The role of glial cell line-derived neurotrophic factor (GDNF) and integrins for invasion and metastasis in human pancreatic cancer cells.
OBJECTIVE
It is generally accepted that the malignancy of pancreatic cancer is dependent upon the extent of invasion as well as metastasis. However, the factors and mechanisms are incompletely understood. We investigated whether glial cell lined-derived neurotrophic factor (GDNF) enhances the invasive and adhesive behaviors of pancreatic cancer cells by altering of the expression of integrins.


METHODS
The expression of the GDNF receptor in pancreatic cancer cell lines (SW1990 and Capan-2) was confirmed by RT-PCR. Then we determined the expression of integrin subunits and the alteration of their expression by GDNF using flow-cytometric analysis and a cellular enzyme-linked immunosorbent assay (CELISA). Adhesion and invasion assay were performed to investigate whether increased integrin expression affected the interaction between cancer cells and ECM proteins.


RESULTS
The GDNF receptor subunits were expressed in pancreatic cancer cells. GDNF enhanced the expression of some of the integrin subunits and increased their adhesive and invasive abilities. The enhanced expression and associated increase in adhesive and invasive abilities were inhibited by blocking the GDNF receptor or the integrin beta1 subunit.


CONCLUSIONS
The enhancement of integrin expression by GDNF signaling through the GDNF receptor strongly influences invasion and adhesion to ECM proteins by pancreatic cancer cells.
Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. funa84@med.nagoya-cu.ac.jp
Hitoshi
H
Funahashi
Yuji
Y
Okada
Hirozumi
H
Sawai
Hiroki
H
Takahashi
Yoichi
Y
Matsuo
Hiromitsu
H
Takeyama
Tadao
T
Manabe
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000502:physiology; D005434:Flow Cytometry; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009414:Nerve Growth Factors / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
C490607:ECM1 protein, human; D016326:Extracellular Matrix Proteins; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D016023:Integrins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases