Abstract
BackgroundHyaluronan (HA) an important component of the extracellular matrix, has been linked to tumor progression and drug resistance in several malignancies. However, limited data is available for ovarian cancer. This study investigated the role of hyaluronan (HA) and a potential link between the HA-CD44 pathway and membrane ATP binding cassette (ABC) transporter proteins in ovarian cancer chemoresistance.MethodsWe investigated the ability of HA to block the cytotoxic effects of the chemotherapy drug carboplatin, and to regulate the expression of ABC transporters in ovarian cancer cells. We also examined HA serum levels in ovarian cancer patients prior to and following chemotherapy and assessed its prognostic relevance.ResultsHA increased the survival of carboplatin treated ovarian cancer cells expressing the HA receptor, CD44 (OVCAR-5 and OV-90). Carboplatin significantly increased expression of HAS2, HAS3 and ABCC2 and HA secretion in ovarian cancer cell conditioned media. Serum HA levels were significantly increased in patients following platinum based chemotherapy and at both 1st and 2nd recurrence when compared with HA levels prior to treatment. High serum HA levels (>50 μg/ml) prior to chemotherapy treatment were associated with significantly reduced progression-free (P = 0.014) and overall survival (P = 0.036). HA production in ovarian cancer cells was increased in cancer tissues collected following chemotherapy treatment and at recurrence. Furthermore HA treatment significantly increased the expression of ABC drug transporters (ABCB3, ABCC1, ABCC2, and ABCC3), but only in ovarian cancer cells expressing CD44. The effects of HA and carboplatin on ABC transporter expression in ovarian cancer cells could be abrogated by HA oligomer treatment. Importantly, HA oligomers increased the sensitivity of chemoresistant SKOV3 cells to carboplatin.ConclusionsOur findings indicate that carboplatin chemotherapy induces HA production which can contribute to chemoresistance by regulating ABC transporter expression. The HA-CD44 signaling pathway is therefore a promising target in platinum resistant ovarian cancer.
Highlights
Hyaluronan (HA) an important component of the extracellular matrix, has been linked to tumor progression and drug resistance in several malignancies
Chemotherapy treatment increases HA production and ABCC2 expression by ovarian cancer cells We investigated whether CBP increases HA production and the expression of ABCC2, an ATP binding cassette (ABC) transporter shown to confer ovarian cancer cell resistance to platinum based chemotherapy agents including CBP [13,39]
Our results show that HA induces chemoresistance against CBP, and increases the expression of the ABC transporters, ABCB3, ABCC1, ABCC2, and ABCC3 in ovarian cancer cell lines expressing the HA receptor, CD44
Summary
Hyaluronan (HA) an important component of the extracellular matrix, has been linked to tumor progression and drug resistance in several malignancies. This study investigated the role of hyaluronan (HA) and a potential link between the HA-CD44 pathway and membrane ATP binding cassette (ABC) transporter proteins in ovarian cancer chemoresistance. A well established cause involves increased expression of members of the membrane efflux ATP binding cassette (ABC) transporter family, which decrease the intracellular accumulation and retention of chemotherapy drugs [3]. ABCB1 plays a critical role in drug fluxes and chemoresistance in many malignancies, including ovarian cancer [7,8,9,10]. Other ABC transporters, including ABCB3 (TAP2), ABCC1 (MRP1), ABCC2 (MRP2, cMOAT), and ABCC3 (MRP3), have been shown to be involved in ovarian cancer chemoresistance [11,12,13,14,15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
