March 6, 2013
Human Cancer Tumors Replicated In Mice And Then Cured
April Flowers for redOrbit.com - Your Universe Online
A group of scientists led by UT Southwestern Medical Center has reported the first successful blocking of tumor development in a genetic mouse model of an incurable human cancer.
"To my knowledge, this is the first time that a mouse model of a genetically defined malignant human cancer has been generated in which the formation of the tumor from beginning to end can be monitored and in which blocking the pathway cures the mouse of the tumor," said Dr. Luis Parada, chair of the department of developmental biology at UT Southwestern.
The study results are described both online and in the recent issue of Cell.
"We showed that blocking the activity of a receptor molecule named CXCR4 in these tumors — through genetic manipulation or by chemical blockade — inhibited tumor development. Together, these data reveal a potential target for therapy of these uncommon but currently untreatable malignant peripheral nerve sheath tumors (MPNSTs)," Dr. Parada added.
The study is the result of collaboration between the scientists of Dr. Parada's laboratory and Dr. Lu Q. Le, assistant professor of dermatology and director of the adult Comprehensive Neurofibromatosis Clinic at UT Southwestern. This is the first clinic of its kind in North Texas and is part of the Simmons Cancer Center. The research efforts were greatly accelerated by collaborators at The University of Texas MD Anderson Cancer Center and Baylor College of Medicine, Houston.
Rare but highly aggressive tumors, MPNSTs are resistant to therapy and typically fatal. The tumors can occur sporadically or in a subset of patients with a condition called neurofibromatosis 1 (NF1). NF1 is one of the most commonly inherited disorders of the nervous system, affecting an estimated 1 in 3,500 people.
Even among family members, the severity of NF1 can vary widely, ranging from mild dermatological symptoms to benign tumors. Such tumors wrap around nerves and can be disfiguring, debilitating, and even life threatening depending on where they form. Patients with an improperly functioning NF1 gene also have an increased risk of developing cancerous tumors such as MPNSTs.
The mouse model created for the study spontaneously develops MPNSTs. The researchers compared gene expression activity in cancerous tumors and in the precursor cells that give rise to the tumors. These precursor cells are where MPNSTs develop.
The comparison showed that a a protein (CXCR4), which is essential for tumor growth, is more abundant in cancerous cells than in precursor cells. The team also found that a molecule (CXCL12) produced by the cancer cells themselves works with CXCR4 to further the growth of cancer by stimulating the expression of the cyclin D1 protein. The cyclin D1 protein promotes cell division through a signaling pathway outlined in the study.
The scientists found increased expression of CXCR4 accompanied by activity in the same pathway as the one identified in the mice when they examined human MPNSTs.
The scientists blocked the activity of CXCR4 in the MPNST mice next, using either genetic manipulation or an FDA-approved antagonist drug for CXCR4 called AMD3100. Cancer development in mice whose tumors expressed increased levels of CXCR4 were inhibited by both strategies. Additionally, both were found to be less effective in tumors without increased CXCR4 expression. This was true in human cancer cells as well.
"We are very encouraged by these findings because they provide us with new directions and therapeutic windows to combat this deadly cancer, where none exist today," said Dr. Le, who added that the researchers are currently planning human trials.