Researchers from Thomas Jefferson University have discovered that the
protein guanylyl cyclase C (GCC) is expressed in humans solely in the intestines,
including the colon and rectum, making it a selective marker for colorectal
tumors that metastasize. These findings appear in the December 10th issue
of the Proceedings of the National Academy of Sciences.
The research, led by Scott Waldman, MD, PhD, associate professor of
medicine, biochemistry and molecular pharmacology and acting director of
the division of clinical pharmacology, is groundbreaking because it has
the potential to lead to the first effective way of detecting colorectal
tumors once they spread beyond the intestines.
"The survival rate for patients who have metastatic colorectal
cancer is presently very poor, with only 5% surviving after five years,
because there has not been an effective way of tracking its spread to other
organs and present chemotherapy does not make an enormous impact,"
explains Dr. Waldman. "Knowing that GCC is specific to the intestines
allows us to use it as a tag or marker to detect where the cancer has spread."
Protein Expressed Only in Normal and Malignant Intestinal Cells
By examining human tissue samples with the reverse transcription-polymerase
chain reaction (RT-PCR), researchers discovered that GCC is expressed only
by two different cells in the body. It is present in the single layer of
cells that lines the normal intestine and continues to be expressed after
these cells undergo malignant transformation and migrate out of the intestines
into other sites. As a result of this, GCC acts as a marker, demarcating
the cancer's spread throughout the body.
Guanylyl cyclase C also is the receptor for the heat-stable enterotoxin
(ST) produced by Escherichia coli. With this working knowledge, the Jefferson
team exposed preparations of human tissues to ST and discovered that the
only tissues that interact with this small protein were those that expressed
GCC. Only tissues outside the intestine, containing metastatic colorectal
cancer, expressed GCC and interacted with ST.
"We found that ST effectively binds to GCC in all tissues which
contained metastatic colorectal cancer, regardless of the type of tissue
or its location," says Dr. Waldman. "It is our hope that this
research leads to new treatments that use ST as a guided missile to target
cancer-fighting poisons directly to metastatic tumor cells, without harming
normal surrounding tissues."
Diagnostic Tests and Therapies in the Works
Targeted Diagnostics and Therapeutics, Inc, a biotechnology company
that has acquired the worldwide exclusive license to the work from Dr.
Waldman's laboratory, is laying the groundwork for the birth of new diagnostic
and therapeutic options by developing a tissue biopsy test that will accurately
stage patients to determine whether colorectal cancer has spread outside
of the intestine. The company is also developing a blood test that will
determine whether colorectal cancer has spread beyond the intestine or
has recurred after definitive surgery. In addition, work has begun on new
therapeutics that will use ST to target and kill metastatic colorectal
"It is our goal to make diagnostic tests available for clinical
use in the next two to three years, reducing the number of lives colorectal
cancer claims each year, which is currently close to 50,000," says
Harry A. Arena, CPA, MBA, President and CEO of Targeted Diagnostics and