Like many biomedical researchers, George Tuszynski would like to cure cancer. But in his quest, he may have stumbled across a solution to a humbler problem: wrinkled skin. Professor of Neuroscience in Temple’s School of Medicine and Professor of Biology in Temple’s College of Science and Technology.
Tuszynski and his group, along with In Kine Pharmaceutical Co., a small pharmaceutical company based in Blue Bell, PA, have developed three molecules that prevent tumor growth by inhibiting blood vessel formation, which is called angiogenesis. One of the molecules has been named angiocidin, while the other two are peptides.
Angiocidin, a tumor-inhibiting novel protein discovered by Temple University researchers, was revealed last year to have a therapeutic application in treating leukemia. The study, “The Novel Angiogenic Inhibitor, Angiocidin, Induces Differentiation of Monocytes to Macropahges,” published in 2008 in the journal Cancer Research. The research was done by Temple biology doctoral student Anita Gaurnier-Hausser under Tuszynski’s direction.
What cancer has in common with aging skin is that in both conditions, cells have stopped growing properly. Stem cells, characterized by their ability to renew themselves through mitotic cell division and differentiating into a diverse range of specialized cell types, create healthy well-behaved cells. Tuszynski has shown that he “can repair damaged skin. Given the right stem cells, you can make the cells grow up and behave.”
“Angiocidin is a protein that has a lot of anti-cancer activity and inhibits angiogenesis, a physiological process involving the growth of new blood vessels from pre-existing vessels, which is a fundamental step in the transition of tumors from a dormant state to a malignant state,” said Tuszynski, who discovered the protein.
Tuszynski said that over the years, the researchers had looked at the protein’s effect on solid tumors like breast cancer, prostate cancer and colon cancer.
“All of these cancers are inhibited by Angiocidin by virtue of the fact that this protein inhibits vascularization or the formation of new vessels,” he said. “We decided we wanted to look to see if Angiocidin had any effect on hematologic malignancy, and we chose leukemia.”
Tuszynski said leukemia cells arise from monocytes, a specific white blood cell that is a part of the human body’s immune system that protects against bloodborne pathogens and moves quickly to sites of infection. As monocytes enter tissue, they undergo a series of changes to become macrophages.
When the researchers treated the leukemia cells, “our molecule was able to induce a differentiation of these monocytic leukemia cells into a normal, macrophage-like phenotype,” he said.
“This indicates perhaps a new therapeutic application for this protein, that it could differentiate hematologic malignancies into a normal-like state, allowing then for chemotherapy because normal cells are susceptible to chemotherapy treatment,” said Tuszynski, who is also a member of the Sol Sherry Thrombosis Research Center in Temple’s School of Medicine.
He added, however, that Angiocidin must remain present with the differentiated cells or they will revert back to their leukemia phenotype. “We haven’t repaired the genetic abnormality in the cell, but what we have done is push them into a more normal phenotype that could then be treated more easily.”
Tuszynski also said that the research demonstrates the ability of Angiocidin to stimulate the body’s immune system by differentiating monocytic cells into macrophages, which function to ingest bacteria and protein debris as part of the immune system.
“We did gene array analysis of the differentiated versus the undifferentiated cells and we discovered that there were many genes characteristic of immune cells that were up-regulated in the differentiated leukemia cells,” he said. “That Angiocidin can stimulate differentiation and stimulate the immune system is basically a new activity that we discovered with this protein that we had never really anticipated before.”
The research was funded by the National Institutes of Health and Temple University.
In 1987, our laboratory first showed that thrombospondin -1 (TSP-1), a platelet protein, functioned as a cell and platelet adhesive protein and that TSP-1 could promote metastasis formation in a murine model of experimental metastasis. Since then we have identified structural domains within the TSP-1 molecule and a new TSP-1 receptor that may mediate cell-cell and cell-substratum interactions operative during the metastatic cascade and the process of angiogenesis. We found that a number of peptides homologous to CSVTCG promoted the adhesion of a variety of normal and tumor cells and inhibited platelet aggregation and tumor cell metastasis, whereas control peptides had no effect. Our results further demonstrated that these peptides inhibited tumor lung metastases and angiogenesis presumably by competing with endogenous TSP-1 for TSP-1 tumor cell receptor sites. This conclusion was further supported by the observation that anti-CSTSCG antibody, which specifically recognized TSP-1, inhibited TSP-1-dependent cell adhesion, platelet aggregation, and tumor cell metastasis, whereas control IgG had no effect. These results suggest that CSVTCG and CSTSCG present in the type I repeat sequences of TSP-1 function in the adhesive interactions of TSP-1 that mediate platelet aggregation, angiogenesis and tumor cell metastasis.
The TSP-1 receptor specific for the CSVTCG residues in the type 1 repeats of TSP-1 was isolated from lung carcinoma by CSVTCG-Sepharose chromatography. Anti-receptor IgG and inhibited lung carcinoma cell spreading and adhesion and platelet adhesion on TSP-1 but not on fibronectin and laminin. Anti-CSVTCG receptor antibody blocked breast cancer invasion in vitro and metastasis and tumor progression in an in vivo athymic model of breast cancer progression. These data as well as immunohistochemical studies showing that this receptor highly over-exepressed in breast carcinoma and its neovasculature as well as many other tumors, including lung, melanoma, ovarian, prostate, pancreatic, colon, gastric, and hepatocelluar carcinoma and that this receptor is predictive of poor patient outcome in squamous carcinoma of the head and neck strongly support the conclusion that both TSP-1 and its receptor mediate cancer progression.
The receptor has recently been cloned and expressed as a soluble protein in bacteria. Recombinant protein, referred to as angiocidin, specifically inhibited endothelial adhesion, tube formation and viability, while having no effect on a variety of cells including fibroblasts, smooth muscle cells, and tumor cells. Angiocidin localized to the vasculature and inhibited Lewis Lung carcinoma and B16F10 melanoma growth in mice by more than 95%. Similarly, a monoclonal receptor antibody inhibited more than 50% tumor growth. Therefore, angiocidin may be new target for the development of an anti-angiogenic agent for the treatment of cancer.
Based on these results, we believe that CSVTCG peptides and the CSVTCG specific TSP-1 receptor (angiocidin) are targets for the development of cancer therapeutics, angiogenesis inhibitors and imaging agents as well as anti-thrombotics. Preclinical studies are now underway in preparation for the use of angiocidin, anti-angiocidin antibodies and the CSVTCG peptides for the treatment of cancer in man. Finally our laboratory is searching for new molecules and new mechanisms that can be targeted for development of cancer therapeutics and diagnostics. In collaboration with Dr. Mahesh Sharma, we have identified annexin II as a potential receptor mediating angiogenesis and tumor progression. We have developed a monoclonal annexin II antibody that reduces tumor growth by more than 50%. This antibody may also find utility as a diagnostic tool for the detection of annexin II in sera and solid tumors.
Posted by Paul Statt 
Paul Statt Communications 