My laboratory has been centered around angiogenesis factors released from tumor cells as molecularly defined therapeutic targets. We have purified a novel heparin-binding polypeptide growth factor (pleiotrophin, PTN) from supernatants of breast cancer cells and cloned the respective genomic and cDNA. The respective protein is secreted from different human tumor cells, is expressed in a number of primary human tumors (breast, prostate and lung cancer and melanoma), and can function as an angiogenesis factor. Since this gene is normally only expressed at appreciable levels during embryonal development, we have been interested in the mechanisms depression during the malignant process and have charactered different promoter and enhancer elements as regulators of the gene. In addition, we have generated different cell lines overexpressing the pleiotrophin gene to obtain defined targets for in vitro and in vivo studies of drugs that inhibit this gene product and have targeted the transcript with ribozymes. Finally, we have generated sufficient amounts of recombinant pleiotrophin protein to characterize signal transduction and clone a candidate receptor cDNA by expression screening.

In addition to this gene product, we have engaged in an extensive series of studies on another gene that modulates fibroblast growth factor activity; FGF-BP. We studied transcriptional and posttranscriptional regulation, biological function, tissue-specific expression during development and carcinogenesis as well as in a series of diseased states in mouse and human. The laboratory applies numerous different molecular techniques involving DNA, RNA as well as proteins in mammalian and other eukaryotic cells, including extensive cell biology, protein and RNA detection in cells and tissues, gene cloning, regulation and expression studies. Cellular or animal models of development/differentiation and diseases, human tissue or bodily fluid samples from patients are used. PhD students in the laboratory would be able to chose the appropriate technique to answer the question being asked in their research.

Selected Publications:

• Stylianou DC, Auf der Maur A, Kodack DP, Henke RT, Hohn S, Toretsky JA, Riegel AT, Wellstein A.: Effect of single-chain antibody targeting of the ligand-binding domain in the anaplastic lymphoma kinase receptor. Oncogene. 2009

• Gibby KA, McDonnell K, Schmidt MO, Wellstein A. A distinct role for secreted fibroblast growth factor-binding proteins in development. Proc Natl Acad Sci U S A. 106:8585-90, May 2009

• Lahusen T, Henke RT, Kagan BL, Wellstein A, Riegel AT. The role and regulation of the nuclear receptor co-activator AIB1 in breast cancer. Breast Cancer Res Treat. 116:225-37, July 2009

• Oh AS, Lahusen JT, Chien CD, Fereshteh MP, Zhang X, Dakshanamurthy S, Xu J, Kagan BL, Wellstein A, Riegel AT. Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells. Mol Cell Biol. 28:6580-93, Nov 2008

• Bachis A, Mallei A, Cruz MI, Wellstein A, Mocchetti I. Chronic antidepressant treatments increase basic fibroblast growth factor and fibroblast growth factor-binding protein in neurons. Neuropharmacology. 55:1114-20, Dec 2008

• Zhang W, Chen Y, Swift MR, Tassi E, Stylianou DC, Gibby KA, Riegel AT, Wellstein A. Effect of FGF-binding protein 3 on vascular permeability. J Biol Chem. 283:28329-37, Oct 2008

• Fereshteh MP, Tilli MT, Kim SE, Xu J, O'Malley BW, Wellstein A, Furth PA, Riegel AT. The nuclear receptor coactivator amplified in breast cancer-1 is required for Neu (ErbB2/HER2) activation, signaling, and mammary tumorigenesis in mice. Cancer Res. 68:3697-706, May 2008

• Lahusen T, Fereshteh M, Oh A, Wellstein A, Riegel AT.: Epidermal growth factor receptor tyrosine phosphorylation and signaling controlled by a nuclear receptor coactivator, amplified in breast cancer 1. Cancer Res. 67:7256-65, 2007

• Tassi E, Walter S, Aigner A, Cabal-Manzano RH, Ray R, Reier PJ, Wellstein A.: Effects on neurite outgrowth and cell survival of a secreted fibroblast growth factor binding protein upregulated during spinal cord injury. Am J Physiol Regul Integr Comp Physiol. 293:R775-83, 2007

• Tassi E, Wellstein A.: The angiogenic switch molecule, secreted FGF-binding protein, an indicator of early stages of pancreatic and colorectal adenocarcinoma. Semin Oncol. 33:S50-6, 2006

• Mani A, Oh AS, Bowden ET, Lahusen T, Lorick KL, Weissman AM, Schlegel R, Wellstein A, Riegel AT.: E6AP mediates regulated proteasomal degradation of the nuclear receptor coactivator amplified in breast cancer 1 in immortalized cells. Cancer Res. 66:8680-6, 2006

• Kuo AH, Stoica GE, Riegel AT, Wellstein A.: Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene. 26:859-69, 2007

• Henke RT, Eun Kim S, Maitra A, Paik S, Wellstein A.: Expression analysis of mRNA in formalin-fixed, paraffin-embedded archival tissues by mRNA in situ hybridization. Methods. 38:253-62, 2006

• Tassi E, Henke RT, Bowden ET, Swift MR, Kodack DP, Kuo AH, Maitra A, Wellstein A.: Expression of a fibroblast growth factor-binding protein during the development of adenocarcinoma of the pancreas and colon. Cancer Res. 66:1191-8, 2006

• Modlinger P, Chabrashvili T, Gill PS, Mendonca M, Harrison DG, Griendling KK, Li M, Raggio J, Wellstein A, Chen Y, Welch WJ, Wilcox CS.: RNA silencing in vivo reveals role of p22phox in rat angiotensin slow pressor response. Hypertension. 47:238-44, 2006

• Ray PE, Tassi E, Liu XH, Wellstein A.: Role of fibroblast growth factor-binding protein in the pathogenesis of HIV-associated hemolytic uremic syndrome. Am J Physiol Regul Integr Comp Physiol. 290:R105-13, 2006

• Xie B, Tassi E, Swift MR, McDonnell K, Bowden ET, Wang S, Ueda Y, Tomita Y, Riegel AT, Wellstein A.: Identification of the fibroblast growth factor (FGF)-interacting domain in a secreted FGF-binding protein by phage display. J Biol Chem. 281:1137-44, 2006

• McDonnell K, Bowden ET, Cabal-Manzano R, Hoxter B, Riegel AT, Wellstein A.: Vascular leakage in chick embryos after expression of a secreted binding protein for fibroblast growth factors. Lab Invest. 85:747-55, 2005

• Stoica GE, Franke TF, Wellstein A, Morgan E, Czubayko F, List HJ, Reiter R, Martin MB, Stoica A.: Heregulin-beta1 regulates the estrogen receptor-alpha gene expression and activity via the ErbB2/PI 3-K/Akt pathway. Oncogene. 24:1964, 2005

• Henke RT, Maitra A, Paik S, Wellstein A.: Gene expression analysis in sections and tissue microarrays of archival tissues by mRNA in situ hybridization. Histol Histopathol. 20:225-37, 2005

• Malerczyk C, Schulte AM, Czubayko F, Bellon L, Macejak D, Riegel AT, Wellstein A.: Ribozyme targeting of the growth factor pleiotrophin in established tumors: a gene therapy approach. Gene Ther. 12:339-46, 2005

• Oh A, List HJ, Reiter R, Mani A, Zhang Y, Gehan E, Wellstein A, Riegel AT.: The nuclear receptor coactivator AIB1 mediates insulin-like growth factor I-induced phenotypic changes in human breast cancer cells. Cancer Res. 64:8299-308, 2004

• Kurtz A, Aigner A, Cabal-Manzano RH, Butler RE, Hood DR, Sessions RB, Czubayko F, Wellstein A.: Differential regulation of a fibroblast growth factor-binding protein during skin carcinogenesis and wound healing. Neoplasia. 6:595-602, 2004

• Henke RT, Haddad BR, Kim SE, Rone JD, Mani A, Jessup JM, Wellstein A, Maitra A, Riegel AT.: Overexpression of the nuclear receptor coactivator AIB1 (SRC-3) during progression of pancreatic adenocarcinoma. Clin Cancer Res. 10:6134-42, 2004

• Burbelo P, Wellstein A, Pestell RG.: Altered Rho GTPase signaling pathways in breast cancer cells. Breast Cancer Res Treat. 84:43-8, 2004

• Beagles K, Wellstein A, Bayer B.: Systemic morphine administration suppresses genes involved in antigen presentation. Mol Pharmacol. 65:437-42, 2004

• Reiter R, Oh AS, Wellstein A, Riegel AT.: Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Delta3 on estrogenic ligands with different intrinsic activity. Oncogene. 23:403-9, 2004

• Ray R, Cabal-Manzano R, Moser AR, Waldman T, Zipper LM, Aigner A, Byers SW, Riegel AT, Wellstein A.: Up-regulation of fibroblast growth factor-binding protein, by beta-catenin during colon carcinogenesis. Cancer Res. 63:8085-9, 2003

• Stoica GE, Franke TF, Wellstein A, Morgan E, Czubayko F, List HJ, Reiter R, Martin MB, Stoica A.: Heregulin-beta1 regulates the estrogen receptor-alpha gene expression and activity via the ErbB2/PI 3-K/Akt pathway. Oncogene. 22:2073-87, 2003

• Kagan BL, Henke RT, Cabal-Manzano R, Stoica GE, Nguyen Q, Wellstein A, Riegel AT.: Complex regulation of the fibroblast growth factor-binding protein in MDA- MB-468 breast cancer cells by CCAAT/enhancer-binding protein beta. Cancer Res. 63:1696-705, 2003

• Stoica GE, Franke TF, Wellstein A, Czubayko F, List HJ, Reiter R, Morgan E, Martin MB, Stoica A.: Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Mol Endocrinol. 17:818-30, 2003

• Lauritsen KJ, List HJ, Reiter R, Wellstein A, Riegel AT.: A role for TGF-beta in estrogen and retinoid mediated regulation of the nuclear receptor coactivator AIB1 in MCF-7 breast cancer cells. Oncogene. 21:7147-55, 2002

• Stoica GE, Kuo A, Powers C, Bowden ET, Sale EB, Riegel AT, Wellstein A.: Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem. 277:35990-8, 2002

• Jäger R, List B, Knabbe C, Souttou B, Raulais D, Zeiler T, Wellstein A, Aigner A, Neubauer A, Zugmaier G.: Serum levels of the angiogenic factor pleiotrophin in relation to disease stage in lung cancer patients. Br J Cancer. 86:858-63, 2002

• Bowden ET, Stoica GE, Wellstein A.: Anti-apoptotic signaling of pleiotrophin through its receptor, anaplastic lymphoma kinase. J Biol Chem. 277:35862-8, 2002

• Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A.: Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth. J Biol Chem. 277:14153-8, 2002

• Aigner A, Ray PE, Czubayko F, Wellstein A.: Immunolocalization of an FGF-binding protein reveals a widespread expression pattern during different stages of mouse embryo development. Histochem Cell Biol. 117:1-11, 2002

• Klomp HJ, Zernial O, Flachmann S, Wellstein A, Juhl H.: Significance of the expression of the growth factor pleiotrophin in pancreatic cancer patients. Clin Cancer Res. 8:823-7, 2002

• Reiter R, Wellstein A, Riegel AT.: An isoform of the coactivator AIB1 that increases hormone and growth factor sensitivity is overexpressed in breast cancer. J Biol Chem. 276:39736-41, 2001

• Tassi E, Al-Attar A, Aigner A, Swift MR, McDonnell K, Karavanov A, Wellstein A.: Enhancement of fibroblast growth factor (FGF) activity by an FGF-binding protein. J Biol Chem. 276:40247-53, 2001