Transplantation of placenta-derived multipotent cells in rats with dimethylhydrazine-induced colon cancer decreases survival rate.

Transplantation of placenta-derived multipotent cells (PDMCs) is a promising treatment method for many diseases. However, the impact of PDMCs on colon cancer has not yet been studied. PDMCs were obtained from rat placentas by culturing tissue explants. Colon cancer was experimentally induced in male albino Wistar rats by administering 20 mg/kg dimethylhydrazine (DMH) once a week for 20 consecutive weeks. The administration of the PDMCs was performed at the 20th week after the first DMH injection. The number and size of each tumour lesion were calculated in the 5th week after transplantation. The tumour type was determined by standard histological methods. To study the engraftment of PDMCs in the body of rats, the cells were transduced with enhanced green fluorescent protein. Cell engraftment was determined by assessing the presence of EGFP by PCR and immunohistochemistry. Survival of all rats was monitored daily. Allogeneic transplantation of PDMCs to rats at middle phase of DMH-induced colon carcinogenesis did not significantly influence the number of neoplasms and the parameters of mean and total tumour area, but led to an increase in size of the most invasiveness tumours. Intravenous allogeneic transplantation of PDMCs reduced the survival rate of rats with colon cancer by 17 days. PDMCs from rats engrafted into tissues of the normal intestine, tumours, lungs, liver, and spleen of rats for five weeks after intravenous transplantation. These results suggest that intravenous allogeneic transplantation of PDMCs promotes colon cancer progression and has a negative impact on survival of rats.

Placenta-derived multipotent cells have no effect on the size and number of DMH-induced colon tumors in rats.

Transplantation of placenta-derived multipotent cells (PDMCs) is a promising approach for cell therapy to treat inflammation-associated colon diseases. However, the effect of PDMCs on colon cancer cells remains unknown. The aim of the present study was to characterize PDMCs obtained from human (hPDMCs) and rat (rPDMCs) placentas and to evaluate their impact on colon cancer progression in rats. PDMCs were obtained from human and rat placentas by tissue explant culturing. Stemness- and trophoblast-related gene expression was studied using reverse transcription-polymerase chain reaction (RT-PCR), and surface markers and intracellular proteins were detected using flow cytometry and immunofluorescence, respectively. Experimental colon carcinogenesis was induced in male albino Wistar rats by injecting 20 mg/kg dimethylhydrazine (DMH) once a week for 20 consecutive weeks. The administration of rPDMCs and hPDMC was performed at week 22 after the initial DMH-injection. All animals were sacrificed through carbon dioxide asphyxiation at week 5 after cell transplantation. The number and size of each tumor lesion was calculated. The type of tumor was determined by standard histological methods. Cell engraftment was determined by PCR and immunofluorescence. Results demonstrated that rPDMCs possessed the immunophenotype and differentiation potential inherent in MSCs; however, hPDMCs exhibited a lower expression of cluster of differentiation 44 and did not express trophoblast-associated genes. The data of the present study indicated that PDMCs may engraft in different tissues but do not significantly affect DMH-induced tumor growth during short-term observations.

Two closely related human members of chitinase-like family, CHI3L1 and CHI3L2, activate ERK1/2 in 293 and U373 cells but have the different influence on cell proliferation.

The activation of extracellular signal-regulated kinases (ERK1/2) has been associated with specific outcomes. Sustained activation of ERK1/2 by nerve growth factor (NGF) is associated with translocation of ERKs to the nucleus of PC12 cells and precedes their differentiation into sympathetic-like neurons whereas transient activation by epidermal growth factor (EGF) leads to cell proliferation. It was demonstrated that different growth factors initiating the same cellular signaling pathways may lead to the different cell destiny, either to proliferation or to the inhibition of mitogenesis and apoptosis. Thus, further investigation on kinetic differences in activation of certain signal cascades in different cell types by biologically different agents are necessary for understanding the mechanisms as to how cells make a choice between proliferation and differentiation.It was reported that chitinase 3-like 1 (CHI3L1) protein promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts similarly to insulin-like growth factor 1 (IGF1). Both are involved in mediating the mitogenic response through the signal-regulated kinases ERK1/2. In addition, CHI3L1 which is highly expressed in different tumors including glioblastomas possesses oncogenic properties. As we found earlier, chitinase 3-like 2 (CHI3L2) most closely related to human CHI3L1 also showed increased expression in glial tumors at both the RNA and protein levels and stimulated the activation of the MAPK pathway through phosphorylation of ERK1/2 in 293 and U87 MG cells. The work described here demonstrates the influence of CHI3L2 and CHI3L1 on the duration of MAPK cellular signaling and phosphorylated ERK1/2 translocation to the nucleus. In contrast to the activation of ERK1/2 phosphorylation by CHI3L1 that leads to a proliferative signal (similar to the EGF effect in PC12 cells), activation of ERK1/2 phosphorylation by CHI3L2 (similar to NGF) inhibits cell mitogenesis and proliferation.

Gene Encoding Chitinase 3-Like 1 Protein (CHI3L1) is a Putative Oncogene.

An important task in understanding oncogenesis is the identification of those genes whose copy number and expression increase during tumorigenesis. Previously, in an effort to identify genes which could be used as molecular markers for glial tumors, we compared gene expression in glioblastoma to the normal brain cells. Among the genes with the most pronounced increased expression in tumors there was CHI3L1, encoding the secreted chitinase 3-like 1 protein (also known as HC gp-39 or YKL-40). Expression of CHI3L1 was found increased significantly in various tumors in comparison with corresponding normal tissues. Here we show that CHI3L1 can decrease the doubling time of 293 cells. We have also demonstrated that CHI3L1 allows the anchorage-independent growth in soft agar and, in addition, stable CHI3L1 expression made 293 cells tumorigenic: these cells stimulate the initiation of tumors after their xenograft transplantation into the Wistar rat brains. Thus, the overexpression of CHI3L1 is likely to be critical in the development of some tumors and when we gain more information about mechanisms of CHI3L1 oncogenicity, it could be used as one of the potential targets for anticancer therapy.