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Novel Extracellular Sulfatases and Smoke-induced Lung Cancer

Institution: University of California, San Francisco
Investigator(s): Steven Rosen, Ph.D.
Award Cycle: 2008 (Cycle 17) Grant #: 17RT-0117 Award: $394,380
Subject Area: Cancer
Award Type: Research Project Awards

Initial Award Abstract
Among all cancers, lung cancer is most frequently diagnosed and the leading cause of death worldwide. The majority of lung cancers are attributable to cigarette smoking, which results from exposure of airways to cancer-causing chemicals in tobacco smoke. There is great interest in the mechanisms, which cause lung cancer cells to grow in an uncontrolled manner, so that they form tumors. Scientists are therefore interested in the chemical messages that cause cancer cells to grow.

One type of “message” which is receiving a lot of attention in cancer research are proteins known as the “Wnts”. These proteins bind to the outside of cancer cells and stimulate them to grow. We are studying two proteins, which are responsible for controlling the amount of Wnts available on the outside of cells and thus can exert control on the growth of the cells. These proteins are called the “Sulfs”. They are called Sulf-1 and Sulf-2. We have been studying the Sulfs in pancreatic cancer and have found that they are very important in controlling the growth of these cancer cells. In our recent work, we have used published gene profiles of lung tumors from human patients and have found that the Sulf genes are significantly upregulated in this disease. We have also found the Sulfs in lung cancer cells that can be grown in plastic dishes. Some of the lung cancer cells have been isolated from human tumors (“tumor-derived’) and retain the ability to grow in an uncontrolled way as they did in the original tumor. We also have obtained another kind of lung cancer cell by treating normal cells of the lung with smoke (“smoke-induced’). This causes the cells to grow in an abnormal way and may mimic events that occur in tobacco-induced lung cancer. Our hypothesis is that the two classes of lung cancer cells need the Sulfs in order to grow.

To test the hypothesis, we have treated the lung cancer cells in such a way so as to greatly reduce the amount of Sulf-2 by a new “gene-silencing” method. We have determined that having less Sulf-2 protein caused the cells to grow at a slower rate in the plastic plates and caused them to die. Lung cancer cells can also form tumors when injected into mice. A further test of our hypothesis was to determine whether suppressing the amount of Sulf-2 in these cells resulted in smaller tumors in the mice. This finding was confirmed for both types of lung cancer cells. We plan to further study the role of the Sulfs in lung cancer. We have developed a series of antibodies against Sulf-2 and will test them in the same assays that were used in the gene silencing experiments above. We will also investigate the contributions of the other Sulf to the development of lung cancer using the same kinds of tools employed for Sulf-2. If our experiments are successful, the Sulfs should be considered as possible targets for new drugs. Our hypothesis predicts that if a drug reduces the amount of the Sulfs or blocks the function of the Sulfs in a tumor, the tumor will grow slower. This drug could be an antibody or a small molecule inhibitor. Our experiments with the smoke-induced lung cancer cells may tell us if the Sulfs are relevant to lung cancer, which arises from exposure to tobacco.

Thus, our work has great relevance to the mission of the TRDRP. Another potential benefit from our research concerns cancer screening. It is plausible that certain lung tumors (for example those related to tobacco smoking) may produce so much of the Sulfs that the proteins escape into the circulation and accumulate in the blood. Thus, detecting the Sulfs in blood might provide the basis of a diagnostic test for early tumors. There is a great need for new diagnostic tests in lung cancer (especially in high risk populations such as smokers), since early detection greatly improves prognosis. We will do pilot studies to see if the Sulfs become elevated in the blood of lung cancer patients.

Functional Consequences of the subdomain organization of the Sulf's
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Tang, R; & Rosen, S ART
Yr: 2009 Vol: 284 Nbr: Abs: Pg: 21505-21514

Direct detection of HSulf-1 and HSulf-2 activities on extracelluar heparan sulfate and their inhibition by PI-88
Periodical: Glycobiology Index Medicus:
Authors: Hossain, Hosono-Fukao, Tang, Sugaya, van Kuppevelt, Jenniskens, Kimata, Rosen, Uchimura ART
Yr: 2010 Vol: 20 Nbr: Abs: Pg: 175-186

Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenes.
Periodical: Oncogene Index Medicus:
Authors: Lemjabbar-Alaoui H, van Zante A, Singer MS, Xue Q, Wang Y, Tsay, He, Jablons, Rosen ART
Yr: 2010 Vol: 29 Nbr: Abs: Pg: 635-646