Nerve invasion distance is dependent on laminin gamma2 in tumors of pancreatic cancer.
The distance of nerve invasion is an important prognostic factor in pancreatic cancer. The extracellular matrix (ECM) of nerve, mainly composed of laminin, collagen IV and anchoring fibrils, might affect nerve invasion. However, this relationship has not been demonstrated. Our study aimed at discovering the promoting factor of nerve invasion within the tumoral ECM. An animal model was established to evaluate the distance of nerve invasion in murine sciatic nerves by intraneural injection of 6 human pancreatic cancer cell lines. mRNA expression of laminins and anchoring fibrils was compared to the distance of nerve invasion for each cancer cell line. A target molecule provided the strong association between mRNA expression and the distance of nerve invasion. To evaluate the role of a target molecule in nerve invasion, protein expression and function were examined using an animal model and surgical cases. Cancer cells with high laminin gamma2 mRNA and protein expression in their basement membranes were associated with long nerve invasion. Knockdown of laminin gamma2 in cancer cells significantly shortened nerve invasion in the animal model. In 75 patients with pancreatic cancer, a large distance of nerve invasion was associated with high expression levels of laminin gamma2 mRNA and basement membranous deposition of laminin gamma2 protein. Our results indicate that laminin gamma2 plays an important role in nerve invasion. The measurement of the nerve invasion distance in our mouse nerve invasion model is useful for evaluating the molecular mechanisms of nerve invasion.
Mitsunaga
Shuichi
S
Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Fujii
Satoshi
S
Ishii
Genichiro
G
Kinoshita
Taira
T
Hasebe
Takahiro
T
Aoyagi
Kazuhiko
K
Sasaki
Hiroki
H
Ochiai
Atsushi
A
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007797:Laminin / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009423:Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000473:pathology*; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D024141:Collagen Type IV; C400567:LAMC2 protein, human; D007797:Laminin; D012333:RNA, Messenger; D034741:RNA, Small Interfering