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Molecular Biology of Cancer Invasion and Metastasis

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Metastatic Cell Gene Regulation:

Differences in gene expression characterize highly metastatic cells. Scientists at The Institute for Molecular Medicine have used differential gene expression techniques to identify genes that are over- or under-expressed in highly metastatic cells. We were the first to find that certain mitochondrial genes can be over-expressed in highly metastatic cells in relation to their ability to avoid respiration inhibition by macrophages and endothelial cells. We have identified several genes that are differentially expressed in breast cancer cells that are metastatic. For example, one novel gene, called mta1 in the rat and MTA1 in human breast cancer cells, is over-expressed in metastatic rodent and human metastatic mammary cells. This gene encodes a 80 kDa SH3-binding protein that has been localized to the cytoplasm and nucleus and is probably involved in signaling transduction. Recently the human MTA1has been found associated with a histone remodeling complex containing histone deacylase, suggesting that MTA1 may be part of a multifunction complex.

Recent Publications

  1. Yu, D., Wang, S.S., Dulski, K.M., Nicolson, G.L. and Hung, M.C. c-erb-2/neu overexpression enhances metastatic potential in human lung cancer cells by induction of metastasis-associated properties. Cancer Res. 54: 3260-3266 (1994).

  2. Toh, Y., Pencil, S.D. and Nicolson, G.L. A novel candidate metastasis-associated gene mta1 differentially expressed in highly metastatic mammary adenocarcinoma cell lines: cDNA cloning, expression and protein analyses. J. Biol. Chem. 269: 22958-22963 (1994).

  3. Toh, Y., Pencil, S.D. and Nicolson, G.L. Analysis of the complete sequence of the novel gene mta1 differentially expressed in highly metastatic mammary adenocarcinoma and breast cancer cell lines and clones. Gene 159: 99-104 (1995).

  4. Fukuda, M., Ishii, A., Yasutomo, Y., Shimada, N., Ishikawa, N., Hanai, N., Nagata, N., Irimura, T., Nicolson, G.L. and Kimura, N. Decreased expression of nucleoside diphosphate kinase is associated with metastatic potential of rat mammary adenocarcinoma cells. Int. J. Cancer 65: 531-537 (1996).

  5. Nicolson, G.L. The role of cancer metastasis-associated genes in the progression of a tumor to the metastatic state. Cope 12: 16-17 (1996).

  6. Moustafa A.S. and Nicolson G.L. Breast cancer metastasis-associated genes: Prognostic significance and therapeutic implications. Oncology Res. 9: 505-525 (1997)

  7. Nicolson, G.L. Breast cancer metastasis-associated genes: role in tumor progression to the metastatic state. In: Mammary Development and Cancer. P.S. Rudland, D.G. Fernig, S. Leinster, G.G. Lunt, Eds., The Biochemical Society Symp., 63: 231-243 (1997).

  8. 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. Expl. Metastasis 15: 151-156 (1997).

  9. Toh, Y., Oki, E., Oda, S., Tokunaga, E., Ohno, S., Maehara, Y., Nicolson, G.L. and Sugimachi, K. Overexpression of MTA1 gene in colorectal and gastrointestinal carcinomas: correlation with invasion and metastasis. Intern. J. Cancer 74: 459-463 (1997).

  10. Moustafa, A. and Nicolson, G.L. Breast cancer metastasis-associated genes: prognostic significance and therapeutic implications. Oncol. Res. 9: 505-525 (1998).

  11. Nicolson, G.L. and Moustafa, A.S. Metastasis-associated genes and metastatic tumor progression. In Vivo 12: 579-588 (1998).

  12. Toh, Y., Kuwano, H., Mori, M., Nicolson, G.L. and Sugimachi, K. Overexpression of metastasis-associated MTA1 mRNA in invasive oesophageal carcinomas. Brit. J. Cancer. 79: 1723-1726 (1999).

  13. 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).

  14. 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).

  15. Nicolson, G.L. and Moustafa, M. Gene expression in tumor metastasis and malignant cell progression. In: Intramolecular Cross-talk in Metastasis, (G. Skouteris and G.L. Nicolson, Eds.), NATO ASI series, IOS Press, Amsterdam, 1-9 (1999).

  16. 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).

  17. 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).

  18. 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 proetin translation. Clin. Expl. Metastasis 17: 617-621 (2000).

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

  20. 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).

  21. 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).

  22. 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).

  23. 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. Owen Wangensteen Surgical Forum LI, 260-262 (2000).

  24. 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).

  25. 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).

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

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

  28. Nijs, J., De Meirleir, K., Coomans, D., De Becker, P., Nicolson, G.L. Deregulation of the 2.5A synthetase RNase L antiviral pathway by mycoplasmas in subsets of Chronic Fatigue Syndrome. J. Chronic Fatigue Syndr. In press (2002).

  29. 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).

  30. Hu, M., Nicolson, G.L., Trent, J.C., Yu, D., Zhang, L., Lang, A., Killary, A., Ellis, L.M., Bucana, C.D., and Pollock, R.E. Characterization of 11 human sarcoma cell strains: evaluation of cytogenetics, tumorigenicity, metastasis, and production of angiogenic factors. Cancer 95: 1569-1576 (2002).

  31. Haier, J. and Nicolson, G.L. Hematological malignancies in cancer research. In: Cancer Handbook, (M. Alison, Ed.), Macmillan Publishers, London, 1101-1114 (2001).

  32. 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).

  33. 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).

  34. 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).

  35. 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).

  36. Toh, Y. and Nicolson, G.L. MTA1 (metastasis-associated gene 1). Atlas Genet. Cytogenet. Oncol. Haematol.  9(3): 212-213 (2005).

  37. 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).

  38. 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).

  39. 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).

  40. 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).

  41. 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).

  42. 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).

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

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

  45. 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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Subchromatin complexes and gene regulation:

Using a technique that involves direct restriction digestion of the nucleolus or nucleus followed by gentle acidic extraction and low ionic strength electrophoresis, Nucleoprotein (NP) complexes have been identified by researchers at the Institute for Molecular Medicine that are capable of discrete and faithful transcription as well as DNA synthesis using endogenous rather than synthetic oligonucleotide substrates. The NP complexes have been molecularly dissected into >400 specific NPs, and ongoing work is investigating NP enzymatic activities and tightly bound DNAs and RNAs in these complexes. Our staff have found that certain NP complexes can regulate the expression of specific genes, some by silencing and some by enhancing transcription. We are also characterizing a family of specific eukaryotic endonucleases that we have recently discovered in the NP complexes and that are directly associated with the polymerase function and apoptosis of the NPs.

 

Recent Publications

  1. Rosenberg-Nicolson, N.L. and Nicolson, G.L. The isolation, purification and analysis of specific gene-containing nucleoproteins and nucleoprotein complexes. Meth. Mol. Genet. 5: 281-298 (1994).

  2. Rosenberg-Nicolson, N.L. and Nicolson, G.L. The p53 gene is bound to specific nucleoproteins of nonmetastatic and metastatic murine large-cell lymphoma cells. Cancer Mol. Biol. 1: 95-106 (1994).

  3. Nicolson, N.L., Talpaz, M. and Nicolson, G.L. Interferon-a directly inhibits DNA polymerase activity in isolated chromatin nucleoprotein complexes: correlation with IFN-a treatment outcome in patients with chronic myelogenous leukemia. Gene 159: 105-111 (1995).

  4. Nicolson, N.L., Talpaz, M. and Nicolson, G.L. Chromatin nucleoprotein complexes containing tightly-bound c-abl, p53 and bcl-2 gene sequences: correlation of nucleoprotein-bound genes with progression of chronic myelogenous leukemia. Gene 169: 173-178 (1996).

  5. Nicolson, N.L. and Nicolson, G.L. Nucleoprotein Gene Tracking: localization of specific HIV-1 genes to subchromatin nucleprotein complexes in HIV-1 infected human cells. J. Cell. Biochem. Suppl. 32: 158-165 (1999).

  6. 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).

  7. Nicolson, N.L. and Nicolson, G.L. HIV-1 genes are localized in specific nucleoproteins in subchromatin complexes in HIV-1 infected human cells. Intern. J. Med. Biol. Environ. 28(1): 25-31 (2000).

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

  9. 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).

  10. Taniguchi, S., Moue, K., Nawa, A., Suganuma, S., Nicolson, G.L., and Nishimori, K. GATA-Element Dependent Transcriptional Activation in MDA-MB-231 Breast Cancer Cells Suppressed by Expression of Anti-MTA1 Antisense RNA. Submitted (2001).

  11. 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 (2002).

  12. Nijs, J., De Meirleir, K., Coomans, D., De Becker, P., Nicolson, G.L. Deregulation of the 2.5A synthetase RNase L antiviral pathway by mycoplasmas in subsets of Chronic Fatigue Syndrome. J. Chronic Fatigue Syndr. In press (2002).

  13. 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).

  14. 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).

  15. 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).

  16. Nicolson, G.L. and Conklin, K.A. Molecular replacement for cancer metabolic and mitochondrial dysfunction, fatigue and the adverse effects of cancer therapy.  Cancer Genomics Proteomics 3: 159-168 (2006).

  17. 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).

  18. 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).

  19. 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).

  20. 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).

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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 A?42. 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 -amyloid. Int. Immunol. 15: 505-514 (2003)

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

6. . Vasilevko, V., Ghochikyan, A., Petrushina, I., Tran, M., Sadzikava, N., Cribbs, D.H., Agadjanyan, M.G. Generation of tumor-specific immune responses after gene-gun immunization with plasmids, encoding MUC1 and B7 costimulatory molecules. Submitted 2002.

7. Agadjanyan, M.G., Chattergoon, M., Holterman, M.J., Monzavi-Karbassi, B., Kim J., Dentchev, T., Willson, D., Ayyavoo, V., Montaner, L.J., Kieber-Emmons, T., Sekaly, R-P., Weiner, D.B. Costimulatory molecule immune enhancement in a plasmid vaccine model is regulated in part through the Ig constant-like domain of CD80/86. J. Immunology 171: 4311-4319 (2003).

8. 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). 

9. Ghochikyan, A., Mkrtichyan, M., Petrushina, I., Movsesyan, N., Karapetyan, A., Cribbs, D.H., Agadjanyan, M.G. Prototype Alzheimer’s Disease epitope vaccine induced strong Th2-type anti-A antibody response with Alum to Quil A adjuvant switch. Vaccine 24: 2275-2282 (2006).

10. Agadjanyan M.G., Ghochikyan A., Petrushina I.. Vasilevko V., Movsesyan N., Mkrtichyan M., Saing T., Cribbs D.H. Prototype Alzheimer's disease vaccine utilizing the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope PADRE. J. Immunol. 174(3):1580-1586 (2005).

11. Ghochikyan A., Mkrtichyan M., Petrushina I., Movsesyan N., Karapetyan A., Cribbs D.H., Agadjanyan M.G. Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Abeta antibody response with Alum to Quil A adjuvant switch. Vaccine. 24(13): 2275-2282 (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., Mkrtichyan M., Loukinov D., Mamikonyan G., Pack S.D., Movsesyan N., Ichim T.E., Cribbs D.H., Lobanenkov V.V., 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).

14. Mkrtichyan M, Ghochikyan A, Loukinov D, Davtyan H, Ichim TE, Cribbs DH, Lobanenkov VV, Agadjanyan MG. DNA, but not protein vaccine based on mutated BORIS antigen significantly inhibits tumor growth and prolongs the survival of mice. Gene Ther. 15(1): 61-64 (2008).

15. Mkrtichyan M, Ghochikyan A, Movsesyan N, Karapetyan A, Begoyan G, Yu J, Glenn GM, Ross TM, Agadjanyan MG, Cribbs DH. Immunostimulant adjuvant patch enhances humoral and cellular immune responses to DNA immunization. DNA Cell Biol. 27(1): 19-24 (2008).

16. 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(1): 109-112 (2008).

17. Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG. Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS ONE 3(5): e2124 (2008).

18. 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).

19. 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).

20. 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).

21. 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).

22. 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).

23. 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).

24. 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).

25. 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).

26. 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).

27. 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).

28. 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).

29. 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).

30. 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).

31. 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).

32. 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).

33. Sfera A, Hazan S, Klein C, Zapata-Martin del Campo CM, Sasannia S, Anton JJ, Rahman L, Andronescu CV, Sfera DO, Kozakidis Z, Nicolson GL. Microbial translocation disorders: assigning an etiology to idiopathic illnesses. Applied Microbiology 2023; 3(1): 212-240.

 

 

Selected Publications and Reviews for Download

  • Microbial translocation disorders: assigning an etiology to idiopathic illnesses. Sfera A, Hazan S, Klein C, Zapata-Martin del Campo CM, Sasannia S, Anton JJ, Rahman L, Andronescu CV, Sfera DO, Kozakidis Z, and Nicolson GL. Applied Microbiology 2023; 3(1): 212-240. pdf_doc
    https://doi.org/10.3390/applmicrobiol301001

  • Long COVID and the neuroendocrinology of microbial translocation outside the GI tract: some treatment strategies. Sfera A, Osorio C, Hazan S, Kozlakidis Z, Maldonado JC, Martin del Campo CMZ, Anton JJ, Rahman L, Andronescu CV, and Nicolson GL.. Endocrines 2022; 3: 703-725. pdf_doc

  • Lipid Replacement Therapy: a Functional Food Approach with New
    Formulations for Reducing Cellular Oxidative Damage, Cancer-Associated
    Fatigue and the Adverse Effects of Cancer Therapy,     by G. L. Nicolson and
    R. Settineri, Functional Foods in Health and Disease 2011; 4: 135-160.     pdf_doc

  • The role of the MTA family and their encoded products in human cancers: molecular functions and clinical implications, by Toh, Y. and Nicolson, G.L. Clin. Expl. Metastasis 26: 215-277 (2009). pdf_doc

  • Elicitation of T cell responses to histologically unrelated tumors by immunization with the novel cancer-testis antigen, Brother of the Regulator of Imprinted Sites, by Ghochikyan, A., Mkritchyan, M., Loukinov, D., Mamikonyan, G., et al. J. Immunol. 178: 566-573 (2007). pdf doc

  • 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 syngenic mouse mammary tumors., by Vasilevko, V., Ghochikyan, A., Sadzikava, N., Petrushina, I., Tran, M., Cohen, E.P., Kesslak, P.J., Cribbs, D.H., Nicolson, G.L. and Agadjanyan, M.G., Clin. Expl. Metastasis 20: 489-498 (2003) pdf doc

  • Nucleoprotein complexes from metastatic cells containing oncogenes and tissue-specific genes: a novel method to track genes associated with specific nucleoproteins, by Rosenberg-Nicolson, N.L. and Nicolson, G.L., Cancer Detection Prevention 18: 31-41 (1994).pdf doc

 

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