The reg4 gene, amplified in the early stages of pancreatic cancer development, is a promising therapeutic target.
BACKGROUND
The aim of our work was to identify the genes specifically altered in pancreatic adenocarcinoma and especially those that are altered early in cancer development.


RESULTS
Gene copy number was systematically assessed with an ultra-high resolution CGH oligonucleotide microarray in DNA from samples of pancreatic cancer. Several new cancer-associated variations were observed. In this work we focused on one of them, involving the reg4 gene. Gene copy number gain of the reg4 gene was confirmed by qPCR in 14 cancer samples. It was also found with increased copy number in most PanIN3 samples. The relationship betweena gain in reg4 gene copy number and cancer development was investigated on the human pancreatic cancer cell line Mia-PaCa2 xenografted under the skin of nude mice. When cells were transfected with a vector allowing reg4 expression, they generated tumors almost twice larger in size. In addition, these tumors were more resistant to gemcitabine treatment than control tumors. Interestingly, weekly intraperitoneal administration of a monoclonal antibody to reg4 halved the size of tumors generated by Mia-PaCa2 cells, suggesting that the antibody interfered with a paracrine/autocrine mechanism involving reg4 and stimulating cancer progression. The addition of gemcitabine resulted in further reduction, tumors becoming 5 times smaller than control. Exposure to reg4 antibody resulted in a significant decrease in intra-tumor levels of pAkt, Bcl-xL, Bcl-2, survivin and cyclin D1.


CONCLUSIONS
It was concluded that adjuvant therapies targeting reg4 could improve the standard treatment of pancreatic cancer with gemcitabine.
Legoffic
Aude
A
INSERM U.624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, Marseille, France.
Calvo
Ezequiel
E
Cano
Carla
C
Folch-Puy
Emma
E
Barthet
Marc
M
Delpero
Jean Robert
JR
Ferrés-Masó
Montse
M
Dagorn
Jean Charles
JC
Closa
Daniel
D
Iovanna
Juan
J
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D000818:Animals; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D000073718:Pancreatitis-Associated Proteins; D000093542:Gemcitabine
D037181:Lectins, C-Type; D009363:Neoplasm Proteins; D000073718:Pancreatitis-Associated Proteins; C428528:REG4 protein, human; C546117:REG4 protein, mouse; D003841:Deoxycytidine; D000093542:Gemcitabine