Pancreatic cancer cells enhance the ability of collagen internalization during epithelial-mesenchymal transition.
BACKGROUND
Extracellular matrix (ECM) remodeling is predominantly mediated by fibroblasts using intracellular and extracellular pathways. Although it is well known that extracellular degradation of the ECM by proteases derived from cancer cells facilitates cellular invasion, the intracellular degradation of ECM components by cancer cells has not been clarified. The aim of this study was to characterize collagen internalization, which is the initial step of the intracellular degradation pathway in pancreatic cancer cells, in light of epithelial-mesenchymal transition (EMT).


RESULTS
We analyzed the function of collagen internalization in two pancreatic cancer cell lines, SUIT-2 and KP-2, and pancreatic stellate cells (PSCs) using Oregon Green 488-gelatin. PSCs had a strong ability for collagen uptake, and the pancreatic cancer cells also internalized collagen although less efficiently. The collagen internalization abilities of SUIT-2 and KP-2 cells were promoted by EMT induced by human recombinant transforming growth factor β1 (P<0.05). Expression of Endo180, a collagen uptake receptor, was high in mesenchymal pancreatic cancer cell lines, as determined by EMT marker expression (P<0.01). Quantitative RT-PCR and western blot analyses showed that Endo180 expression was also increased by EMT induction in SUIT-2 and KP-2 cells. Endo180 knockdown by RNA interference attenuated the collagen uptake (P<0.01) and invasive abilities (P<0.05) of SUIT-2 and KP-2 cells.


CONCLUSIONS
Pancreatic cancer cells are capable of collagen internalization, which is enhanced by EMT. This ECM clearance system may be a novel mechanism for cellular invasion and a potential therapeutic target in pancreatic cancer.
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Naoki
N
Ikenaga
Kenoki
K
Ohuchida
Kazuhiro
K
Mizumoto
Shin
S
Akagawa
Kenji
K
Fujiwara
Daiki
D
Eguchi
Shingo
S
Kozono
Takao
T
Ohtsuka
Shunichi
S
Takahata
Masao
M
Tanaka
D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D010190:Pancreatic Neoplasms; D058954:Pancreatic Stellate Cells / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D014746:Vimentin / Q000378:metabolism
D015820:Cadherins; C408294:Endo180; D038982:Integrin alpha2beta1; D011975:Receptors, Mitogen; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D003094:Collagen