Breast cancer is a common cancer in women. Breast cancer cells synthesize large amounts of hyaluronan to assist their proliferation, survival, migration and invasion. Accumulation of hyaluronan and overexpression of its receptor CD44 and hyaluronidase TMEM2 in breast tumors correlate with tumor progression and reduced overall survival of patients. Currently, the only known small molecule inhibitor of hyaluronan synthesis is 4-methyl-umbelliferone (4-MU). Due to the importance of hyaluronan for breast cancer progression, our aim was to identify new, potent and chemically distinct inhibitors of its synthesis. Here, we report a new small molecule inhibitor of hyaluronan synthesis, the thymidine analog 5′-Deoxy-5′-(1,3-Diphenyl-2-Imidazolidinyl)-Thymidine (DDIT). This compound is more potent than 4-MU and displays significant anti-tumorigenic properties. Specifically, DDIT inhibits breast cancer cell proliferation, migration, invasion and cancer stem cell self-renewal by suppressing HAS-synthesized hyaluronan. DDIT appears as a promising lead compound for the development of inhibitors of hyaluronan synthesis with potential usefulness in breast cancer treatment.

Hyaluronan is one of the major components of the extracellular matrix and is involved in the regulation of multiple processes in both human physiology and disease. In human cancers, hyaluronan metabolism displays remarkable alterations, leading to the accumulation of large amounts of hyaluronan matrices in the tumoural tissues. The altered levels of hyaluronan in the tumours stem from the enhanced expression and activity of hyaluronan synthases in both tumour and stromal cells. Moreover, hyaluronidase activity is also upregulated in cancer, leading to the generation of lower molecular weight hyaluronan fragments that in turn assist tumour growth, neo-angiogenesis and the metastatic cascade. Hyaluronan accumulation in malignant tissues not only assists tumour growth and metastases but is also associated with worse outcomes in cancer patients. Therefore, targeting hyaluronan synthesis emerges as an interesting strategy that might be employed for cancer treatment. This review article summarises current evidence and discusses ways to move forward in the field of targeting hyaluronan synthesis for cancer therapy.

Lysophosphatidic acid (LPA) is a phospholipid that displays potent signalling activities that are regulated in both an autocrine and paracrine manner. It can be found both extra- and intracellularly, where it interacts with different receptors to activate signalling pathways that regulate a plethora of cellular processes, including mitosis, proliferation and migration. LPA metabolism is complex, and its biosynthesis and catabolism are under tight control to ensure proper LPA levels in the body. In cancer patient specimens, LPA levels are frequently higher compared to those of healthy individuals and often correlate with poor responses and more aggressive disease. Accordingly, LPA, through promoting cancer cell migration and invasion, enhances the metastasis and dissemination of tumour cells. In this review, we summarise the role of LPA in the regulation of critical aspects of tumour biology and further discuss the available pre-clinical and clinical evidence regarding the feasibility and efficacy of targeting LPA metabolism for effective anticancer therapy.