Ernst Lengyel, M.D., Ph.D.

Understand the Role of Tumor-Associated Proteases in Ovarian Cancer Invasion and Metastasis and Identify Novel Targets for Treatment.

Research Summary

My laboratory is dedicated to improving our understanding of the biology of ovarian cancer growth and dissemination, and to exploring the use of novel drugs for its treatment. Ovarian cancer , has the highest mortality rate of all gynecologic tumors and is the 5th leading cause of cancer death among U.S. women. It is often diagnosed at a late stage when tumor cells are disseminated within the peritoneal cavity. After malignant transformation of ovarian surface epithelial cells and growth within the ovary, tumor cells detach from the ovary and attach to the peritoneum where they grow as nodules but rarely leave the peritoneal cavity. Despite this aggressive treatment more than two thirds of all patients succumb to their disease within 5 years.

Several classes of extracellular matrix degrading proteases have been shown to play an important role in tumor invasion and metastasis. We have chosen to focus on two of these, the plasminogen activator plasmin system and the matrix metalloproteases, and we are attempting to understand what role they play during the malignant transformation, invasion, dissemination, and recurrence of human ovarian cancer. Since many proteases are regulated transcriptionally, our focus is on the regulation of proteases in ovarian cancer cells and their interaction with adhesion molecules of the integrin class. We have shown that one protease receptor, the urokinase receptor, downregulates the B3-integrin receptor and therefore affects adhesion. Currently, we are investigating how protease and adhesion receptors regulate each other, and how this activity affects tumor cell attachment and proteolysis in vitro and in vivo. In addition, the laboratory is exploring the role of HGF and c-Met in breast and ovarian cancer to determine if c-Met is a therapeutic target. We have characterized HGF and c-Met expression and are now investigating the effect of the inhibition of c-Met on tumor growth and the dissemination of ovarian cancer cells.

We have performed our research with ovarian cancer cell lines and a mouse model of ovarian cancer, but we intend to test our hypothesis in human ovarian cancer tissue. Towards this end we have a large tumor bank and cooperate closely with Dr. Montag, a Gynecologic Pathologist at the University of Chicago. Ultimately, we hope to realize the major goal of the laboratory; to translate our findings and understanding of ovarian cancer tumor biology into novel therapeutic treatments of ovarian cancer.

Selected Papers

Lengyel E, Gum R, Juarez J, Sato H and Boyd D. (1995). Induction of Mr 92,000 Type IV collagenase expression in a squamous cell carcinoma cell line by fibrobasts. Cancer Research 55, 963-967.

Schaller G, Fuchs I, Pritze W, Ebert A, Kratzsch HC, Herbst H, Pantel K, Weitzel H and Lengyel E. (1996). Elevated Keratin 18 protein expression indicates a favorable prognosis in patients with breast cancer. Clinical Cancer Research 2 (11), 1879-1885.

Lengyel E, Wang H, Stepp E, Juarez J, Wang Y, Doe W, Pfarr CM and Boyd D. (1996). Requirement of an upstream AP-1 motif for the constitutive and phorbol ester-inducible expression of the urokinase-type plasminogen activator receptor gene. Journal of Biological Chemistry, 271, 23176-23184.

Lengyel E, Wang H, Gum R, Simon C, Wang Y and Boyd D. (1997). Elevated urokinase-type plasminogen activator receptor expression in a colon cancer cell line is due to a constitutively activated extracellular signal-regulated kinase-1-dependent signaling cascade. Oncogene 14, 2563-2574.

Ried S, Jäger C, Jeffers M, Vande Woude G, Graeff H, Schmitt M and Lengyel E. (1999). Activation mechanisms of the urokinase-type plasminogen activator promoter by hepatocyte growth factor/scatter factor (HGF/SF). Journal of Biological Chemistry 274, 16377-16386.

Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Harbeck N, Schmitt M and Lengyel E. (2000). Rac1 in human breast cancer: Overexpression, mutation analysis, and characterization of a new Rac1 isoform, Rac1b. Oncogene 19 (26), 3013-3020.

Hannke-Lohmann A, Pildner von Steinburg S, Dehne K, Benard V, Kolben M, Schmitt M and Lengyel E. (2000). Downregulation of the JNK signal transduction pathway in preeclampsia and HELLP syndrome. Obstetrics and Gynecology 96 (4), 582-587.

Lengyel E, Ried S, Heiss MM, Jäger C, Schmitt M, Allgayer H. (2001). Ras regulation of urokinase-type plasminogen activator. Methods in Enzymology 333, 105-116.

Hapke S, Gawaz M, Reuning U, Köhler J, Dehne K, Marshall JF, Graeff H, Schmitt M and Lengyel E. (2001). Overexpression of B3A-integrin downregulates urokinase-type plasminogen activator receptor (u-PAR) expression through a PEA3/ets transcriptional silencing element in the u-PAR promoter. Molecular and Cellular Biology 21 (6), 2118-2132.

Schmalfeldt B, Prechtel D, Härthing K, Späthe K, Rutke S, Berger U, Schmitt M, Kuhn W and Lengyel E. (2001). Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-typeplasminogen activator is associated with progression from benign to advanced ovarian cancer Clincal Cancer Research 7 (8), 2396-2404.

Besta F, Massberg S, Brand K, Müller E, Page S, Grüner S, Lorenz M, Sadoul K, Kolanus W, Lengyel E and Gawaz M. (2002). Role of B3-endonexin in the regulation of NF-kB-dependent expression of urokinase-type plasminogen activator receptor Journal of Cell Science, 115, 3879-3888.