Possible cause and potential treatment found for aggressive head and neck cancer
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
According to researchers, this discovery could potentially lead
to new treatments.
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, said
lead author Lilly Bourguignon, PhD, a research career scientist at
SFVAMC and a professor of medicine at the University of California,
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 said.
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,
said 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
" In the
future, LARG could be utilized as a drug target leading to a new therapeutic
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
Bourguignon said that since the presence of EGFR marks particularly
" ... 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.
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Source: Source: University of California, San Francisco (UCSF).