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Cancer Cell Biology Research


Studies on the Cellular and Biochemical
Properties of Metastatic Cancer Cells

Contents

Cellular Membranes

After over 40 years, the accepted model of all cellular membranes, The Fluid-Mosaic Membrane Model, has remained relevant for describing the basic nano-structures of a variety of intracellular and cellular membranes of plant and animal cells and lower forms of life. In the intervening years new information has documented the importance and roles of specialized membrane domains, such as lipid rafts and protein/glycoprotein complexes, in describing the macrostructure, dynamics and functions of cellular membranes as well as the roles of membrane-associated cytoskeletal fences and extracellular matrix structures in limiting the lateral diffusion and range of motion of membrane components. This new information has build on the foundation of the original model and added new layers of complexity and hierarchy, but the concepts described in the original 1972 model are still applicable today. In updated versions of the cellular membrane model more emphasis has been placed on the mosaic nature of the macrostructure of cellular membranes where many protein and lipid components are limited in their rotational and lateral motilities in the membrane plane, especially in their natural states where lipid-lipid, protein-protein and lipid-protein interactions as well as cell-matrix, cell-cell and intracellular membrane-associated protein and cytoskeletal interactions are important in restraining the lateral motility and range of motion of particular membrane components. The formation of specialized membrane domains and the presence of tightly packed integral membrane protein complexes due to membrane-associated structures are considered very important in describing membrane dynamics and architecture. These structures along with membrane-associated cytoskeletal and extracellular structures maintain the long-range, non-random mosaic macro-organization of membranes, while smaller membrane nano- and submicro-sized domains, such as lipid rafts and protein complexes, are important in maintaining specialized membrane structures that are in cooperative dynamic flux in a crowded membrane plane.

Selected Publications

1. Singer, S.J. and Nicolson, G.L. The fluid mosaic model of the structure of cell membranes. Science 175: 720-731 (1972).

2. Nicolson, G.L. Transmembrane control of the receptors on normal and tumor cells. I. Cytoplasmic influence over cell surface components. Biochim. Biophys. Acta 457: 57-108 (1976).

3. Nicolson, G.L. Transmembrane control of the receptors on normal and tumor cells. II. Surface changes associated with transformation and malignancy. Biochim. Biophys. Acta 458:1-72 (1976).

4. Nicolson, G.L. and Poste G. The cancer cell: Dynamic aspects and modifications in cell-surface organization. Part 1. New Eng. J. Med. 295: 197-203 (1976).

5. Nicolson, G.L. and Poste G. The cancer cell: Dynamic aspects and modifications in cell-surface organization. Part 2. New Eng. J. Med. 295: 253-258 (1976).

6. Kelley, P., Cotman, C.W., Gentry, C. and Nicolson, G.L. Distribution and mobility of lectin receptors on synaptic membranes of identified neurons in the central nervous system. J. Cell Biol. 71: 487-496 (1976).

7. Nicolson, G.L., Poste, G. and Ji, T.H. The dynamics of cell membrane organization. In Dynamic Aspects of Cell Surface Organization, Vol. 3 of Cell Surface Reviews (G. Poste and G.L. Nicolson, eds.), North-Holland, Amsterdam, 1-73 (1977).

8. Nicolson, G.L. Topographic display of cell surface components and their role in transmembrane signaling. Curr. Top. Devel. Biol. 13: 305-338 (1979).

9. Nicolson, G.L. Cell surfaces and cancer metastasis. Hospital Practice 17(8): 75-86 (1982).

10. Nicolson, G.L. Cell surface molecules and tumor metastasis. Regulation of metastatic diversity. Exp. Cell Res. 150: 3-22 (1984).

11. Nicolson, G.L. Update of the 1972 Singer-Nicolson Fluid—Mosaic Model of membrane structure. Discoveries 1(1): e3 (2013). doi: 10.15190/d.2013.3

12. Escrib·, P.V. and Nicolson, G.L. Membrane structure and function: Relevance of lipid and protein structures in cellular physiology, pathology and therapy. Biochim. Biophys. Acta 1838: 1449-1450 (2014).

13. Nicolson, G.L. The Fluid—Mosaic Model of Membrane Structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years. Biochim. Biophys. Acta 1838: 1451-1466 (2014).

14. Nicolson, G.L. and Ash, M.E. Lipid Replacement Therapy: a natural medicine approach to replacing damaged phospholipids in cellular membranes and organelles and restoring function. Biochim. Biophys. Acta 1838: 1657-1679 (2014).

15. Cell membrane fluid—mosaic structure and cancer metastasis, by Garth L. Nicolson, Cancer Research 75(7): 1169-1176 (2015). pdf_doc

16. Nicolson, G.L., Ferreira de Mattos, G. A brief introduction to some aspects of the Fluid—Mosaic Model of membrane structure and its importance to Membrane Lipid Replacement. Membranes 2021; 11(12): article 947. pdf_doc

17. Nicolson GL, Ferreira de Mattos G. Fifty years of the Fluid—Mosaic Model of biomembrane structure and organization and its importance in biomedicine with particular emphasis of Membrane Lipid Replacement. Biomedicines 2022; 10: article 1711. pdf_doc

 

Metastatic Cell Adhesion:

Researchers at the Institute for Molecular Medicine have found that multiple adhesive mechanisms are responsible for malignant cell adhesion to microvessel endothelial cells and to underlying subendothelial matrix, and they have begun to identify and isolate the receptors responsible. In some cases, this has led to the isolation, sequencing and identification of new cell surface components. These studies are being extended into an examination of the role of integrins and nonintegrin adhesion components in the adhesion of metastatic cells to specific microvessel endothelial cells that have been established in culture and characterized.

Recent Publications

1. Patton, J.T., Menter, D.G., McIntire, L.V., and Nicolson, G.L. Tumor cell-substrate stabilization: initiation by integrins. Materials Science Res., (1996).

2. Smith, T.W., Yun, Z., Menter, D.G., McIntire, L.V. and Nicolson, G.L. Computerized analysis of tumor cell interactions with extracellular matrix proteins, peptides and endothelial cells under laminar flow. Biotech. Bioengineer. 50: 598-607 (1996).

3. Smith, T.W., Menter, D.G., Nicolson, G.L. and McIntire, L.V. Regulation of melanoma cell adhesion stabilization to fibronectin. Melanoma Res. 6: 351-362 (1996).

4. Yun, Z., Menter, D.G. and Nicolson, G.L. Involvement of integrin avb3 in cell adhesion, motility and liver metastasis of murine RAW117 large-cell lymphoma. Cancer Res. 56: 3103-3111 (1996).

5. Yun, Z., Smith, T.W., Menter, D.G., McIntire, L.V. and Nicolson, G.L. Differential adhesion of metastatic RAW117 large-cell lymphoma cells under static or hydrodynamic conditions: role of integrin avb3. Clin. Expl. Metastasis 15: 3-11 (1997).

6. Haier, J. Nasralla, M., Buhr, H.J. and Nicolson, G.L. Different integrin-mediated adehsion of poorly and highly metastatic colon carcinoma cell lines on extracellular matrix. Langebecks Arch. Chir. 103: 307-313 (1998).

7. Ahn, S.-H., Sawada, H., Ro, J.-Y. and Nicolson, G.L. Expression of annexin I in human mammary ductal epithelial cells from normal tissue and benign and malignant breast lesions. Clin. Exp. Metastasis 15: 1997).

8. Haier, J. Nasralla, M. and Nicolson, G.L. Different adhesion properties of poorly and highly metastatic HT-29 colon carcinoma cell lines with extracellular matrix components: role of integrin expression and cytoskeletal components. Brit. J. Cancer 80: 1867-1874 (1999).

9. Haier, J. Nasralla, M. and Nicolson, G.L. Influence of phosphotyrosine kinase inhibitors on adhesive properties of highly and poorly metastatic HT-29 colon carcinoma cells to collagen. Int. J. Colorectal Dis. 14: 119-127 (1999).

10. Haier, J., Nasralla, M. and Nicolson, G.L. b1-integrin mediated dynamic adhesion of colon carcinoma cells to extracellular matrix under laminar flow. Clin. Expl. Metastasis 17: 377-387 (1999).

11. Haier, J. and Nicolson, G.L. Tumor cell adhesion of human colon carconoma cells with different metastatic properties to extracellular matrix under dynamic conditions of laminar flow. Cancer Res. Clin. Oncol. In press (2000).

12. Haier, J., Nasralla, M. and Nicolson, G.L. Cell Surface molecules and their prognostic values in assessing colorectal carcinomas. Ann. Surgery 231(1):11-24 (2000).

13. Papadimitriou, M.N.B., Menter, D.M., Konstantopoulos, K., Nicolson, G.L. and McIntire, L.V. Integrin a4b1/VCAM-1 pathway mediates primary adhesion of RAW117 lymphoma cells to hepatic sinusoidal endothelial cells under laminar flow. Clin. Expl. Metastasis 17: 669-676 (2000).

14. Haier, J. and Nicolson, G.L. Role of the cytoskeleton in adhesion stabilization of human colorectal carcinoma cells to extracellular matrix components under dynamic conditions of laminar flow. Clin. Expl. Metastasis 17: 713-721 (2000).

15. Haier, J. and Nicolson, G.L. Time-dependent dephosphorylation through Ser/Thr phosphatases is required for stable adhesion of highly and poorly metastatic HT-29 colon carcinoma cells to collagen. Anticancer Res. 20: 2265-2271 (2000)

16. Haier, J., Gallick, G.E. and Nicolson, G.L. Adhesion stabilization of HT-29 colon carcinoma cells to extracellular matrix is regulated by pp60src under dynamic conditions of laminar flow. J. Amer. Coll. Surg., in press (2000).

17. Haier, J. and Nicolson, G.L. Models for tumor cell adhesion and invasion. In: Cancer Handbook, (Alison, M., Ed.), Macmillan Publishers, 983-998 (2002).

18. Haier, J. and Nicolson, G.L. Prognostic value of cell surface molecules in colorectal carcinomas. Visceralchirurgie 35: 172-181 (2000).

19. Haier, J. and Nicolson, G.L. Role of the cytoskeleton in adhesion stabilization of human colorectal carcinoma cells to extracellular matrix components under dynamic conditions of laminar flow. Clin. Expl. Metastasis 17: 713-721 (2000).

20. Haier, J. and Nicolson, G.L. Tumor cell adhesion of human colon carconoma cells with different metastatic properties to extracellular matrix under dynamic conditions of laminar flow. J. Cancer Res. Clin. Oncol. 126: 699-709 (2000).

21. Haier, J., Gallik, G.E., Buhr, H.J., Nicolson, G.L. Adhesion stabilization of HT-29 colon carcinoma cells to extracellular matrix is regulated by pp60src under dynamic conditions of laminar flow. Owen Wangensteen Surgical Forum LI: 260-262 (2000).

22. Haier, J. and Nicolson, G.L. Role of tumor cell adhesion as an important factor in formation of distant metastases. Diseases Colon Rect. 44: 876-884 (2001).

23. Haier, J. and Nicolson, G.L. Cell biology and clinical implications of adhesion molecules in colorectal diseases: colorectal cancers, infections and inflammatory bowel diseases. Clin. Expl. Metastasis 18: 623-638 (2001).

24. Dombrowski, J., Menter, D.G., Nicolson, G.L. and McIntire, L.V. Dynamic adhesion and adhesion stabilization of RAW117 large cell lymphoma cells to hepatic sinusoidal endothelial cells: role of E-selectin and VCAM-1. Clin. Expl. Metastasis, In press (2002).

25. Haier, J. and Nicolson, G.L. Role of tumor cell adhesion as an important factor in formation of distant metastases. Diseases Colon Rect. 44: 876-884 (2001).

26. Haier, J. and Nicolson, G.L. Tumor cell adhesion under hydrodynamic conditions of fluid flow. Acta Pathol Microbiol. Infect. Scand. 109: 241-262 (2001).
27. Haier, J. and Nicolson, G.L. PTEN regulates tumor cell adhesion of colon carcinoma cells under dynamic conditions of fluid flow. Oncogene 21: 1450-1460 (2002).

28. Haier, J. and Nicolson, G.L. Cell surface molecules as indicators of prognosis in colorectal carcinomas. New Surg. 1: 152-157 (2001).

29. Haier, J., Gallick, G.E. and Nicolson, G.L. Src protein kinase pp60c-src influences adhesion stabilization of HT-29 colon carcinoma cells to extracellular matrix components under dynamic conditions of laminar flow. J. Exp. Therapeutics Oncol. 2: 237-246 (2002).

30. Korb, T., Schluter, K., Enns, A., Spiegel, H.U., Senninger, N., Nicolson, G.L. and Haier, J. Integrity of actin fibers and microtubules influences metastatic tumor cell adhesion.  Exp. Cell Res. 299: 236-247 (2004).

31. von Sengbusch, A., Gassmann, P., Fisch, K., Nicolson, G.L. and Haier, J. Focal adhesion kinase regulates dynamic adhesion of carcinoma cells to collagens. Am. J. Pathol. 166: 585-596  (2005).

32. Gassmann, P., Haier, J., Nicolson, G.L. Cell adhesion and invasion during secondary tumor formation. In: Cancer Growth and Progression, vol. 3, Kluwer, Amsterdam , in press (2007).

33. Schlüter K, Korb T, Enns A, Gassmann P, Spiegel HU, Senninger N, Haier J. Organ-specific metastatic tumor cell adhesion correlates with metastasis formation. Am. J. Pathol. 169: 1064-1073 (2006).

34. Bahde R, Palmes D, Minin E, Stratmann U, Diller R, Haier J, Spiegel HU. Bromelain Ameliorates Hepatic Microcirculation After Warm Ischemia. J Surg Res. 139: 88-96 (2007).
35. Küpper S, Mees ST, Gassmann P, Brodde MF, Kehrel B, Haier J. Hydroxyethyl starch normalizes platelet and leukocyte adhesion within pulmonary microcirculation during lipopolysaccharide induced endotoxemia. Shock 28:300-308 (2007).

36. Gassmann P, Nicolson GL, Haier J. Models for tumor cell – endothelial cells interactions. The Cancer Handbook, 2nd edition, editor-in-chief: Malcolm R. Alison, John Wiley & Sons Ltd., Chichester, ISBN-13 978-0-470-01852-1(2007).

37. Gassman, P., Haier, J. and Nicolson, G.L. Cell adhesion and invasion during secondary tumor formation: interactions between tumor cells and host organs. In: Selected Aspects of Cancer Progression: Metastasis, Apoptosis and Immune Response, (H.E. Kaiser and A. Nasir, eds.), Springer Science, 21-32 (2008).

38. Kanda, Y., Osaki, M., Onuma, K., Sonoda, A., Kobayashi, M., Hamada, J., Nicolson, G.L., Chiva, T. and Okada, F. Amigo2-upregulation in tumor cells facilitates their attachment to liver endothelial cells resulting in liver metastases. Nature Sci. Rep. 7: article 43567 (2017).


 

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Metastatic Cell Migration:

An important property of highly metastatic cells is their ability to respond to paracrine and autocrine motility factors. Scientists at the Institute for Molecular Medicine were among the first to have isolated and studied these factors. Concentrating on soluble paracrine factors, such as those from organ-derived microvessel endothelial cells, the first paracrine motility factor was isolated and characterized from hepatic sinusoidal endothelial cells. Sequence data indicate that this factor is related to complement component C3b. A different motility factor has been isolated from lung microvessel endothelial cells, and sequence analysis of this factor indicates that it is a known macrophage motility factor (MCP-1). Other factors are being characterized from different organ-derived fibroblast and parenchymal cells.

Recent Publications

1. Hu, M., Pollock, R.E., Nakamura, T. and Nicolson, G.L. Human peritumoral and lung fibroblasts produce paracrine motility factors for recently established human sarcoma cell strains. Int. J. Cancer 62: 585-592 (1995).

2. Wakabayashi, H., Cavanaugh, P.G. and Nicolson, G.L. Purification and identification of mouse lung microvessel endothelial cell-derived chemoattractant for lung-metastasizing murine large-cell lymphoma cells: identification as mouse monocyte chemotactic protein-1. Cancer Res. 55: 4458-4464 (1995).

3. Sawada, H., Wakabayashi, H., Nawa, A., Mora, E., Cavanaugh, P.G. and Nicolson, G.L. Differential motility stimulation but not growth stimulation or adhesion of metastatic human colorectal carcinoma cells by target organ-derived liver sinusoidal endothelial cells. Clin. Exp. Metastasis 14: 308-314 (1996).

4. Yun, Z., Menter, D.G. and Nicolson, G.L. Involvement of integrin avb3 in cell adhesion, motility and liver metastasis of murine RAW117 large-cell lymphoma. Cancer Res. 56: 3103-3111 (1996).

5. Wakabayashi, H. and Nicolson, G.L. Transfilter cell invasion assays. In: Cell Biology: A Laboratory Handbook, J.E. Celis, ed., Academic Press, New York, 1: 296-301 (1997).

6. Marchetti, D. and Nicolson, G.L. Neurotrophin stimulation of human melanoma cell invasion: selected enhancement of heparanase activity and heparanase degradation of specific heparan sulfate subpopulations. Adv. Enzyme Regul. 37: 111-134 (1997).

7. Hu, M., Pollock, R.E. and Nicolson, G.L. Purification and characterization of human lung fibroblast motility-stimulating factor for human soft tissue sarcoma cells. Identification as an N-terminal fragment of human fibronectin. Cancer Res. 57: 3577-3584 (1997).

8. Marchetti, D. and Nicolson, G.L. Human melanoma cell invasion: Selected neurotrophin enhancement of invasion and heparanase activity. J. Investig. Determatol. Symp. 2: 99-105 (1997).

9. Go, Y., Chintala, S.K., Rayford, A., Gagercas, E., Ali-Osman, F., Venkaiah, B., Sawaya, R, Gokaslan, Z., Nicolson, G.L., and Rao, J.S. Inhibition of in vivo tumorigenicity and invasiveness of a human glioblastoma cell line transfected with antisense uPAR vectors. Clin. Expl. Metastasis 15: 440-446 (1997).

10. Nicolson, G.L., Nakajima, M., Wakabayashi, H., Boyd, D., Diaz, D. and Irimura, T. Cancer cell heparanase associated with invasion and metastasis. Adv. Enzyme Regulat. 38: 19-32 (1998).

11. Nicolson, G.L. Brain invasion, trophic factors and central nervous system metastasis. In: Brain Tumor Invasion: Biological, Clinical and Therapeutic Considerations, (R. Bjerkvig, O.D. Laerum and M.L. Rosenblum, Eds.), Wiley-Liss, NY, 357-374 (1999).

12. Haier, J. and Nicolson, G.L. Role of the vascular endothelium in cancer metastasis. In: Intramolecular Cross-talk in Metastasis, (G. Skouteris and G.L. Nicolson, Eds.), NATO ASI series, IOS Press, Amsterdam, 225-249 (1999).

13. Haier, J., Nasralla, M. and Nicolson, G.L. ß1-integrin mediated dynamic adhesion of colon carcinoma cells to extracellular matrix under laminar flow. Clin. Expl. Metastasis 17: 377-387 (1999).

14. Haier, J. and Nicolson, G.L. Tumor cell adhesion of human colon carconoma cells with different metastatic properties to extracellular matrix under dynamic conditions of laminar flow. J. Cancer Res. Clin. Oncol. 126: 699-709 (2000).

15. Haier, J. and Nicolson, G.L. Role of the cytoskeleton in adhesion stabilization of human colorectal carcinoma cells to extracellular matrix components under dynamic conditions of laminar flow. Clin. Expl. Metastasis 17: 713-721 (2000).

16. Haier, J. and Nicolson, G.L. Tumor cell adhesion under hydrodynamic conditions of fluid flow. Acta Pathol Microbiol. Infect. Scand. 109: 241-262 (2001).

17. Lakka, S.S., Jasti, S.L., Kyritsis, A.P., Yung, W.K.A., Ali-Osman, F., Nicolson, G.L. and Rao, J.S. Regulation of MMP-9 (Type IV Collagenase) production and invasiveness in gliomas by the extracellular signal-regulated kinase and Jun amino-terminal kinase signaling cascades. Clin. Expl. Metastasis 18: 245-252 (2000).

18. Lakka, S.S., Konduri, S.D., Mohanam, S., Nicolson, G.L. and Rao, J.S. In vitro modulation of human lung cancer cell line invasiveness by antisense cDNA of tissue pathway inhibitor-2. Clin. Expl. Metastasis 18: 239-244 (2001).

19. Chandrasekar, N., Jasti, S., Yung, A.W.K., Ali-Osman, F., Kyritsis, A.P., Nicolson, G.L., Rao, J.S. and Mohanam, S. Modulation of endothelial cell morphogenesis in vitro by MMP-9 during glial-endothelial cell interactions. Clin. Expl. Metastasis 18: 337-342 (2001).

20. Haier, J., Gallik, G.E., Buhr, H.J., Nicolson, G.L. Adhesion stabilization of HT-29 colon carcinoma cells to extracellular matrix is regulated by pp60src under dynamic conditions of laminar flow. Owen Wangensteen Surgical Forum LI: 260-262 (2000).

21. Haier, J. and Nicolson, G.L. Role of tumor cell adhesion as an important factor in formation of distant metastases. Diseases Colon Rect. 44: 876-884 (2001).

22. Haier, J. and Nicolson, G.L. Tumor cell adhesion under hydrodynamic conditions of fluid flow. Acta Pathol Microbiol. Infect. Scand. 109: 241-262 (2001).

23. Haier, J. and Nicolson, G.L. PTEN regulates tumor cell adhesion of colon carcinoma cells under dynamic conditions of fluid flow. Oncogene 21:1450-1460 (2002).

24. Haier, J. and Nicolson, G.L. Cell surface molecules as indicators of prognosis in colorectal carcinomas. New Surg. 1: 152-157 (2001).

25. Haier, J. and Nicolson, G.L. Models for tumor cell adhesion and invasion. In: Cancer Handbook, (Alison, M., Ed.), Macmillan Publishers, London, 983-998 (2002).

26. Haier, J., Gallick, G.E. and Nicolson, G.L. Src protein kinase pp60c-src influences adhesion stabilization of HT-29 colon carcinoma cells to extracellular matrix components under dynamic conditions of laminar flow. J. Exp. Therapeutics Oncol. 2: 237-246 (2002).

27. Nicolson, G.L., Nawa, A., Toh, Y., Taniguchi, S., and Nishimori, K. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin. Expl. Metastasis 20: 14-19 (2002).

28. von Sengbusch, A., Gassmann, P., Fisch, K., Nicolson, G.L. and Haier, J. Focal adhesion kinase regulates dynamic adhesion of carcinoma cells to collagens. Am. J. Pathol. 166: 585-596  (2005).

29. Nicolson, G.L. Transfilter cell invasion assays . In: Cell Biology: A Laboratory Handbook, 3 rd Edition (J.E. Celis, Ed.), Academic Press, New York , 359-362 (2006).

30. Krasnyanska J, Gaßmann P, Haier J. Wachstumsfaktoren steigern die trajektorielle chemotaktische Tumorzellmigration in Abhängigkeit von der extrazellulären Matrix. Surgical Forum 2006, Eds.: H.-D. Saeger, K.-W. Jauch, H. Bauer; Springer-Verlag; 35: 89-91(2006).

31. Bembenek A; Rosenberg R; Wagler E; Gretschel S; Sendler A; Siewert, JR; Nahrig J; Witzigmann H; Hauss J; Knorr C; Dimmler A; Grone J; Buhr HJ; Haier J; Herbst H; Tepel J; Siphos B; Kleespies A; Koenigsrainer A; Stoecklein N; Horstmann O; Grutzmann R; Imdahl A; Svoboda D; Wittekind W; Schneider W; Wernecke KD; Schlag PM. Sentinel Lymph Node Biopsy in Colon Cancer: A Prospective Multicenter Trial. Ann Surg 245: 858-863 (2007).

32. Fisch KM, Haier J. Tumor cell adhesion and invasion.
The Cancer Handbook, 2nd edition, editor-in-chief: Malcolm R. Alison, John Wiley & Sons Ltd., Chichester; ISBN-13 978-0-470-01852-1(2007).

33. Gaßmann P, Hemping-Bovenkerk A, Küpper J, Haier J.
Einfluß der sinusoidalen Architektur und der T-Zellimmunität auf metastatische Tumorzelladhäsion und –migration in vivo.Surgical Forum Eds. H.U.- Steinau, H.K. Schackert, H. Bauer, 36: 91-39 (2007).

34. Gassman, P., Haier, J. and Nicolson, G.L. Cell adhesion and invasion during secondary tumor formation: interactions between tumor cells and host organs. In: Selected Aspects of Cancer Progression: Metastasis, Apoptosis and Immune Response, (H.E. Kaiser and A. Nasir, eds.), Springer Science, 21-32 (2008).

35. Toh, Y. and Nicolson, G.L. MTA1 of the MTA (metastasis-associated) gene family and its encoded proteins: molecular and regulatory functions and its role in human cancer progression. Atlas Genet, Cytogenet. Oncology Haematol. 15(3): 303-315 (2011).

36. Toh, Y. and Nicolson, G.L. Signaling pathways of MTA family proteins as regulators of cancer progression and metastasis. In: Trends in Stem Cell Proliferation and Cancer Research, R.R. Resende and H. Ulrich (eds.), Springer Science, Dordrecht, 249-273 (2013).

37. Kanda, Y., Osaki, M., Onuma, K., Sonoda, A., Kobayashi, M., Hamada, J., Nicolson, G.L., Chiva, T. and Okada, F. Amigo2-upregulation in tumor cells facilitates their attachment to liver endothelial cells resulting in liver metastases. Nature Sci. Rep. 7: article 43567 (2017).


 

(Back to the Contents)

Metastatic Cell Invasion: 

To extravasate, metastatic cells must penetrate basement membranes and stromal matrix using a battery of degradative enzymes. We have identified and purified new enzymes involved in this process, including heparanase and an aminopeptidase of 29 kDa in size. Scientists at The Institute for Molecular Medicine are studying matrix metalloproteinases, endoglycosidases and other proteases and their role in metastatic cell invasion and growth. We are also studying the role of organ-derived paracrine factors in regulating the synthesis of certain degradative enzymes in host tissues and cancer cells. For example, it was found that nerve growth factor can stimulate the invasion of brain-metastatic melanoma cells by increasing the synthesis of degradative enzymes.

Recent Publications

1. Yamamoto, M., Mohanam, S., Sawaya, R., Fuller, G.N., Seiki, M., Sato, H., Gokslan, Z.L., Liotta, L.A., Nicolson, G.L. and Rao, J.S. Differential expression of membrane-type metalloproteinase and its correlation with gelatinase A activation in human malignant brain tumors in vivo and in vitro. Cancer Res. 56: 384-392 (1996).

2. Nicolson, G.L., Menter, D.G., Herrmann, J.L., Yun, Z., Cavanaugh, P.G. and Marchetti, D. Brain metastasis: role of trophic, autocrine and paracrine factors in tumor invasion and colonization of the central nervous system. Curr. Top. Microbiol. Immunol. 213: 89-115 (1996).

3. Rao, J.S., Yamamoto, M., Mohaman, S., Gokaslan, Z.L., Fuller, G.N., Stetler-Stevenson, W.G., Rao, V.H., Liotta, L.A., Nicolson, G.L. and Sawaya, R. Expression of and localization of 92-kDa type IV collagenase/gelatinase B (MMP-9) in human gliomas. Clin. Exp. Metastasis 14: 12-18 (1996).

4. Sivaparvathi, M., Yamamoto, M., Nicolson, G.L., Gokaslan, Z.L., Fuller, G.N., Liotta, L.A., Sawaya, R. and Rao, J.S. Expression and immunohistochemical localization of cathepsin L during the progression of human gliomas. Clin. Exp. Metastasis 14: 27-34 (1996).

5. Sivaparvathi, M., McCutcheon, I., Sawaya, R., Nicolson, G.L. and Rao, J.S. Expression of cysteine protease inhibitors in human gliomas and meningiomas. Clin. Exp. Metastasis 14: 344-350 (1966).

6. Marchetti, D., McQuillan, D.J., Spohn, W.C., Carson, D.D. and Nicolson, G.L. Neurotrophin stimulation of human melanoma cell invasion: enhancement of heparanase activity and degradation of specific heparan sulfacte subpopulations. Cancer Res. 56: 2856-2863 (1996).

7. Simon, C., Juarez, J., Nicolson, G.L. and Boyd, D. PD 098059, a specific inhibitor of mitogen-activated protein kinase kinase reduces urokinase expression and in vitro invasion. Cancer Res. 56: 5369-5374 (1996).

8. Chintala, S.K., Gokaslan, Z.L., Go, Y., Sawaya, R., Nicolson, G.L. and Rao, J.S. Role of extracellar matrix proteins in regulation of human glioma cell invasion in vitro. Clin. Expl. Metastasis 14: 358-366 (1966).

9. Nicolson, G.L., Nakajima, M., Wakabayashi, H., Boyd, D., Diaz, D. and Irimura, T. Cancer cell heparanase associated with invasion and metastasis. Adv. Enzyme Regulat. 38: 19-32 (1998).

10. Nicolson, G.L. Brain invasion, trophic factors and central nervous system metastasis. In: Brain Tumor Invasion: Biological, Clinical and Therapeutic Considerations, (R. Bjerkvig, O.D. Laerum and M.L. Rosenblum, Eds.), Wiley-Liss, NY, 357-374 (1999).

11. Haier, J., Nasralla, M. and Nicolson, G.L. Cell Surface molecules and their prognostic values in assessing colorectal carcinomas. Ann. Surgery 231(1):11-24 (2000).

12. Haier, J., Gallick, G.E. and Nicolson, G.L. Adhesion stabilization of HT-29 colon carcinoma cells to extracellular matrix is regulated by pp60src under dynamic conditions of laminar flow. Oncogene 21:1450-1460 (2002).

13. Haier, J. and Nicolson, G.L. Models for tumor cell adhesion and invasion. In: Cancer Handbook, (Alison, M., Ed.), Macmillan Publishers, 983-998 (2002).

14. Nicolson, G.L., Nakajima, M., Wakabayashi, H., Boyd, D., Diaz, D. and Irimura, T. Cancer cell heparanase associated with invasion and metastasis. Adv. Enzyme Regulat. 38: 19-32 (1998).

15. Gokaslan, Z.L., Chintala, S.K., York, J.E., Boyapati, V., Jasti, S., Sawaya, R., Fuller, G., Wildrick, D.M., Nicolson, G.L. and Rao, J.S. Expression and localization of urokinase-type plasminogen activator in human spinal column tumors. Clin. Expl. Metastasis 16: 713-719 (1998).

16. Gokaslan, Z.L., Chintala, S.K., York, J.E., Boyapati, V., Jasti, S., Sawaya, R., Fuller, G., Wildrick, D.M., Nicolson, G.L. and Rao, J.S. Expression and role of matrix metalloporteinases MMP-2 and MMP-9 in human spinal column tumors. Clin. Expl. Metastasis 16: 721-728 (1998).

17. Nicolson, G.L. Brain invasion, trophic factors and central nervous system metastasis. In: Brain Tumor Invasion: Biological, Clinical and Therapeutic Considerations, R. Bjerkvig, O.D. Laerum and M.L. Rosenblum, eds., Wiley-Liss, NY, 357-374 (1999).

18. Zucker, S., Hymowitz, M., Conner, C., Zarrabi, H.M, Hurewitz, A.N., Matrisian, L., Boyd, D. Nicolson, G.L. and Montana, S. Measurement of matrix metallo-proteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs) in blood and tissues: clinical and experimental applications. Ann. N. Y. Acad. Sci. 818: 212-227 (1999).

19. Mohan, P.M., Lakka, S.S., Mohanam, S., Yoshiaki Kin, Y., Sawaya, Kyritsis, A.P., Nicolson, G.L. and Rao, J.S. Down-regulation of urokinase-type plasminogen activator receptor by antisense construct is due to inhibition of protein translation. Clin. Exp. Metastasis, 17:617-621 (2000)

20. Lakka, S.S., Jasti, S.L., Kyritsis, A.P., Yung, W.K.A., Ali-Osman, F., Nicolson, G.L. and Rao, J.S. Regulation of MMP-9 (Type IV Collagenase) production and invasiveness in gliomas by the extracellular signal-regulated kinase and Jun amino-terminal kinase signaling cascades. Clin. Expl. Metastasis 18: 245-252 (2000).

21. Marchetti, D. and Nicolson, G.L. Human heparanase: a molecular determinant of brain metastasis. Adv. Enzyme Regulat. 41: 343-359 (2001).

22. Haier, J. and Nicolson, G.L. Models for tumor cell-- endothelial cell interactions. In: Cancer Handbook, (M. Alison, Ed.), Macmillan Publishers, London, 983-998 (2002).

23. Konduri, S.D., Tasiou, A., Chandrasekar, N., Nicolson, G.L. and Rao, J.S. Role of Tissue Factor Pathway Inhbitor-2 in amelanotic melanoma C-32 invasion. Clin. Expl. Metastasis 18: 303-308 (2001).

24. Chandrasekar, N., Jasti, S., Yung, A.W.K., Ali-Osman, F., Kyritsis, A.P., Nicolson, G.L., Rao, J.S. and Mohanam, S. Modulation of endothelial cell morphogenesis in vitro by MMP-9 during glial-endothelial cell interactions. Clin. Expl. Metastasis 18: 337-342 (2001).

25. Chandrasekar, N., Jasti, S., Yung, A.W.K., Ali-Osman, F., Kyritsis, A.P., Nicolson, G.L., Rao, J.S. and Mohanam, S. Modulation of endothelial cell morphogenesis in vitro by MMP-9 during glial-endothelial cell interactions. Clin. Expl. Metastasis 18: 337-342 (2001).

26. Haier, J. and Nicolson, G.L. Models for tumor cell adhesion and invasion. In: Cancer Handbook, (Alison, M., Ed.), Macmillan Publishers, London, 983-998 (2001).

27. Haier, J., Nasralla, M. and Nicolson, G.L. Cell Surface molecules and their prognostic values in assessing colorectal carcinomas. Ann. Surgery 231(1):11-24 (2000).

28. Konduri, S.D., Tasiou, A., Chandrasekar, N., Nicolson, G.L. and Rao, J.S. Role of Tissue Factor Pathway Inhbitor-2 in amelanotic melanoma (C-32) invasion. Clin. Expl. Metastasis 18: 303-308 (2001).

29. Nicolson, G.L. Autocrine and paracrine growth mechanisms in cancer progression and metastasis. In: Encyclopedia of Cancer (J.R. Bertino, Ed.), 2nd Edition, Academic Press, San Diego, 1: 165-177 (2002).

30. Nicolson, G.L., Nawa, A., Toh, Y., Taniguchi, S., and Nishimori,K. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin. Expl. Metastasis 20: 14-19 (2002).

31. Yanamandra, N., Berhow, M.A., Konduri, S., Dinh, D.H., Olivero, W.C., Nicolson, G.L.and Rao, J.S. Triterpenoids from Glycine max decrease invasiveness and induce caspase-mediated cell death in human SNB19 glioma cells. Clin. Expl. Metastasis 20: 375-383 (2003). 

32.  Nicolson, G.L. Transfilter cell invasion assays. In: Cell Biology: A Laboratory Handbook, 3rd Edition (J.E. Celis, Ed.), Academic Press, New York, 359-362 (2006). 

33. Gassmann, P., Haier, J., Nicolson, G.L. Cell adhesion and invasion during secondary tumor formation. In: Cancer Growth and Progression, vol. 3, Kluwer, Amsterdam, in press (2006).

34. Toh, Y. and Nicolson, G.L. The role of the MTA family and their encoded products in human cancers: molecular functions and clinical implications. Clin. Expl. Metastasis 26: 215-227 (2009).

35. Toh, Y. and Nicolson, G.L. MTA1 of the MTA (metastasis-associated) gene family and its encoded proteins: molecular and regulatory functions and its role in human cancer progression. Atlas Genet. Cytogenet. Oncology Haematol. 15(3): 303-315 (2011).

36. Toh, Y. and Nicolson, G.L. Signaling pathways of MTA fmily proteins as regulators of cancer progression and metastasis. In: Trends in Stem Cell Proliferation and Cancer Research, R.R. Resende and H. Ulrich (eds.), Springer Science, Dordrecht, 249-273 (2013)

 

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Metastatic Cell Growth:

Scientists at the Institute for Molecular Medicine were the first to identify and purify paracrine growth factors that differentially stimulate the growth of highly metastatic cells. A prominent growth factor was found to be released from endothelial cells and found to be highly homologous to transferrin. The gene of this factor is being cloned and studied. We have also found that fibroblasts and mast cells isolated from different organs release different amounts of various growth factors that can differentially stimulate the growth of highly metastatic cells.

Recent Publications

1. Marchetti, D., McCutcheon, I.E., Ross, M.J. and Nicolson, G.L. Inverse expression of neurotrophins and neurotrophin receptors at the invasion front of human melanoma brain metastases. Int. J. Oncol. 7: 87-94 (1995).

2. Nicolson, G.L. and Menter, D.G. Trophic factors and central nervous metastasis. Cancer Metastasis Rev. 14: 303-321 (1995).

3. Nicolson, G.L. Autocrine and paracrine growth mechanisms in cancer progression and metastasis. In Encyclopedia of Cancer (J.R. Bertino, ed.), Academic Press, San Diego, 112-124 (1996).

4. Nicolson, G.L., Menter, D.G., Herrmann, J.L., Yun, Z., Cavanaugh, P.G. and Marchetti, D. Brain metastasis: role of trophic, autocrine and paracrine factors in tumor invasion and colonization of the central nervous system. Curr. Top. Microbiol. Immunol. 213: 89-115 (1996).

5. Nicolson, G.L. Bioregulators come of age in the control of tumor growth and metastasis. J. Natl. Cancer Inst. 88: 479-480 (1996).

6. Cavanaugh, P.G. and Nicolson, G.L. Selection of highly metastatic rat MTLn2 mammary adenocarcinoma cell variants using in vitro growth response to transferrin. J. Cell. Physiol. 174: 48-57 (1997).

7. Cavanaugh, P.G., Jia, L. and Nicolson, G.L. Transferrin receptor overexpression enhances transferrin responsiveness and the metastatic capability of a rat mammary adenocarcinoma cells. Breast Cancer Res. Treat. 56: 203-217 (1999).

8. Nicolson, G.L. Brain invasion, trophic factors and central nervous system metastasis. In: Brain Tumor Invasion: Biological, Clinical and Therapeutic Considerations, R. Bjerkvig, O.D. Laerum and M.L. Rosenblum, eds., Wiley-Liss, NY, 357-374 (1999).

9. Nawa, A., Nishimori, K., Lin, P., Maki, Y., Moue, K., Sawada, H., Toh, Y., Funitaka, K. and Nicolson, G.L. Tumor metastasis-associated human MTA1 gene: its deduced protein sequence, localization and association with breast cancer cell proliferation using antisense phosphorothioate oligonucleotides. J. Cell. Biochem. 79: 202-212 (2000).

10. Toh, Y., Kininaka, S., Endo, H., Ohshiro, T., Ikeda, Y., Nakashima, H., Baba, H., Kohnoe, S., Okamura, T., Nicolson, G.L. and Sugimachi, K. Molecular analysis of a candidate metastasis-associate gene mta1: interaction with histone deacetylase. J. Exp. Clin. Cancer Res. 19: 105-111 (2000).

11. Nicolson, G.L. and Nasralla, M. Advantages and limitations of models for cancer and mailgnant cell progression in breast cancer. In: Cancer Handbook, (M. Alison, Ed.), Macmillan Publishers, New York, 863-872 (2001).

12. Nicolson, G.L. Autocrine and paracrine growth mechanisms in cancer progression and metastasis. In: Encyclopedia of Cancer (J.R. Bertino, Ed.), 2nd Edition, Academic Press, San Diego, 165-177 (2002).

13. Nawa, A., Sawada, H., Toh, Y. and Nicolson, G.L. Tumor metastasis-associated human MTA1 gene: effects of antisense oligonucleotides on cell growth. Int. J. Med. Biol. Environ. 28(1): 33-39 (2000).

14. Nicolson, G.L., Nawa, A., Sawada, H., Toh, Y., Taniguchi, S., and Nishimori,K. Tumor metastasis-associated human MTA1 gene: role in epithelial cell proflieration and regulation. In: Metastasis Associated Genes, Welch, D., Ed., Kluwer Publishers, Amsterdam, 51-63 (2001).

15. Lakka, S.S., Konduri, S.D., Mohanam, S., Nicolson, G.L. and Rao, J.S. In vitro modulation of human lung cancer cell line invasiveness by antisense cDNA of tissue pathway inhibitor-2. Clin. Expl. Metastasis, 18: 239-244 (2000).

16. Yanamandra, N., Konduri, S.D., Mohanam, S., Dinh, D.H., Olivero, W.C., Gujrati, M., Nicolson, G.L. and Rao, J.S. Down-regulation of urokinase-type plasminogen activator receptor (uPAR) induces capase-mediated cell death in human glioblastoma cells. Clin. Expl. Metastasis 18: 611-615 (2001).

17. Cavanaugh P.G. and Nicolson, G.L. Partial purification of a liver-derived tumor cell growth inhibitor that differentially inhibits poorly-liver metastatic cell lines: identification as an active subunit of arginase. Clin. Expl. Metastasis 18: 509-518 (2001).

18. Haier, J., Nasralla, M. and Nicolson, G.L. Cell Surface molecules and their prognostic values in assessing colorectal carcinomas. Ann. Surgery 231(1):11-24 (2000).

19. Haier, J. and Nicolson, G.L. Models for tumor cell adhesion-endothelial cell interaction and invasion. In: Cancer Handbook, (Alison, M., Ed.), Macmillan Publishers, London, 983-998 (2002).

20. Nicolson, G.L. and Nasralla, M. Advantages and limitations of models for cancer and malignant cell progression in breast cancer. In: Cancer Handbook, (M. Alison, Ed.), Macmillan Publishers, 863-872 (2002).

21. Haier, J. and Nicolson, G.L. Hematological malignancies in cancer research. In: Cancer Handbook, (M. Alison, Ed.), Macmillan Publishers, London, 1101-1114 (2002).

22. Nicolson, G.L. and Nasralla, M.Y. Advantages and limitations of models for cancer and malignant cell progression. In: Cancer Handbook, (M. Alison, Ed.), Macmillan Publishers, London, 863-872 (2001).

23. Nicolson, G.L. Autocrine and paracrine growth mechanisms in cancer progression and metastasis. In: Encyclopedia of Cancer (J.R. Bertino, Ed.), 2nd Edition, Academic Press, San Diego, 1: 165-177 (2002).

24. Nicolson, G.L., Nawa, A., Toh, Y., Taniguchi, S., and Nishimori, K. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin. Expl. Metastasis 20: 14-19 (2002).

25. Yanamandra, N., Berhow, M.A., Konduri, S., Dinh, D.H., Olivero, W.C., Nicolson, G.L. and Rao, J.S. Triterpenoids from Glycine max decrease invasiveness and induce caspase-mediated cell death in human SNB19 glioma cells. Clin. Expl. Metastasis 20: 375-383 (2003).

26. Toh, Y., Ohga, T., Endo, K., Adachi, E., Kusumoto, H., Haraguchi, M., Okamura, T., Nicolson, G.L. Expression of the metastasis-associated MTA1 protein and its relationship to deacylation of the histone H4 in esophageal squamous cell carcinomas. Int. J. Cancer 110: 362-367 (2004).

27.    Toh, Y., Ohga, T., Endo, K., Adachi, E., Kusumoto, H., Haraguchi, M., Okamura, T., Nicolson, G.L. Expression of the metastasis-associated MTA1 protein and its relationship to deacylation of the histone H4 in esophageal squamous cell carcinomas.  Int. J. Cancer 110: 362-367 (2004).

28. Nicolson, G.L. and Mareel, M. Molecular cell biology and cancer metastasis:  an interview with Garth Nicolson. Int. J. Dev. Biol. 48: 355-363 (2005).

29. Clarke R, Haier J. Human tumors in animal hosts. The Cancer Handbook, 2nd edition, editor-in-chief: Malcolm R. Alison, John Wiley & Sons Ltd., Chichester; ISBN-13 978-0-470-01852-1(2007).

30. Cavanaugh P, Haier J. Basic Tissue and Cell Culture in Cancer Research. The Cancer Handbook, 2nd edition, editor-in-chief: Malcolm R. Alison, John Wiley & Sons Ltd.,Chichester 2007; ISBN-13 978-0-470-01852-1 (2007).

31. Gassmann P, Nicolson GL, Haier J. Models for tumor cell – endothelial cells interactions. The Cancer Handbook, 2nd edition, editor-in-chief: Malcolm R. Alison, John Wiley & Sons Ltd., Chichester; ISBN-13 978-0-470-01852-1(2007).

32. Haier J, Nicolson GL. Advantages and Limitations of Models for Cancer and Malignant Cell Progression. The Cancer Handbook, 2nd edition, editor-in-chief: Malcolm R. Alison, John Wiley & Sons Ltd., Chichester; ISBN-13 978-0-470-01852-1(2007).

33. Rodel C, Liersch T, Hermann R, Arnold D, Reese T, Hipp M, Furst A, Schwella N, Bieker M, Hellmich G, Ewald E, Haier J, Lordick F, Flentje M, Sülberg H, Hohenberger W, Sauer R. Multicenter Phase II Trial of the German Rectal Cancer Study Group: Preoperative Radiation with Concomitant and Adjuvant Capecitabine and Oxaliplatin for Rectal Cancer. J Clin Oncol. 25: 110-117 (2007).

34. Toh, Y. and Nicolson, G.L. The role of the MTA family and their encoded products in human cancers: molecular functions and clinical implications. Clin. Expl. Metastasis 26: 215-227 (2009).

35. Toh, Y. and Nicolson, G.L. MTA1 of the MTA (metastasis-associated) gene family and its encoded proteins: molecular and regulatory functions and its role in human cancer progression. Atlas Genet. Cytogenet. Oncology Haematol. 15(3): 303-315 (2011).

36. Toh, Y. and Nicolson, G.L. Signaling pathways of MTA fmily proteins as regulators of cancer progression and metastasis. In: Trends in Stem Cell Proliferation and Cancer Research, R.R. Resende and H. Ulrich (eds.), Springer Science, Dordrecht, 249-273 (2013)

37. Toh, Y. and Nicolson, G.L. Signaling pathways of MTA family proteins as regulators of cancer progression and metastasis. In: Trends in Stem Cell Proliferation and Cancer Research, R.R. Resende and H. Ulrich (eds.), Springer Science, Dordrecht, 249-273 (2013).

38. Toh, Y. and Nicolson, G.L. Identification and characterization of metastasis-associated gene/protein 1 (MTA1). Cancer Metastasis Rev. 33(4): 837-842 (2014).

39. Toh, Y. and Nicolson, G.L. Properties and clinical relevance of MTA1 protein in human cancer. Cancer Metastasis Rev. 33(4): 891-900 (2014).

40. Kanda, Y., Osaki, M., Onuma, K., Sonoda, A., Kobayashi, M., Hamada, J., Nicolson, G.L., Chiva, T. and Okada, F. Amigo2-upregulation in tumor cells facilitates their attachment to liver endothelial cells resulting in liver metastases. Nature Sci. Rep. 7: article 43567 (2017).

 

 

 

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Cellular Immunology of Cancer and Chronic Diseases:

The Institute has been involved in the development of DNA vaccine technology for generation of humoral and cellular immune responses against foreign and modified self-antigens. We have recently focused on developing DNA vaccines against different viral, tumor, bacterial, and other antigens. The significant advantage of DNA immunization is that it offers the capability to modify genes encoding desired antigen(s) to change the cellular localization of an antigen by adding or removing signal sequences or transmembrane domains and to target the desired type of immune response (humoral or cellular). More specifically, we have constructed DNA vaccines that encode not only an appropriate immunogen but also a special molecular adjuvant (molecules that stimulate the immune system, such as costimulatory molecules or cytokines) to direct immunity towards either antibody production (Th1 type of response) or cellular immune responses (Th2 responses). Employing this multiple gene technology approach we generated humoral immune response in an Alzheimer’s disease (AD) mouse model and cellular response in breast cancer mouse model.

Alzheimer’s Disease mouse model:
Recently, immunotherapy as a possible treatment for Alzheimer’s Disease (AD) has received considerable attention. It has been demonstrated that active or passive immunization of APP transgenic (APP/Tg) mice significantly reduced amyloid plaque deposition, neuritic dystrophy, and astrogliosis in APP/Tg mouse models of AD. Th1-type immune responses have been implicated in many autoimmune disorders, whereas Th2-type responses have been shown to inhibit autoimmune disease. Accordingly, it was suggested that Th2 type of humoral immune responses would be more beneficial in case of AD immunotherapy. Recently, we have analyzed the role of different adjuvants in the generation of B, Th1, and Th2 immune responses to immunization with fibrillar A42. Both the magnitude and the type of the immune response were affected by the choice of adjuvant. To generate anti-A humoral immune responses without the limitations of direct peptide and conventional adjuvant delivery, a plasmid DNA encoding A? fused with IL4 was generated and a potent Th2 type of immune responses was induced.

Breast cancer mouse model:
There are three major mechanisms whereby tumors escape immune recognition: (i) poor immunogenicity, when tumor cells lack expression of peptide:MHC ligands, adhesion molecules, and/or B7 (CD80/CD86) costimulatory molecules; (ii) antigenic modulation by antibodies; (iii) tumor-induced immune suppression by factors secreted by tumor cells (for example, TGFb). Published results support the presence of reactive T-cell clones specific to MUC1 breast cancer specific antigen, which are functionally inactive in the MUC1 transgenic mice (MUC1/Tg) because the lack of expression of B7 costimulatory molecules. More importantly, using the more potent B7 signal several authors have abrogated this tolerance. In an attempt to maximize the anti-tumor immune responses, we developed a plasmid vaccine that encodes MUC1 self-antigen and CD80 or CD86 costimulatory molecules. Only co-delivery of MUC1 vaccine and CD80 or CD86 to syngeneic mice induces protection against the challenge with breast cancer cells (4T1/2 subline of breat carcinoma line 410.4).

In addition to immune based strategies, we have also focused on analyzing of mechanisms of generation of Th1 or Th2 type of immune responses, including generation of cytotoxic lymphocytes and antibodies against self or altered self molecules.

Selected References:

1. Agadjanyan, M.G., Kim J., Trivedi N.,Willson D., Monzavi-Karbassi B., Morrison L., Nottingham L., Dentchev T., Chalian A., Moldonado M.A., Williams W.V., Weiner D.B., CD86 (B7-2) can function to drive MHC-restricted antigen-specific CTL responses in vivo. J. Immunology 162: 3417-3427 (1999).

2. Bennett, M. and Agadjanyan, M.G. HTLV-1 and 2 infections: Immunological and molecular aspects. Kluwer Academic/Plenum Publishers, NY, 87-107 (2000).

3. Vasilevko, V., Ghochikyan, A., Holterman, M.J., Agadjanyan, M.G. CD80 (B7-1) and CD86 (B7-2) are Functionally Equivalent in the Initiation and Maintenance of CD4+ T cell Proliferation after Activation with Suboptimal Doses of PHA. DNA Cell Biol 21: 137-149 (2002).

4. Cribbs, D.H., Ghochikyan, A. Vasilevko, V., Tran, M., Petrushina, I., Sadzikava, N., Babikyan, D., Kieber-Emmons, T., Cotman, C.W., Agadjanyan, M.G. Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with b-amyloid. Int. Immunol. 11: 23-36 (2003).

5. Ghochikyan, A. Vasilevko, V., Petrushina, I., Tran, M., Sadzikava, N., Babikyan, D., Movsesyan, N, Cribbs, D.H., Agadjanyan, M.G. T-helper 2 biased humoral immune responses to DNA immunization with a chimeric b-amyloid-interleukin-4 minigene. Eur. J. Immunol. 33: 3232-3241 (2003).

6. Vasilevko, V., Ghochikyan, A., Sadzikava, N., Petrushina, I., Tran, M., Cohen, E., Kesslak, P.J., Cribbs, D.H., Nicolson, G.L., Agadjanyan, M.G. Immunization with a vaccine that combines the expression of MUC1 and B7 co-stimulatory molecules prolongs the survival of mice and delays the appearance of mouse mammary tumors. Clin. Exp. Metastasis 20: 489-98 (2003).

7. Gevorkian, G., Petrushina, I., Manoutcharian, K., Ghochikyan, A., Acero, G., Vasilevko, V., Cribbs, D.,  Agadjanyan, M.  Detection of conformational antigenic determinants mimicking fibrillar b-amyloid. J. Neuroimmunology 156: 10-20 (2004). 

8. Agadjanyan, M.G, A., Ghochikyan, I., Petrushina, V. Vasilevko, N. Movsesyan, M. Mkrtichyan, T. Saing, D.H. Cribbs, D.H. Prototype Alzheimer’s disease vaccine utilizing the immunodominant B cell epitope from b-amyloid and promiscuous T cell epitope PADRE.  J. Immunology 174: 1580-1586 (2005). 

9. Cribbs, D.H., Agadjanyan, M.G. Immunotherapy for Alzheimer’s Disease: Potential problems and possible solutions. Current Immunology Reviews 1: 139-155 (2005). 

10. Ghochikyan, A., Mkrtichyan, M., Petrushina, I., Movsesyan, N., Karapetyan, A., Cribbs, D.H., Agadjanyan, M.G. Prototype Alzheimer’s disease epitope vaccine induced strong Thy2-type anti-Ab antibody response with alum to Quil A adjuvant switch. Vaccine 24: 2275-2282 (2006).

11. Head, E., Barrett, E.G., Murphy, P.M., Das, P., Nistor, M., Sarsoza, F., Glabe, C.C., Kayed, R., Milton, S., Vasilevko, V., Milgram, N.W., Agadjanyan, M.G., Cribbs, D.H., Cotman, C.W. Immunization with fibrillar Ab1-42 in young and aged canines:  Antibody Generation and Characteristics, and effects on CSF and Brain Ab. Vaccine 24: 2824-2834 (2006). 

12. Loukinov D., Ghochikyan A., Mkrtichyan M., Itchim T.E., Lobanenkov V.V., Cribs .H., Agadjanyan M.G. Antitumor efficacy of DNA vaccination to the epigenetically acting tumor promoting transcription factor BORIS and CD80 molecular adjuvant.
J. Cell. Biochem. 98(5): 1037-1043 (2006). 

13. Ghochikyan A., Petrushina I., Lees A., Vasilevko V., Movsesyan N., Karapetyan A., Agadjanyan M.G., Cribbs D.H. Ab-immunotherapy for Alzheimer’s disease using mannan-amyloid-beta peptide immunoconjugates. DNA and Cell Biology, 10: 571-580 (2006).

14. Parachikova, A., Agadjanyan, M.G., Cribbs, D.H., Blurton-Jones, M., Perreau, V., Rogers, J., Beach, T.G., Cotman, C.W. Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiol. Aging. 28: 1821-1833 (2006).

15. Zhong, Z., Kusznieruk, K.P., Popov, I.A., Riordin, N.H., Izadi, H., Yijian, L., Sher., S., Szczurko, O.M., Agadjanyan, M.G., Tullis, R.H., Harandi., A., Reznik, B.N., Mamikonyan, G.V., Ichim, T.E. Induction of antitumor immunity through xenoplacental immunization. J. Transl. Med. 25; 4-22 (2006).

16. Ghochikyan, A., Mkrtichyan, M., Loukinov, D., Mamikonyan, G., Movsesyan, N., Ichim, T.E., Lobanenkov, V.V., Cribbs, D.H., Agadjanyan, M.G. Elicitation of T cell responses to histologically unrelated tumors by immunization with the novel cancer-testis antigen, brother of the regulator of imprinted sites. J. Immunol. 178: 566-573 (2007).

17. Mamikonyan G., Necula M., Mkrtichyan M., Ghochikyan A., Petrushina I., Movsesyan N., Mina E., Kiryakin A., Glabe C., Gribbs D.H, Agadjanyan M.G, Anti-Ab1-11 antibody binds to different b-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligoners. J. Biol. Chem. 2007, 282: 22376-22386 (2007).

18. Petrushina I, Ghochikyan A, Mkrtichyan M, Mamikonyan G, Movsesyan N, Davtyan H, Patel A, Head E, Cribbs DH, Agadjanyan MG, Alzheimer's disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Abeta species in amyloid precursor protein transgenic mice. J. Neurosci. 27: 12721-12731 (2007).

19. Mkrtichyan, M., Ghochikyan, A., Movsesyan, N., Karapetyan, A., Begoyan, G., Glenn, G.M., Ross, T.M., Agadjanyan, M.G., Cribbs, D. H. Immunostimulant Adjuvant Patch Enhances Humoral and Cellular Immune Responses to DNA Immunization. DNA Cell Biol. 27(1): 19-24 (2008).

20. Mkrtichyan, M, Ghochikyan, A., Loukinov, D., Davtyan, D, Ichim, T.E. Cribbs, D.H., Lobanenkov, V.V. and Agadjanyan, M.G. DNA, but not protein vaccine based on mutated BORIS antigen significantly inhibits tumor growth and prolongs the survival of mice. Gene Therapy15:61-64 (2008).

21. Dougherty CJ, Ichim TE, Liu L, Reznik G, Min WP, Ghochikyan A, Agadjanyan MG, Reznik BN. Selective apoptosis of breast cancer cells by siRNA targeting of BORIS Biochem. Biophys. Res. Commun. 370: 109-112 (2008).

22. Mamikonyan G, Kiyatkin A, Movsesyan N, Mkrtichyan M, Ghochikyan A, Petrushina I, Hwang J, Ichim T, Agadjanyan MG. Detection of the Active Components of Calf Thymus Nuclear Proteins (TNP), Histones that are Binding with High Affinity to HIV-1 Envelope Proteins and CD4 Molecules Current HIV Research 6: 318-326 (2008).

23. Movsesyan N, Mkrtichyan M, Petrushina I, Ross T, Cribbs DH, Agadjanyan MG, Ghochikyan A. Generation of functional anti-amyloid antibodies after immunization with DNA encoding multiple copies of Ab-peptide immunogen fused with C3d. Journal Neuroimmunol. 205: 57-63 (2008).

24. Petrushina I., Ghochikyan A., Mkrtichyan M., Mamikonyan G., Movsesyan N., Ajdari R., Vasilevko V., Karapetyan A., Lees A., Agadjanyan MG., Cribbs DH. Mannan-Ab28 conjugate prevented Ab-plaque deposition, but increased microhemorrhages in the brains of vaccinated Tg2576 (APPsw) mice, Journal of Neuroinflammation, 5: 42-49 (2008).

25. Cribbs DH and Agadjanyan MG. Active and passive Ab-immunotherapy: preclinical and clinical studies and future directions: part I/II. CNS Neurol Disord Drug Targets 1: 1-16 (2009).

26. Agadjanyan M.G. and Cribbs D.H. Active and passive Ab-immunotherapy: preclinical and clinical studies and future directions: part I/II. CNS Neurol Disord Drug Targets, 2: 82-87 (2009).

27. Davtyan H, Mkrtichyan M, Movsesyan N, Petrushina I, Mamikonyan G, Cribbs DH, Agadjanyan MG, Ghochikyan A. DNA prime-protein boost increased the titer, avidity and persistence of anti-Abeta antibodies in wild-type mice. Gene Ther. 17(2): 261-71 (2010).

28. Movsesyan N, Davtyan H, Mkrtichyan M, Petrushina I, Tiraturyan T, Ross TM, Agadjanyan MG, Ghochikyan A, Cribbs DH. 2010. Low concentrations of anti-Abeta antibodies generated in Tg2576 mice by DNA epitope vaccine fused with 3C3d molecular adjuvant do not affect AD pathology. Hum Gene Therapy 21(11): 1569-1576 (2010).

29. Robert R, Lefranc MP, Ghochikyan A, Agadjanyan MG, Cribbs DH, Van Nostrand WE, Wark KL, Dolezal O. Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid b peptide. Mol. Immunol. 48(1-3): 59-72 (2010).

30. Mkrtichyan M, Ghochikyan A, Davtyan H, Movsesyan N, Loukinov D, Lobanenkov V, Cribbs DH, Laust AK, Nelson EL, Agadjanyan MG. Cancer-testis antigen, BORIS based vaccine delivered by dendritic cells is extremely effective against a very aggressive and highly metastatic mouse mammary carcinoma. Cell Immunol. 270(2):188-197 (2011).

31. Davtyan, H., Ghochikyan, A., Cadagan, R., Zamarin, D., Petrushina, I., Movsesyan, N., Martinez-Sobrido, L., Albrecht, RA., GarcÌa-Sastre, A., Agadjanyan, MG. The immunological potency and therapeutic potential of a prototype dual vaccine against influenza and Alzheimer's disease. J. Translational Med. 9:127 (2011).

32. de Necochea-Campion R., Ghochikyan A., Josephs S.F., Zacharias S., Woods E., Karimi-Busheri F., Alexandrescu D.T., Chen C.S., Agadjanyan M.G., Carrier E. Expression of the epigenetic factor BORIS (CTCFL) in the human genome. J. Transl Med. 9:213 (2011).

33. Davtyan, H., Ghochikyan, A., Movsesyan, N., Ellefsen, B., Petrushina, I., Cribbs DH, Hannaman, D., Evans, CF, Agadjanyan, MG. Delivery of a DNA vaccine for Alzheimer’s disease by electroporation or gene gun generates potent and similar immune responses. Neurodegener Dis. 10: 261-264 (2012).

34. Davtyan, H., Ghochikyan, A., Petrushina,I., Hovakimyan, A., Davtyan, A., Poghosyan, A., Marleau, A.M., Movsesyan, N., Kiyatkin, A., Rasool, S., Larsen, S.A., Madsen, P.J., Wegener, K.M., Ditlevsen, D.K., Cribbs, D.H., Pedersen, L.O., Agadjanyan, M.G.. Immunogenicity, Efficacy, Safety, and Mechanism of Action of Epitope Vaccine (Lu AF20513) for Alzheimer’s Disease: Prelude to a Clinical Trial. J. Neurosci. 33(11):4923-4934 (2013).

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Selected Publications and Reviews for Download

  • A brief introduction to some aspects of the Fluid—Mosaic Model of membrane structure and its importance to Membrane Lipid Replacement, by Nicolson, G.L., Ferreira de Mattos, G.. Membranes 11(12): article 947 (2021). pdf_doc

  • Membrane Lipid Replacement—a functional approach to repairing cellular membranes, reducing symptoms, and restoring function, by Nicolson, G.L. Functional Food Science 2(8): 198-204 (2022). pdf_doc

  • The Fluid—Mosaic Model of Membrane Structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years, by Nicolson, G.L., Biochim. Biophys. Acta 1838: 1451-1466 (2014). pdf doc

  • Lipid Replacement Therapy: a natural medicine approach to replacing damaged phospholipids in cellular membranes and organelles and restoring function, by Nicolson, G.L. and Ash, M.E. Biochim. Biophys. Acta 1838: 1657-1679 (2014). pdf doc

  • Gulf War Illnesses: chemical, radiological and biological exposures resulting in chronic fatiguing illnesses can be identified and treated., by Nicolson G.L, Berns P., Nasralla M., Haier J., Nicolson N.L., Nass M.,  J. Chronic Fatigue Syndr. 11(1): 135-154 (2003). pdf doc

  • Isolation, purification and analysis of specific gene-containing nucleoproteins and nucleoprotein complexes, by Rosenberg-Nicolson, N.L. and Nicolson, G.L., Methods Molec. Genetics 5: 281-298 (1994). pdf doc


 

 


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