Importance of hyaluronan and CD44 in metastasis

Abstract

Previous studies have shown that the level of hyaluronic acid (HA) in the lung tumor stroma correlates with tumor aggressiveness; supporting the hypothesis that HA promotes cell migration and invasion. The lack of information regarding HA and its relation with lung cancer, in addition to the possible role of this extracellular matrix molecule in the development of neoplasias, encouraged us to develop a collaboration with Prof Dr. Heldin's lab. Recently, the involvement of hyaluronan in the early invasive phase of a clone of breast cancer cell line MDA-MB-231 that forms bone metastases was studied using an in vivo-like basement membrane model. The metastatic to bone tumor cells exhibited a 7-fold higher hyaluronan-synthesizing capacity compared with MDA-MB-231 cells predominately due to an increased expression of hyaluronan synthase 2 (HAS2). Heldin et al, 2011, found that knockdown of HAS2 completely suppressed the invasive capability of these cells by the induction of tissue metalloproteinase inhibitor 1 (TIMP-1) and dephosphorylation of focal adhesion kinase (FAK). HAS2 knockdown-mediated inhibition of basement membrane remodeling was rescued by HAS2 overexpression, transfection withTIMP-1 siRNA, or addition of TIMP-1-blocking antibodies. Moreover, knockdown of HAS2 suppressed the EGF-mediated induction of the FAK/PI3K/Akt signaling pathway. Thus, this study provides new insights into a possible mechanism during breast cancer progression whereby FAK functions downstream of activated EGF receptor and silencing of HAS2 interferes with that signaling. So, the major goal of this internship is to develop an in vivo-like model to explore the role of HAS2-synthesized hyaluronan and its interaction with CD44 in breast cancer progression as well as develop the student skills in relation to extracellular matrix and cancer research, including lung cancer. (AU)