Gene expression changes induced by HIPEC in a murine model of gastric cancer.
BACKGROUND
Peritoneal carcinogenesis (PC) is the most frequent pattern of metastasis in patients with locally advanced gastric cancer. Despite this, there is a consensus on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC from gastric cancer. The molecular mechanisms involved in beneficial effects of HIPEC remain unexplored.


METHODS
Human gastric cancer MKN45 cells were injected into the peritoneal cavity of immune-deficient NOD-SCID mice. After induction of PC, the animals were randomized into five groups: HIPEC with mitomycin and cisplatin; normothermic intraperitoneal chemotherapy (NIPEC); normothermic intraperitoneal saline; hyperthermic intraperitoneal saline alone; no treatment. After 10 days of treatment, the mice were sacrificed and the extent of PC was assessed.


RESULTS
Compared with the other groups of treatment, HIPEC reduced the extent and severity of peritoneal dissemination as measured by assessing the total number of peritoneal and mesenteric nodules (p<0,05) and the HIPEC procedure increased median survival significantly. By gene array analysis, HIPEC was found to effectively modulate the expression of a subset of genes involved in formation of peritoneal metastasis, including adenomatous polyposis coli; beta (3) subunit of the integrin gene; chemokine stromal cell-derived factor-1 receptor; spleen tyrosine kinase; vascular endothelial growth factor receptor 3; collagen, type IV, alpha 2 and Carbossi-terminal binding proteins 1.


CONCLUSIONS
In the present study we have provided evidence that HIPEC protects against peritoneal dissemination in a mouse model of peritoneal gastric carcinogenesis and brings about specific changes in gene expression wich may be related to this protection.
Department of Surgery, School of Medicine, University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy. luiginagraziosi@yahoo.it
Luigina
L
Graziosi
Andrea
A
Mencarelli
Barbara
B
Renga
Chiara
C
Santorelli
Francesco
F
Cantarella
Walter
W
Bugiantella
Emanuel
E
Cavazzoni
Annibale
A
Donini
Stefano
S
Fiorucci
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D007274:Injections, Intraperitoneal; D039661:Integrin beta3 / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016685:Mitomycin / Q000008:administration & dosage; D020411:Oligonucleotide Array Sequence Analysis; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy; D011897:Random Allocation; D019718:Receptors, CXCR4 / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D025601:Adenomatous Polyposis Coli Protein; D039661:Integrin beta3; D019718:Receptors, CXCR4; D016685:Mitomycin; D002945:Cisplatin