William Schiemann Associate Professor Department of Pharmacology MS 8309, RC1 S, L18-6110 Phone: (303) 724 1541   E-mail: Bill.Schiemann@uchsc.edu

The process of tumorigenesis and its assortment of associated genetic and epigenetic events enable newly malignant cells to evade the cytostatic activities of TGF-b, which normally functions as a potent antagonist of tumorigenesis. As cancer cells continue down the evolutionary path towards advanced malignancy, they ultimately acquire the ability to transform the cytostatic signals produced by TGF-b into oncogenic activities, including enhanced proliferation, invasion, and metastasis. Clinically, the acquisition of invasive and metastatic phenotypes by malignant cells represents the most lethal characteristics of cancer and the leading causes of cancer-related death.

The primary goal of our research is to solve the “TGF-b Paradox,” which refers the mysterious mechanisms whereby cancer cells convert the biological actions of TGF-b (i.e., tumor suppression) into pathological symptoms (i.e., tumor promotion). Indeed, deciphering this pathophysiological puzzle remains the most important and unanswered question concerning the physiological functions of this multifunctional cytokine. In trying to unravel this mystery, we combine contemporary techniques in molecular and cellular biology, in biochemistry, and in genomic- and proteomic-based differential gene expression analyses. We also translate our in vitro analyses into animal models capable of interrogating the function of TGF-b in promoting (i) the growth, invasion, and metastasis of mammary tumors produced in mice, and (ii) the development of angiogenesis under normal and malignant conditions in mice.

Major ongoing research efforts are directed at understanding (i) the role of integrins and protein tyrosine kinases in regulating the oncogenic activities of TGF-b; (ii) the function of NF-kB and Cox-2 in mediating breast cancer cell resistance to TGF-b; and (iii) the mechanisms whereby altered tumor microenvironments and tissue tension impact breast cancer cell response to TGF-b. A final focus of the lab seeks to translate and develop these findings into novel cancer chemotherapeutics capable of selectively targeting the oncogenic activities of TGF-b and, consequently, of “normalizing” malignant tissues in such a way that cancer itself can be converted from an acute, symptomatic, and life-threatening disease to one that is chronic, asymptomatic, and manageable through the normal lifespan of affected individuals.

Selected Publications

Albig, A.R., Roy, T.G. and Schiemann, W.P. (2007) Transcriptome analysis of endothelial cell gene expression induced by growth on Matrigel matrices: Identification and characterization of MAGP-2 and lumican as novel regulators of angiogenesis. Angiogenesis. 10, 197-216.

Galliher, A.J. and Schiemann, W.P. (2007) Src phosphorylates Tyr284 in TbR-II and regulates TGF-b stimulation of p38 MAP kinase during breast cancer cell proliferation and invasion. Cancer Research. 67, 3752-3758.

Freire-de-Lima, C.G., Xiao, Y.Q., Gardai, S.J., Bratton, D.L., Schiemann, W.P. and Henson, P.M. (2006) Apoptotic cells, through transforming growth factor-b coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. Journal of Biological Chemistry. 281, 38376-38384.

Galliher, A.J. and Schiemann, W.P. (2006) b3 integrin and Src facilitate TGF-b-mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Research. 8, R42.

Albig, A.R., Neil, J.R. and Schiemann, W.P. (2006) Fibulins 3 and 5 antagonize tumor angiogenesis in vivo. Cancer Research. 66, 2621-2629.

Sokol JP, Neil JR, Schiemann BJ, Schiemann WP. The use of cystatin C to inhibit epithelial-mesenchymal transition and morphological transformation stimulated by transforming growth factor-beta. Breast Cancer Res. 2005;7(5):R844-53. Epub 2005 Aug 23.

Albig AR, Schiemann WP. Identification and characterization of regulator of G protein signaling 4 (RGS4) as a novel inhibitor of tubulogenesis: RGS4 inhibits mitogen-activated protein kinases and vascular endothelial growth factor signaling. Mol Biol Cell. 2005 Feb;16(2):609-25. Epub 2004 Nov 17.

Albig AR, Schiemann WP. Fibulin-5 antagonizes vascular endothelial growth factor (VEGF) signaling and angiogenic sprouting by endothelial cells. DNA Cell Biol. 2004 Jun;23(6):367-79.

Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW, Schwarz MI, Cool CD, Worthen GS. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Respir Crit Care Med. 2004 Aug 1;170(3):242-51. Epub 2004 Apr 29.

Schiemann WP, Rotzer D, Pfeifer WM, Levi E, Rai KR, Knaus P, Kadin ME. Related Articles, Links
Transforming growth factor-beta (TGF-beta)-resistant B cells from chronic lymphocytic leukemia patients contain recurrent mutations in the signal sequence of the type I TGF-beta receptor. Cancer Detect Prev. 2004;28(1):57-64.

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