P-0186 - Antitumor activity of placenta-derived mesenchymal stem cells on rat colon cancer model
|Date||28 June 2014|
|Event||World GI 2014|
|Topics|| Basic Science
|Citation||Annals of Oncology (2014) 25 (suppl_2): ii14-ii104. 10.1093/annonc/mdu165|
H. Kuznietsova1, A. Svitina2, V. Shablii2, V. Rybalchenko1
Systemically administered mesenchymal stem cells could migrate to sites of malignant tumor. Genetic modification of stem cells to overexpress antitumor genes has provided prospects for clinical use as anticancer therapy. However the data about the effects of stem cells themselves on tumor formation and progression are controversial. Moreover, the impact of stem cells in vivo was evaluated by changes of xenografted tumors in immune-deficient host that differ from humans or animals with spontaneous cancer. So determination the effect of intravenous allogenic and xenogenic transplantation of placenta-derived mesenchymal stem cells (PDMSC) at chemically induced colon cancer in rats was aimed.
Rat PDMSC were obtained from placentas of Albino rats by spontaneous migration from the tissue onto the culture plate and cultivated at DMEM high glucose medium with 10% FBS for 4 passages. Real time PCR, FISH, flow cytometry and immunocytochemistry methods were used for obtained cells description and immunophenotyping. Human PDMSC were obtained from human placentas after normal labors and cultivated at the same conditions. Male Albino rats were injected of 1,2-dymethylhydrazine (DMH, 20 mg/kg weekly), a specific colorectal carcinogen, subcutaneously for 20 weeks and treated with rat or human PDMSC intravenously (0.5*106 and 2.0*106 cells per animal) at 22nd week (after adenocarcinomas formation equal Т1-2N0-1M0 stage of human colorectal cancer). Animals were euthanized at 27th week, tumor number and size in dissected colon were measured, tumors and normal colonic mucosa slides stained with hematoxylin-eosin-orange were examined (light microscopy), morphometry analysis was carried out.
The trophoblast derivation and the “stemness” of PDMSC were confirmed. Rat PDMSC didn't alter the bowel mucosa of healthy rats when applied at any dose, as opposed to human PDMSC, which caused inflammation in rectum mucosa. Allogenic transplantation of PDMSC to DMH-induced animals at dose of 2.0*106 cells decreased the tumor number twice, the tumor size by 20% and the total dysplasia/cancers area tripled, which remain equal that ones at the 22nd week. PDMSC allogenic transplantation at dose of 0.5*106 cells since PDMSC xenogenic transplantation at any dose had no effect on tumor progression. Rat PDMSC protective effect against carcinogen-induced alterations of bowel mucosa with no tumors was observed: inflammation decrease, microvascular violations diminution caused by rat PDMSC applied at high dose have been occurred. On the contrast human PDMSC escalated the DMH-induced inflammation in both colon and rectum mucosa, supposing an important role of immune system in PDMSC-host relationship. Different changes of mucosa morphological parameters under as allogenic as xenogenic PDMSC application were revealed suggesting the impact of PDMSC on mucosa functional activity even there were no effects on tumor growth or mucosa inflammatory status.
Allogenic transplantation of PDMSC at high dose inhibits tumor progression and protects the normal bowel mucosa under rat DMH-induced colon cancer model. Thus: 1) PDMSC has a prospect for clinical use as anticancer therapy when applied in adequate dose; 2) in vivo investigations of human stem cells on animal models require corrections.