Special Interests:Regulation of Gene Expression and Cell Proliferation by Hormones and Cytokines as Part of Homeostasis, Stress Response, Inflammation and Tumorigenesis
About Heinz Baumann
Roswell Park Comprehensive Cancer Center
- Professor of Oncology
- Department of Molecular and Cellular Biology
Education and Training:
- 1966 - BA - Natural Sciences, Cantonal College, Winterthur, Switzerland
- 1971 - MS - Biology, University of Zurich, Switzerland
- 1974 - PhD - Biology, University of Zurich, Switzerland
Regulation of Gene Expression and Cell Proliferation by Hormones and Cytokines as Part of Homeostasis, Stress Response, Inflammation and Tumorigenesis
A network of cytokines, growth factors, hormones, and various biologically active metabolites control systemic homeostasis in the postnatal organism. Cytokines are major regulators of those evolutionarily conserved processes that determine, among others, the tissue response to injury, mediate inflammation, activate systemic acute phase reaction and fever, and direct the innate and adaptive immune responses. This laboratory pursues two long-term research programs. The first program has the overall goal of characterizing the cellular and molecular action of cytokines that mediated the local and systemic response to tissue damage and modulated tumor growth. The second program focuses on the genetics and biology of the hepatic acute phase response and the physiological role of the plasma proteins induced by inflammation.
Current work on the first program concerns the identification of the mechanisms by which members of the hematopoietic cytokine family control proliferation and expression of differentiation genes in various normal and transformed cell types. The studies address two questions: (1) What are the mechanisms by which the heteromeric receptors for the interleukin 6 class cytokines – namely IL-6, IL-31, leukemia inhibitory factor (LIF) and oncostatin M (OSM) – control cell proliferation and the expression of differentiated genes? And (2) how is the responsiveness to these IL-6 class cytokines controlled during malignant transformation of epithelial cells? The biochemical analysis of signaling employs various tissue culture cell lines in which the specific functions of the receptor subunits for the cytokines are reconstituted. The signaling action of the OSM receptor has been defined by the suppression of proliferation through mediating G1 arrest in part by the induction of cyclin kinase inhibitors and to trigger induction as well as suppression of genes through transcription factors that include STAT3 and STAT5, AP-1/ATFs, C/EBP and CREB. These cellular responses are used to characterize the structural motifs within the signal transducing receptor subunits (gp130, LIFR-alpha, OSMR-beta, IL-31R-alpha [or GPL]) that are required for engaging the intracellular signaling pathways, in particular leading to the activation of the JAKs, PI3K, and the MAPK pathways engaging ERK and JNK. Genetic targets through which the receptor signals induce transcription have been established in the examples of acute phase plasma protein genes in liver and other cell types. The cytokine-specific action determining the expression of intercellular adhesion molecules (ICAM), cytokines and chemokines in endothelial, stromal and epithelial cells as part of inflammation and fever response is identified in collaboration with members on the program for hyperthermia and photodynamic therapy. The altered profile of cytokine responses in cancer cell types compared to the normal counterparts has allowed the identification of changes in the expression of signaling proteins (as in the case of myeloid leukemias) and cytokine receptors (as in the case of lung epithelial cells) as function of malignant transformation. The tumor-specific expression of cytokine receptor subunits is in part correlated with epigenetic alterations in DNA methylation and histone acetylation. The information gain on inflammatory mediators and receptor functions in tissue culture model system are currently applied to the identification of regulatory processes in complex reconstituted systems using 3-dimensional cultures of primary cells isolated from the lung.
The work on the second program investigates how the acute phase response in various organs is controlled and what the physiological role of the acute phase proteins is. In the last few years, mouse models have been developed in which the expression of the major acute phase proteins, haptoglobin (hemoglobin binding protein), hemopexin (heme-binding protein) and alpha-1-acid glycoprotein (ligand-binding protein), are altered either by silencing through gene knockout or by overproduction through introducing constitutively expressed transgenes. These plasma proteins are effective regulators of three major processes associated with inflammation: inhibition of extracellular proteases, reduction of oxidative damages to tissue, and attenuation of the activity of inflammatory and immune cells. The recent studies on the biology of haptoglobin have focused on the anti-inflammatory function of this acute phase protein and its role in directing progression of tissue injury response, stimulated proliferation of tumor cells at site of inflammation, and directing the immune response through direct regulation of development of lymphoid organs and differentiation of lymphocytes. The hypothesis that inflammatory mediators are promoting proliferation of epithelial tumor cells is addressed by the effects of haptoglobin deficiency or overexpression in the intestinal tumor model provided by the Apc+/MIN mouse.
- Kariapper M, Balogh Lajos, Hutson A, Slocum HK, Baumann H, Lesniak W, Kariapper IA, Tan W, Tracy E, Kasturirangan V, Khan MK. Dendrimer nanoparticle effects on the microenvironment: Examination of cellular motility, mitosis and inflammation. Proceedings of the American Association for Cancer Research Annual Meeting 2010 Apr;70(Suppl. 8):2262. doi: 10.1158/1538-7445.AM10-2262.
- Sunar U, Rohrbach D, Rigual N, Tracy E, Keymel K, Cooper MT, Baumann H, Henderson BH. Monitoring photobleaching and hemodynamic responses to HPPH-mediated photodynamic therapy of head and neck cancer: a case report. Opt Express. 2010 Jul 5;18(14):14969-78. doi: 10.1364/OE.18.014969. PMID: 20639983; PMCID: PMC2964147.
- Wetzler M, Wang E, Thompson J, Baer M, Block AM, Sait S, Barcos M, Tighe S, Ford LA, Andrews C, Baumann H. Priming with arsenic trioxide improves the outcome of newly diagnosed acute myeloid leukemia patients <60 years old treated with high-dose cytarabine and idarubicin. Haematologica 2010;95(Suppl. 2):Abstract #64
- Brady MT, Miller A, Sait S, Ford LA, Hans M, Wang ES, Lee KP, Baumann H, Wetzler M. Down-regulation of signal transducer and activator of transcription 3 enhances acute myeloid leukemia-derived dendritic cell function. Blood. 2010 Nov 19;116(21):3140. doi: 10.1182/blood.V116.21.3140.3140.
- Benekli M, Baumann H, Wetzler M. Targeting signal transducer and activator of transcription signaling pathway in leukemias. J Clin Oncol. 2009 Sep 10;27(26):4422-32. doi: 10.1200/JCO.2008.21.3264. Epub 2009 Aug 10. Review. PMID: 19667270; PMCID: PMC2744278.
- Zheng X, Morgan J, Pandey SK, Chen Y, Tracy E, Baumann H, Missert JR, Batt C, Jackson J, Bellnier DA, Henderson BW, Pandey RK. Conjugation of 2-(1'-hexyloxyethyl)-2-devinylpyropheophorbide-a (HPPH) to carbohydrates changes its subcellular distribution and enhances photodynamic activity in vivo. J Med Chem. 2009 Jul 23;52(14):4306-18. doi: 10.1021/jm9001617. PMID: 19507863; PMCID: PMC2913405.
- Jawa RS, Anillo S, Huntoon K, Baumann H, Kulaylat M. Analytic review: Interleukin-6 in surgery, trauma, and critical care: part I: basic science. J Intensive Care Med. 2011 Jan-Feb;26(1):3-12. doi: 10.1177/0885066610395678. Review. PMID: 21262749; PMCID: PMC6209321.
- Jawa RS, Anillo S, Huntoon K, Baumann H, Kulaylat M. Interleukin-6 in surgery, trauma, and critical care part II: clinical implications. J Intensive Care Med. 2011 Mar-Apr;26(2):73-87. doi: 10.1177/0885066610384188. Review. PMID: 21464062; PMCID: PMC6223019.
- Douglas WG, Wang Y, Gibbs JF, Tracy E, Kuvshinoff B, Huntoon K, Baumann H. Proinflammatory cytokines increase hepatocellular carcinoma cells thermotolerance: evidence of how local inflammation may negatively impact radiofrequency ablation local control rates. J Surg Res. 2008 Nov;150(1):118-24. doi: 10.1016/j.jss.2007.09.012. Epub 2007 Oct 15. PMID: 18262552; PMCID: PMC2610809.
- Ghoshal Gupta S, Baumann H, Wetzler M. Epigenetic regulation of signal transducer and activator of transcription 3 in acute myeloid leukemia. Leuk Res. 2008 Jul;32(7):1005-14. doi: 10.1016/j.leukres.2007.11.035. Epub 2008 Jan 14. Review. PMID: 18192010; PMCID: PMC4629448.
- Huntoon KM, Wang Y, Eppolito CA, Barbour KW, Berger FG, Shrikant PA, Baumann H. The acute phase protein haptoglobin regulates host immunity. J Leukoc Biol. 2008 Jul;84(1):170-81. doi: 10.1189/jlb.0208100. Epub 2008 Apr 24. PMID: 18436583; PMCID: PMC3178501.
- Jawa RS, Chattopadhyay S, Tracy E, Wang Y, Huntoon K, Dayton MT, Baumann H. Regulated expression of the IL-31 receptor in bronchial and alveolar epithelial cells, pulmonary fibroblasts, and pulmonary macrophages. J Interferon Cytokine Res. 2008 Apr;28(4):207-19. doi: 10.1089/jir.2007.0057. PMID: 18439099.
- Appenheimer MM, Girard RA, Chen Q, Wang WC, Bankert KC, Hardison J, Bain MD, Ridgley F, Sarcione EJ, Buitrago S, Kothlow S, Kaspers B, Robert J, Rose-John S, Baumann H, Evans SS. Conservation of IL-6 trans-signaling mechanisms controlling L-selectin adhesion by fever-range thermal stress. Eur J Immunol. 2007 Oct;37(10):2856-67. doi: 10.1002/eji.200636421. PMID: 17823890.
- Chattopadhyay S, Tracy E, Liang P, Robledo O, Rose-John S, Baumann H. Interleukin-31 and oncostatin-M mediate distinct signaling reactions and response patterns in lung epithelial cells. J Biol Chem. 2007 Feb 2;282(5):3014-26. doi: 10.1074/jbc.M609655200. Epub 2006 Dec 5. PMID: 17148439.
- Henderson BW, Daroqui C, Tracy E, Vaughan LA, Loewen GM, Cooper MT, Baumann H. Cross-linking of signal transducer and activator of transcription 3--a molecular marker for the photodynamic reaction in cells and tumors. Clin Cancer Res. 2007 Jun 1;13(11):3156-63. doi: 10.1158/1078-0432.CCR-06-2950. PMID: 17545518.
- Vardam TD, Zhou L, Appenheimer MM, Chen Q, Wang WC, Baumann H, Evans SS. Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance. Cytokine. 2007 Jul;39(1):84-96. doi: 10.1016/j.cyto.2007.07.184. Review. PMID: 17903700; PMCID: PMC2756671.
- Wei LH, Baumann H, Tracy E, Wang Y, Hutson A, Rose-John S, Henderson BW. Interleukin-6 trans signalling enhances photodynamic therapy by modulating cell cycling. Br J Cancer. 2007 Dec 3;97(11):1513-22. doi: 10.1038/sj.bjc.6604073. Epub 2007 Nov 6. PMID: 17987036; PMCID: PMC2360250.
- Chen Y, Ohkubo K, Zhang M, Wenbo E, Liu W, Pandey SK, Ciesielski M, Baumann H, Erin T, Fukuzumi S, Kadish KM, Fenstermaker R, Oseroff A, Pandey RK. Photophysical, electrochemical characteristics and cross-linking of STAT-3 protein by an efficient bifunctional agent for fluorescence image-guided photodynamic therapy. Photochem Photobiol Sci. 2007 Dec;6(12):1257-67. doi: 10.1039/b710395f. Epub 2007 Sep 24. PMID: 18046480.
- Srivatsan A, Wang Y, Joshi P, Sajjad M, Chen Y, Liu C, Thankppan K, Missert JR, Tracy E, Morgan J, Rigual N, Baumann H, Pandey RK. In vitro cellular uptake and dimerization of signal transducer and activator of transcription-3 (STAT3) identify the photosensitizing and imaging-potential of isomeric photosensitizers derived from chlorophyll-a and bacteriochlorophyll-a. J Med Chem. 2011 Oct 13;54(19):6859-73. doi: 10.1021/jm200805y. Epub 2011 Sep 6. PMID: 21842893; PMCID: PMC3188669.
- Chen Q, Vardam T, Fisher D, Wang WC, Rose-John S, Ernst M, Von Andrian U, Baumann H, Evans SS. Central role of the lymphocyte-endothelial-interleukin-6 axis in promoting lymphocyte trafficking during fever-range thermal stress. Cytokine 2007 July; 39(1):6 (Abstract #19) doi: 10.1016/j.cyto.2007.07.024.
- Khan MK, Kariapper MST, Kasturirangan V, Tracy E, Lesniak W, Hutson A,Baumann H, Balogh LP. In vivo inflammation study of PAMAM dendrimer nanoparticles in mice. Proceedings of the American Association for Cancer Research Annual Meeting. 2009 May;69(9):1562.
- Fisher DT, Chen Q, Skitzki JJ, Muhitch JB, Zhou L, Appenheimer MM, Vardam TD, Weis EL, Passanese J, Wang WC, Gollnick SO, Dewhirst MW, Rose-John S, Repasky EA, Baumann H, Evans SS. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest. 2011 Oct;121(10):3846-59. doi: 10.1172/JCI44952. Epub 2011 Sep 19. PMID: 21926464; PMCID: PMC3195455.
- Tracy EC, Bowman MJ, Pandey RK, Henderson BW, Baumann H. Cell-type selective phototoxicity achieved with chlorophyll-a derived photosensitizers in a co-culture system of primary human tumor and normal lung cells. Photochem Photobiol. 2011 Nov-Dec;87(6):1405-18. doi: 10.1111/j.1751-1097.2011.00992.x. Epub 2011 Oct 3. PMID: 21883244; PMCID: PMC3200467.
- Wetzler M, Andrews C, Ford LA, Tighe S, Barcos M, Sait SN, Block AW, Nowak NJ, Baer MR, Wang ES, Baumann H. Phase 1 study of arsenic trioxide, high-dose cytarabine, and idarubicin to down-regulate constitutive signal transducer and activator of transcription 3 activity in patients aged <60 years with acute myeloid leukemia. Cancer. 2011 Nov 1;117(21):4861-8. doi: 10.1002/cncr.26097. Epub 2011 Mar 31. PMID: 21456022; PMCID: PMC3129468.
- Ghoshal S, Brady MT, Ustwani O, Tracy E, Den Haese J, Wallace PK, Baumann H, Wetzler M. Signal Transducer and Activator of Transcription 3 Promotes Leukemogenesis. Blood 2011; 118(21):1395. doi: 10.1182/blood.V118.21.1395.1395.
- Vardam T, Appenheimer M, Zhou L, Chen Q, Wang WC, Ernst M, Rose-John S, Baumann H, Evans S. High endothelial venules at the nexus of an IL-6/gp130/STAT3 axis controlling immune surveillance during fever. J Immunol. 2012 May1;188(1):173.22.
- Rohrbach DJ, Rigual N, Tracy E, Kowalczewski A, Keymel KL, Cooper MT, Mo W, Baumann H, Henderson BW, Sunar U. Interlesion differences in the local photodynamic therapy response of oral cavity lesions assessed by diffuse optical spectroscopies. Biomed Opt Express. 2012 Sep 1;3(9):2142-53. doi: 10.1364/BOE.3.002142. Epub 2012 Aug 16. PMID: 23024908; PMCID: PMC3447556.