M2-polarized tumor-associated macrophage infiltration of regional lymph nodes is associated with nodal lymphangiogenesis and occult nodal involvement in pN0 pancreatic cancer.
OBJECTIVE
Tumor-associated macrophages (TAMs) are reportedly involved in lymphangiogenesis in primary tumors, playing a crucial role in lymphatic metastasis. Furthermore, nodal lymphangiogenesis precedes and promotes regional lymph node (RLN) metastasis. We investigated the relationship of M2-polarized TAM infiltration of the RLNs, nodal lymphangiogenesis, and occult nodal involvement in pN0 pancreatic cancer.


METHODS
Hematoxylin-eosin-stained primary tumor and regional LN specimens from 40 patients diagnosed with pN0 pancreatic cancer according to the pathological TNM classification were assessed. To evaluate lymphangiogenesis, lymphatic vessel density was measured by using D2-40 antibody. CD163 and cytokeratin AE1/AE3 antibodies were used to detect M2-polarized TAMs and isolated tumor cells in the RLNs, respectively.


RESULTS
The nodal lymphatic vessel density had a strong association with the M2-polarized TAM density in the RLNs (P < 0.0001). Most of these TAMs expressed vascular endothelial growth factor C. Furthermore, in the RLNs, the M2-polarized TAM density was significantly associated with the incidence of isolated tumor cells (P = 0.0477).


CONCLUSIONS
M2-polarized TAM infiltration of RLNs is significantly associated with nodal lymphangiogenesis and occult nodal involvement in pN0 pancreatic cancer. Node-infiltrating M2-polarized TAMs may facilitate nodal lymphangiogenesis via the production of vascular endothelial growth factor C and thus promote RLN metastasis.
Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan. h-krhr@m3.kufm.kagoshima-u.ac.jp
Hiroshi
H
Kurahara
Sonshin
S
Takao
Kosei
K
Maemura
Yuko
Y
Mataki
Taisaku
T
Kuwahata
Koki
K
Maeda
Masahiko
M
Sakoda
Satoshi
S
Iino
Sumiya
S
Ishigami
Shinichi
S
Ueno
Hiroyuki
H
Shinchi
Shoji
S
Natsugoe
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008198:Lymph Nodes / Q000737:chemistry / Q000276:immunology / Q000473:pathology* / Q000601:surgery; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000737:chemistry / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000737:chemistry / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000276:immunology / Q000473:pathology* / Q000601:surgery; D011956:Receptors, Cell Surface / Q000032:analysis; D013194:Staining and Labeling / Q000379:methods; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis; D000098902:CD163 Antigen
D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D000098902:CD163 Antigen; D019394:Ki-67 Antigen; D011956:Receptors, Cell Surface; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C500987:monoclonal antibody D2-40; D007633:Keratins