Researchers at the San Francisco VA Medical Center report that they have found a potential molecular cause for the aggressive growth and spread of human head and neck squamous cell carcinoma, a highly malignant form of cancer with a very high death rate.

The discovery could potentially lead to new treatments as well, say the researchers.

Their key finding is the triple interaction between three players: CD44, a surface receptor molecule that plays an important role in a variety of cellular functions; hyaluronan (HA), a complex carbohydrate found in the connective tissues between cells; and LARG, a signal activator found in tumor cells.

That interaction apparently initiates two molecular pathways that simultaneously cause tumor cell growth and tumor cell migration, says lead author Lilly Bourguignon, PhD, a research career scientist at SFVAMC and a professor of medicine at the University of California, San Francisco.

The study results are reported in the current on-line “In Press” section of the Journal of Biological Chemistry.

Working with human cancer cells in culture, Bourguignon and her team found that HA mediates the interaction between CD44 and LARG in a way that stimulates a molecular pathway called RhoA. Through a series of complex steps, the RhoA pathway causes the tumor cell’s cytoskeleton - the structure that maintains the cell’s shape - to reorganize in a way that causes tumor cells to migrate to other sites in the body, resulting in cancer metastasis.

At the same time, the HA-mediated CD44/LARG complex also binds with epidermal growth factor receptor (EGFR), located on the tumor cell’s surface, which sets off a second molecular pathway called Ras. In turn, the Ras pathway promotes tumor cell growth.

The result, according to Bourguignon, is an aggressive, fast-growing, and invasive cancer. “The combination of RhoA and Ras pathway activation is deadly,” she says.

Bourguignon cautions that “this is not the only mechanism” by which aggressive head and neck squamous cell carcinoma grows and spreads, “but it is an important mechanism.”

Because LARG is a central player in these molecular interactions, says Bourguignon, it may be the key to a potential treatment that could prevent both pathways from being initiated in the first place.

She and her fellow researchers found that when a particular segment of LARG, called the PDZ domain, is introduced to the tumor cell, it binds up all available CD44 and EGFR, leaving them unavailable to initiate the deadly twin molecular pathways.

“We have used the molecular binding action of LARG-PDZ against itself,” says Bourguignon. “In the future, LARG could be utilized as a drug target leading to a new therapeutic strategy.”

Currently, there are no really effective chemotherapeutic treatments for human head and neck squamous cell carcinoma, according to Bourguignon. “There are drugs that block EGFR action, but they are not entirely effective,” she notes.

Bourguignon says that since the presence of EGFR marks particularly aggressive cancers, “the CD44/EGFR complex can be used as a marker for potentially aggressive head-neck tumors. This could be correlated with tumor degree and tumor progression in each patient to get a much more accurate picture of the cancer. Most importantly, this complex may be used a clinical predictor for evaluating the potential of head and neck cancers to metastasize,” or spread beyond the initial tumor site.

Co-authors of the study are Eli Gilad, PhD, Amy Brightman, BS, Falko Diedrich, MD, and Patrick Singleton, PhD, all of SFVAMC.

http://www.jbc.org/