The Extracellular Matrix Influences Ovarian Carcinoma Cells’ Sensitivity to Cisplatinum: A First Step towards Personalized Medicine

Abstract

The development of personalized therapies for ovarian carcinoma patients is still hampered by several limitations, mainly the difficulty of predicting patients’ responses to chemotherapy in tumor cells isolated from peritoneal fluids. The main reason for the low predictive power of in vitro assays is related to the modification of the cancer cells’ phenotype induced by the culture conditions, which results in changes to the activation state and drug sensitivity of tumor cells compared to their in vivo properties. We have defined the optimal culture conditions to set up a prognostic test to predict high-grade serous ovarian carcinoma (HGSOC) patients’ responses to platinum chemotherapy. We evaluated the effects of hyaluronic acid (HA) and fibronectin matrices and the contribution of freezing/thawing processes to the cell response to platinum-based treatment, collecting spheroids from the ascitic fluids of 13 patients with stage II or III HGSOC. Our findings indicated that an efficient model used to generate predictive data for in vivo sensitivity to platinum is culturing fresh spheroids on HA, avoiding the use of previously frozen primary tumor cells. The establishment of this easy, reproducible and standardized testing method can significantly contribute to an improvement in therapeutic effectiveness, thus bringing the prospect of personalized therapy closer for ovarian carcinoma patients.

Evaluation of the Role of ITGBL1 in Ovarian Cancer

“…We also observed slightly increased in-vitro chemoresistance in ITGBL1-overexpressing cells; this may be explained only by more efficient ECM proteins deposition providing physical barrier for drug diffusion [ 35 , 36 ], since no classical pathways related with chemoresistance were found in our analysis. Of note, Song et al [ 25 ] also showed that ITGBL1 confers in-vitro resistance to cisplatin and paclitaxel, as well as in-vivo resistance to cisplatin (paclitaxel not tested).…”

Small extracellular vesicles from malignant ascites of patients with advanced ovarian cancer provide insights into the dynamics of the extracellular matrix

“…The same authors underline that the availability of fibronectin to cancer cells is a molecular factor that is critical for metastasis. Functionally, fibronectin induces tumor cell adhesion, proliferation, and invasion and promotes spheroid formation and adhesion [ 22 , 34 ]. Moreover, increased expression of fibronectin, a key component of the ECM, has been detected in OC metastases compared with the primary ovarian tumor [ 36 ].…”

“…Cells were seeded on 6‐well plates (Corning, New York, NY, USA) coated with 50 µg·mL −1 of HMW HA. EOC cells were grown at 37 °C, 5% v/v CO2 in human endothelial serum‐free medium (HESFM), containing 20 ng·mL −1 b‐FGF, 10 ng·mL −1 EGF, 10% fetal bovine serum (FBS), and 1% penicillin/streptomycin [ 22 , 23 ]. Once EOC cells reached 95% confluency within 3–5 days, they were detached and plated in T75 flasks coated with HMW HA and employed within 1/2 passages.…”

Role of Hyaluronic Acid in Selected Malignant Neoplasms in Women

“…It was associated with a shorter OS (p < 0.001), higher disease stage (stage III/IV), and risk of vascular space invasion [15], and thus, CD44 was identified as a potential and independent prognostic indicator of shorter survival of patients with high-grade OC. According to a recent study by Balduit et al [98] among high-grade OC patients with stage II/III disease (according to FIGO), as well as on two cancer cell lines (OVCAR-3, SKOV-3), both HA and fibronectin were found in ovarian tissues. HA enhanced the resistance of cancer cells to the applied treatment with cisplatin, while fibronectin, on the other hand, promoted the proliferation and invasion of cancer cells through the induction of ERK and p38 signaling [98].…”

“…According to a recent study by Balduit et al [98] among high-grade OC patients with stage II/III disease (according to FIGO), as well as on two cancer cell lines (OVCAR-3, SKOV-3), both HA and fibronectin were found in ovarian tissues. HA enhanced the resistance of cancer cells to the applied treatment with cisplatin, while fibronectin, on the other hand, promoted the proliferation and invasion of cancer cells through the induction of ERK and p38 signaling [98].…”