The discovery of the molecular mechanism behind the aggressive head and neck cancer was unveiled by the researchers at the San Francisco VA Medical Center (SFVAMC). It is a highly malignant form of cancer with a very high death rate. They have discovered the triple interaction between CD44, hyaluronan (HA), and LARG. CD44 is a surface receptor molecule that plays an important role in a variety of cellular functions. Hyaluronan (HA) is a complex carbohydrate found in the connective tissues between cells. LARG is a signal activator found in tumor cells. The triple interaction results in the initiation of two molecular pathways that simultaneously cause tumor cell growth and tumor cell migration.
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Lilly Bourguignon, PhD, a research career scientist at SFVAMC and a professor of medicine at the University of California, San Francisco is the lead author. The study results are reported In Press section of the Journal of Biological Chemistry. Bourguignon and her team found that HA mediates the interaction between CD44 and LARG in a way that stimulates a molecular pathway called RhoA. It causes the tumor cell's cytoskeleton to reorganize such that the tumor cells migrate to other sites in the body, resulting in cancer metastasis. Then the HA-mediated CD44/LARG complex binds with epidermal growth factor receptor (EGFR), located on the tumor cell's surface.
This initiates another molecular pathway called Ras which promotes the growth of the tumor cells. LARG is a central player in these molecular interactions and can be used in the potential treatment that could prevent both pathways from being initiated. Inside the LARG segment there is a PDZ domain which when introduced into the tumor cell, it binds up all available CD44 and EGFR, leaving them unavailable to initiate the deadly twin molecular pathways. In the future, LARG could be utilized as a drug target leading to a new therapeutic strategy. The CD44/EGFR complex can be used as a marker for potentially aggressive head-neck tumors. This complex may be used a clinical predictor for evaluating the potential of head and neck cancers to metastasize.
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