BA (Molecular Biology and German), Wellesley College, Wellesley, MA, 1976. MPhil (Pharmacology), Yale University, New Haven, CT, 1978. PhD (Pharmacology), Yale University, New Haven, CT, 1981. Postdoctoral Fellow, Cancer Research Center, University of North Carolina, Chapel Hill, NC, 1980-1982.
Dr. Siegfried investigates the role of growth factors and hormones in the development and growth of human lung cancer. The laboratory focuses on the effects of these cytokines on activation of cell signaling pathways and control of tumor growth, as well as their role in risk for cancer. Growth factors and their receptors currently under investigation include estrogen and its receptors and hepatocyte growth factor and its receptor, c-Met. Growth factors and hormones are also being investigated as possible therapeutic targets and diagnostic or prognostic indicators for lung cancer. Hepatocyte growth factor has been found to be a strong negative prognostic indicator for non-small cell lung cancer, and expression of the enzyme aromatase that mediates estrogen production has also been linked to poor outcome in women with lung cancer. Circulating growth factor levels may also correlate with active cancer. These studies are directed toward development of new methods to identify undetected lung cancer and new therapeutic strategies through increased knowledge of growth-regulatory processes in lung cancer cells.
Hepatocyte growth factor (HGF) and its receptor c-Met are a ligand-receptor pair that initiates signaling pathways promoting proliferation, survival, angiogenesis, and invasion. HGF is a mainly paracrine growth factor that is secreted by fibroblasts in the lung and acts upon the c-Met receptor expressed by airway epithelial and endothelial cells. In lung cancer, c-Met is often upregulated and the tumor cells induce elevated HGF production by neighboring stroma. Elevated HGF in lung cancer patients with early stage disease has identified a population of patients who are most likely to recur and die from their disease. As shown in the Kaplan-Meier survival curves, HGF levels above the median of 22 units was associated with a higher proportion of deaths from all causes (A), lung-cancer specific deaths (B), and recurrence events (C). This observation among others has led us to focus on therapeutic targeting of HGF and its receptor c-Met for control of lung cancer.
To test therapeutic strategies, Dr. Siegfried has engineered a transgenic mouse that over-expresses the human HGF gene in the airways by placing the HGF gene under the control of the Clara cell secretory protein (CCSP) promoter. The lungs of these mice produce human HGF mRNA and protein and contain 2-3 times as many clara cells per micron of airway length as wild-type mice. While the mice show some abnormalities in airway branching, they have normal airway function and they do not develop lung tumors spontaneously at a rate above that of wild-type animals. However, the HGF transgenic mouse is more susceptible to the development of lung tumors initiated by the tobacco carcinogen NNK. Lung tumors produced by carcinogen treatment in the HGF transgenic animal are more invasive and contain higher numbers of blood vessels than wild-type tumors. These effects can be inhibited by a neutralizing antibody to HGF that is now in development for clinical use.
The Siegfried laboratory was one of the first to demonstrate the functional significance of estrogen receptors in lung tumors. This figure shows immunohistochemical staining of a non-small cell lung tumor for the estrogen receptor ß, which we have found to be expressed to some degree in over 85% of lung tumors. Staining is observed both in the nucleus and cytoplasm, and we have evidence that both nuclear signaling through ERE elements in the promoter regions of estrogen-sensitive genes, as well as non-nuclear signaling through the EGFR and MAPK pathway occur in lung tumor cells.
Dr. Siegfried also has evidence that estrogen is locally produced by the enzyme aromatase within lung tumors, and this suggests an autocrine ligand-receptor exists for estrogen and its receptor in many lung tumors. Clinical trials are currently on-going to test the clinical activity of estrogen antagonists for therapy of lung cancer.
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