAMs, in vitro generated M1- and M2-macrophages both mediated EMT in H6c7 and Colo357 cells. M1-macrophages acquired M2-characteristics during coculture that could be prevented by GM-CSF treatment. However, M1-macrophages still potently induced EMT in H6c7 and Colo357 cells although lacking M2-characteristics. Overall, these data demonstrate that TAMs exhibit anti- as well as proinflammatory properties that equally contribute to EMT induction in PDAC initiation and development.
Institute for Experimental Medicine, Group Inflammatory Carcinogenesis, UK S-H Campus, Kiel, Germany.
Ole
O
Helm
Janka
J
Held-Feindt
Evelin
E
Grage-Griebenow
Norbert
N
Reiling
Hendrik
H
Ungefroren
Ilka
I
Vogel
Uwe
U
Krüger
Thomas
T
Becker
Michael
M
Ebsen
Christoph
C
Röcken
Dieter
D
Kabelitz
Heiner
H
Schäfer
Susanne
S
Sebens
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D063646:Carcinogenesis; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; C513384:CDH1 protein, human; D015820:Cadherins; D053583:Interleukin-1beta; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
L1CAM; macrophages; pancreatic cancer; tumor stroma; tumor-associated inflammation