CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer.
OBJECTIVE
Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer by producing extracellular matrix and soluble factors. However, the functional heterogeneity of PSCs has not been identified until now. Detailed characterization of the PSCs in human pancreatic cancer would provide a set of potential targets for stroma-directed therapy.


METHODS
We isolated PSCs from fresh pancreatic ductal adenocarcinoma tissue and sorted them by flow cytometry according to cell surface expression of CD10, which is a stromal prognostic marker for various tumors. We analyzed the functional differences between CD10(+) PSCs and CD10(-) PSCs.


RESULTS
Immunohistochemical analysis showed that the frequency of CD10 expression by PSCs was markedly higher in tumor tissue than in normal tissue (33.7% vs 0%, respectively, P = .028). In pancreatic ductal adenocarcinoma, CD10 expression by PSCs was associated with positive nodal metastases (P = .011) and a shorter survival time (P < .001). In vitro coculture experiments showed that CD10(+) PSCs promoted the invasiveness of pancreatic cancer cell lines, SUIT-2 and Panc-1 cells more intensively than CD10(-) PSCs. CD10(+) PSCs significantly increased the tumor growth and invasiveness of SUIT-2 cells in a murine cotransplantation model. CD10(+) PSCs secreted higher levels of matrix metalloproteinase 3 than CD10(-) PSCs, and knockdown of matrix metalloproteinase 3 in cocultured PSCs reduced the invasion of SUIT-2 and Panc-1 cells.


CONCLUSIONS
CD10(+) PSCs enhance the progression of pancreatic cancer cells. CD10(+) PSCs may be a candidate for selective therapeutic targeting in the treatment of pancreatic cancer.
Ikenaga
Naoki
N
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ohuchida
Kenoki
K
Mizumoto
Kazuhiro
K
Cui
Lin
L
Kayashima
Tadashi
T
Morimatsu
Katsuya
K
Moriyama
Taiki
T
Nakata
Kohei
K
Fujita
Hayato
H
Tanaka
Masao
M
D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000401:mortality / Q000473:pathology* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D002469:Cell Separation; D016009:Chi-Square Distribution; D018920:Coculture Techniques; D018450:Disease Progression; D005355:Fibrosis; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D015260:Neprilysin / Q000032:analysis*; D010179:Pancreas / Q000201:enzymology / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D034622:RNA Interference; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D015260:Neprilysin; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3