4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer

Abstract

We have recently shown that the extracellular matrix molecule hyaluronan (HA) plays a role in the development of ovarian cancer chemoresistance. This present study determined if HA production is increased in chemotherapy-resistant ovarian cancers and if the HA inhibitor 4-methylubelliferone (4-MU) can overcome chemoresistance to the chemotherapeutic drug carboplatin (CBP) and inhibit spheroid formation and the expression of cancer stem cell (CSC) markers. We additionally assessed whether 4-MU could inhibit in vivo invasion of chemoresistant primary ovarian cancer cells in the chicken embryo chorioallantoic membrane (CAM) assay. The expression of the HA synthases HAS2 and HAS3 was significantly increased in chemoresistant compared to chemosensitive primary ovarian cancer cells isolated from patient ascites. 4-MU significantly inhibited HA production, cell survival, and spheroid formation of chemoresistant serous ovarian cancer cells. In combination with CBP, 4-MU treatment significantly decreased ovarian cancer cell survival and increased apoptosis of chemoresistant primary cells compared to CBP alone. 4-MU significantly reduced spheroid formation, expression of CSC markers ALDH1A1 and ABCG2 in primary cell spheroid cultures, and ALDH1 immunostaining in patient-derived tissue explant assays following treatment with CBP. Furthermore, 4-MU was very effective at inhibiting in vivo invasion of chemoresistant primary cells in CAM assays. Inhibition of HA is therefore a promising new strategy to overcome chemoresistance and to improve ovarian cancer survival.

Hyaluronic Acid: Redefining Its Role

“…In fact, it has been shown that in many types of solid tumors, increased synthesis of HA by cancer cells or by tumor stromal cells is correlated with tumor growth and metastasis [ 9 , 142 ]. Recent studies have confirmed that the over-expression of HAS2 promotes tumor progression in breast, ovarian, bladder, colorectal, pancreatic and lung carcinoma and resistance to chemotherapy [ 143 , 144 , 145 , 146 , 147 , 148 ]. On the other hand, it was proved that inhibiting HA synthesis inhibits also metastasis of carcinoma cells in some types of tumors [ 144 , 149 ].…”

“…Recent studies have confirmed that the over-expression of HAS2 promotes tumor progression in breast, ovarian, bladder, colorectal, pancreatic and lung carcinoma and resistance to chemotherapy [ 143 , 144 , 145 , 146 , 147 , 148 ]. On the other hand, it was proved that inhibiting HA synthesis inhibits also metastasis of carcinoma cells in some types of tumors [ 144 , 149 ]. However, other studies reported that HAS3 that was associated with tumor progression, downregulate in early tumor development.…”

Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment

“…In addition to the previous results, new therapies targeting both the ECM [20,293] and the MMPs are now emerging [294]. Since one of the main problems is that tumor ECM prevents the correct diffusion of drugs, numerous studies focus on either degrading the matrix, using collagenases, hyaluronidases or hyperthermia [295][296][297][298][299][300], and on blocking ECM synthesis de novo [301][302][303][304][305], although the latter has not provided positive results in clinical trials [306,307]. MMPs, which promote angiogenesis, metastasis and the release of factors within the matrix, are also the target of new therapies like andecaliximab and several MMPs antibodies, specific or broad-spectrum MMP inhibitors, which have shown promising results in clinical trials [294] (Fig.…”

A Comprehensive Molecular and Clinical Analysis of the piRNA Pathway Genes in Ovarian Cancer

“…Chemosensitive (n = 5) and chemoresistant (n = 7) primary cells were obtained from ascites of high grade OC patients before and after chemotherapy treatment as previously described [103]. Chemoresistance was determined when patients relapse and no longer respond to chemotherapy.…”