To evaluate the safety of this clinical intervention, tumor incidence in NOD SCID mice was monitored after the subcutaneous injection of hUC-MSCs to evaluate tumorigenicity, and the protumorigenic activity of hUC-MSCs was evaluated in subcutaneous models of a solid tumor (human cervical cancer HeLa cells) and hematological cancer (human B cell lymphoma Raji cells) in NOD SCID mice. These products are intended to be delivered via intravenous drip for the treatment of senile degenerative diseases. The hUC-MSCs used for injection are biological products developed by the National and Local Joint Engineering Laboratory of Stem Cell and Immune Cell Biomedicine Technology. These reports all indicate that MSCs can promote tumor cell growth both in vivo and in vitro. This MSC migration promotes tumor stroma formation, which can lead to mutations in tumor cells and cancerous growth in the body. In addition, chemokines and cytokines in the tumor microenvironment can induce the migration of MSCs to such microenvironments. Furthermore, MSCs have multidirectional differentiation potential and can differentiate into matrix components. Related studies have shown that the stability of MSCs in the tumor microenvironment is insufficient, and tumor growth may occur partly through the recruitment of peripheral stem cells and not only through the proliferation of the original tumor cells. Therefore, the tumorigenicity of UC-MSCs infused into patients has been a focus of preclinical evaluations. Moreover, MSCs transfected with the telomerase reverse transcriptase gene (TERT) undergo transformation. Studies have found that long-term in vitro-cultured bone marrow-derived mesenchymal stem cells (MSCs) can spontaneously transform and generate tumors. hUC-MSCs can inhibit the proliferation of mitogen-stimulated T lymphocytes, modulate T cell subsets to affect cytokine secretion, and participate in other mechanisms to exert immunomodulatory effects. Umbilical cord mesenchymal stem cells (UC-MSCs) perform immunoregulatory functions and inhibit T cell proliferation and immune responses through cell–cell interactions and cytokine production. Injected hUC-MSCs were not tumorigenic and did not significantly promote or inhibit solid or hematological tumor growth or metastasis in NOD SCID mice. No cancer cell metastasis was observed in the heart, liver, spleen, lungs, kidneys or other important organs, except that pulmonary venule metastasis was observed in 1 animal in the model group. Thus, hUC-MSCs neither promoted nor inhibited tumor growth. In the Raji tumor model, some animals in each group experienced tumor rupture, and one animal in the medium-dose hUC-MSC group died, perhaps due to increased tumor malignancy. Pathological examination revealed no metastasis to distant organs in any group. The results may have occurred due to the longer feeding time, and the tumor may have caused spontaneous infection and death. In the tumor promotion experiment, some animals in the HeLa groups experienced tumor rupture, and one animal died in each of the low- and medium-dose hUC-MSC groups.
In the tumorigenesis experiment, no general anatomical abnormalities were observed. Various organs were observed microscopically to identify pathological changes and tumor metastasis. Then, the animals were euthanized, gross dissection was performed, and tissues were collected.
Subcutaneous transplantation models were established in NOD SCID mice with human cervical cancer HeLa cells (solid tumor) and human B cell lymphoma Raji cells (hematological tumor). Three generations (P5, P7, and P10) of hUC-MSCs (1 × 10 7) from two donors (hUC-MSC1 and hUC-MSC2) were inoculated subcutaneously into NOD SCID mice. We observed tumor formation in NOD SCID mice after a single subcutaneous injection of hUC-MSCs and the effect of these cells on tumor growth in tumor-bearing mice. The tumorigenesis of infused umbilical cord mesenchymal stem cells (UC-MSCs) is being preclinically evaluated.
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