Abstract
Ovarian cancer is a highly lethal and the second highest in mortality among gynecological cancers. Stem cells either naïve or engineered are reported to inhibit various human cancers in both in-vitro and in-vivo. Herein we report the cancer inhibitory properties of human Wharton's jelly stem cell (hWJSC) extracts, namely its conditioned medium (hWJSC-CM) and cell lysate (hWJSC-CL) against two ovarian cancer cell lines (OVCAR3 and SKOV3) in-vitro. Cell metabolic activity assay of OVCAR3 and SKOV3 cells treated with hWJSC-CM (12.5, 25, 50, 75, 100%) and hWJSC-CL (5, 10, 15, 30, and 50 μg/ml) demonstrated concentration dependent inhibition at 24–72 h. Morphological analysis of OVCAR3 and SKOV3 cells treated with hWJSC-CM (50, 75, 100%) and hWJSC-CL (15, 30, and 50 μg/ml) for 24–72 h showed cell shrinkage, membrane damage/blebbings and cell death. Cell cycle assay demonstrated an increase in the sub-G1 and G2M phases of cell cycle following treatment with hWJSC-CM (50, 75, 100%) and hWJSC-CL (10, 15, and 30 μg/ml) at 48 h. Both OVCAR3 and SKOV3 cells demonstrated mild positive expression of activated caspase 3 following treatment with hWJSC-CM (50%) and hWJSC-CL (15 μg/ml) for 24 h. Cell migration of OVCAR3 and SKOV3 cells were inhibited following treatment with hWJSC-CM (50%) and hWJSC-CL (15 μg/ml) for 48 h. Tumor spheres (TS) of OVCAR3 and SKOV3 treated with hWJSC-CM (50, 75, 100%) and hWJSC-CL (10, 15, 30 μg/ml) for 48 h showed altered surface changes including vacuolations and reduction in size of TS. TS of OVCAR3 and SKOV3 also showed the presence of few ovarian cancer stem cells (CSCs) in minimal numbers following treatment with hWJSC-CM (50%) or hWJSC-CL (15 μg/ml) for 48 h. Real-time gene expression analysis of OVCAR3 and SKOV3 treated with hWJSC-CM (50%) or hWJSC-CL (15 μg/ml) for 48 h demonstrated decreased expression of cell cycle regulatory genes (cyclin A2, Cyclin E1), prostaglandin receptor signaling genes (EP2, EP4) and the pro-inflmmatory genes (IL-6, TNF-α) compared to untreated controls. The results indicate that hWJSC-CM and hWJSC-CL inhibit ovarian cancer cells at mild to moderate levels by inducing cellular changes, cell cycle arrest, apoptosis, decreasing the expression of CSC markers and related genes regulation. Therefore, the stem cell factors in hWJSCs extracts can be useful in cancer management.
Highlights
Ovarian cancer is the most lethal and the second highest in mortality compared to other gynecological cancers
Given the beneficial properties of Human Wharton’s Jelly stem cells (hWJSCs), we evaluated the anticancer properties of hWJSCs on two commercial ovarian carcinoma cell lines (OVCAR3 and SKOV3) in vitro using the following parameters namely, cell morphology, cell metabolic activity, cell cycle, cell death, caspase 3 assay, cell migration, cancer stem cells (CSCs) inhibition, tumor sphere (TS) inhibition and gene expression related to cell cycle, prostaglandin receptor signaling and inflammation
Mesenchymal stem cells (MSCs) including the hWJSCs derived from within the umbilical cord have been used as anticancer agents either naïve or engineered against various human cancers [20–22]
Summary
Ovarian cancer is the most lethal and the second highest in mortality compared to other gynecological cancers. It is estimated the nearly 22,000 ovarian cancer cases are diagnosed each year and the annual death rates are over 14,000 deaths [1]. Given the slow progression of the disease, ovarian cancer is often diagnosed at later stages when metastases have already occurred. Subclinical metastasis associated with ovarian carcinoma renders their localization within the peritoneal cavity, and the disease escapes early detection. Lack of suitable biological markers except for the commonly screened CA125 may be one of the factors for late diagnosis. CA125 is known to be expressed by 85% of serous ovarian tumors, 70% of the undifferentiated tumors and only rarely by mucinous tumors [2]
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