Investigation On The Roles Of Mesenchymal Stem Cells In Tumor Growth And Metastisis And In Mitigating Tumor Chemotherapy-associated Tissue Injuries

Mesenchymal stem cells (MSCs), a subset of multipotential adult stem cells,hold great therapeutic potential in cell therapy and regenerative medicine. However,their therapeutic potential against chemotherapy-induced side effects remains unclear.In the present study, we evaluated the prophylactic or therapeutic action ofhUC-MSCs on chemotherapy agent Doxorubicin-induced side effects in two differenttumor models and analyzed factors that impact MSCs and tumor growth.We isolated MSCs from umbilical cord, adipose tissue, bone marrow throughminced tissue planting, collagenase digestion and density gradient centrifugationrespectively. FACS examination showed that MSCs from different tissue originshowed similar immunophenotype, i.e. positive for CD29，CD44，CD73，HLA-ABCwhereas negative for CD14，CD31，CD34，CD45，HLA-DR. Given appropriatemedium, MSCs were able to differentiate into osteocytes and adipocytes.We developed a solution formula that could preserve MSCs at4℃for up to3weeks. In the solution, trehalose is a key ingredient for maintaining survival of MSCs.Among the concentrations investigated,40mM trehalose showed the best outcomewith the viability maintained more than92.7±1.5%for7days. Cells preserved in thesolution formula for3weeks still remained about70%viability, and produced resultssimilar to those of freshly harvested hMSCs in terms of growth kinetics, expressionprofile of cell surface antigens and differentiation potential.We treated murine Lewis lung carcinoma and xenograft human colon tumorswith Doxorubicin (DOX) for three consecutive days followed by one i.v. injection ofhUC-MSCs for several cycles. MSCs treatment could mitigate DOX-inducedcardiomyopathy, reduce the extent of DOX-induced apoptosis in intestinal crypts,suppress the body weight loss in mice treated with DOX and increase the survival rateof mice treated with lethal dose of DOX. The examination of hematologicalparameters indicated a moderate recovery in MSC injected mice. Systemicadministration of MSC did not increase the growth of murine Lewis lung carcinomacell (LLC) and human colon carcinoma in vivo while strongly inhibited the lungmetastases of LLC cell. Our observations suggest that MSCs can be used as auxiliarymeans in chemotherapy for certain tumor types.We analyzed factors that impact MSCs and tumor growth. Our results showedthat human umbilical cord MSCs could inhibit the migration of lung cancer cell linessuch as A549and95D while promote migration of breast cancer cell lines asMDA-MB-231and MCF-7. For hepatoma cell lines, MSCs could suppress the migration of low metastatic cell line HepG2while facilitate the movement of highmetastatic cell line LM-3and97H. MSCs from different tissue origin showed similarimpact on the same tumor cell line. We got senescent MSCs through replicationsenescence and H2O2induction which showed dramatically different cytokinessecretion profile like40times increased for IL-6secretion. Senescent MSCs couldpromote cancer cell proliferation and migration through IL-6dependent manner.The effect of senescent MSCs on tumor cell in vivo was analyzed byco-implantation with breast cancer cell MDA-MB-231subcutaneously into nude mice.Our results demonstrated that H2O2induced MSCs could significantly promote tumorgrowth. Immunohistochemical analyzation suggested senescent MSCs could improvetumor angiogenesis.