Mikhail Dikov
Faculty Member

Profile

The research of our laboratory for the past few years has been focused on the role of tumor-derived factors in hematopoietic development, immune cell differentiation and function. These studies broadly relate to cancer biology, cancer immunology, tumor-host interaction, and tumor microenvironment. They are aimed on understanding the molecular mechanisms of carcinogenesis, immune suppression, hematopoietic/immune development in cancer, and the mechanisms exploited by tumor to convert tumor-infiltrating cells from protective to tumor supporting factor.
We identified adenosine as an important tumor metabolite that alters differentiation and function of tumor-infiltrating immune cells by activating A2B adenosine receptor. It induces recruitment of myeloid-derived suppressor cells and secretion of tolerogenic and angiogenic factors including VEGF by tumor immune infiltrate. Our research is focused on understanding the molecular mechanisms of adenosine effects and the development of therapeutic strategies to target the A2B adenosine receptor in cancer. This receptor is an especially attractive target for therapy, as due to its low affinity to adenosine it stays silent under normal conditions and becomes active only at pathologically high adenosine levels.
Defects in T cell function are evident in tumor bearing hosts. We found that tumor-associated defects in T cell development are characterized by attenuated levels of delta-like (DLL) 1 and DLL4 in the bone marrow (BM) microenvironment, and elevated circulating VEGF is one causative factor. We also revealed that elective therapeutic stimulation of Notch signaling in animals using multivalent form of DLL1 significantly reduces tumor growth, rescues T cell development and enhances T cell-mediated immune responses and that over-expression of DLL1 alone in BM precursors also inhibits tumor growth and improves anti-tumor immunity. Using mouse models, we selectively stimulated VEGFR1 and VEGFR2 by continuous infusion of receptor-specific ligands or selectively blocked their signaling with VEGF receptor-specific antibodies in mice infused with recombinant VEGF to demonstrate that activation of VEGFR1 and VEGFR2 has selective effects on differentiation and function of various lymphoid and myeloid lineages.
Our ultimate goal is to develop and validate the novel therapeutic strategies targeting the identified mechanisms to correct tumor-induced aberrant hematopoietic differentiation and immune deficiency.

Publications

The following timeline graph is generated from all co-authored publications.

  1. Role of JunB in adenosine A2B receptor-mediated vascular endothelial growth factor production. Ryzhov S, Biktasova A, Goldstein AE, Zhang Q, Biaggioni I, Dikov MM, Feoktistov I (2014) Mol Pharmacol 85(1): 62-73
    › Primary publication · 24136993 (PubMed) · PMC3868903 (PubMed Central)
  2. Structure, stability and function of 5-chlorouracil modified A:U and G:U base pairs. Patra A, Harp J, Pallan PS, Zhao L, Abramov M, Herdewijn P, Egli M (2013) Nucleic Acids Res 41(4): 2689-97
    › Primary publication · 23275540 (PubMed) · PMC3575798 (PubMed Central)
  3. Anti-vascular endothelial growth factor treatment in combination with chemotherapy delays hematopoietic recovery due to decreased proliferation of bone marrow hematopoietic progenitor cells. Novitskiy SV, Csiki I, Huang Y, Johnson DH, Harth EM, Carbone DP, Dikov MM (2010) J Thorac Oncol 5(9): 1410-5
    › Primary publication · 20683208 (PubMed)
  4. The Foxc2 transcription factor regulates tumor angiogenesis. Sano H, Leboeuf JP, Novitskiy SV, Seo S, Zaja-Milatovic S, Dikov MM, Kume T (2010) Biochem Biophys Res Commun 392(2): 201-6
    › Primary publication · 20060810 (PubMed) · PMC2822046 (PubMed Central)
  5. Host A(2B) adenosine receptors promote carcinoma growth. Ryzhov S, Novitskiy SV, Zaynagetdinov R, Goldstein AE, Carbone DP, Biaggioni I, Dikov MM, Feoktistov I (2008) Neoplasia 10(9): 987-95
    › Primary publication · 18714400 (PubMed) · PMC2517644 (PubMed Central)
  6. Single amino acid substitution in aquaporin 11 causes renal failure. Tchekneva EE, Khuchua Z, Davis LS, Kadkina V, Dunn SR, Bachman S, Ishibashi K, Rinchik EM, Harris RC, Dikov MM, Breyer MD (2008) J Am Soc Nephrol 19(10): 1955-64
    › Primary publication · 18701606 (PubMed) · PMC2551576 (PubMed Central)
  7. Adenosine receptors in regulation of dendritic cell differentiation and function. Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y, Tikhomirov OY, Blackburn MR, Biaggioni I, Carbone DP, Feoktistov I, Dikov MM (2008) Blood 112(5): 1822-31
    › Primary publication · 18559975 (PubMed) · PMC2518889 (PubMed Central)
  8. Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells. Ryzhov S, Zaynagetdinov R, Goldstein AE, Novitskiy SV, Dikov MM, Blackburn MR, Biaggioni I, Feoktistov I (2008) J Immunol 180(11): 7212-20
    › Primary publication · 18490720 (PubMed) · PMC3628765 (PubMed Central)
  9. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Huang Y, Chen X, Dikov MM, Novitskiy SV, Mosse CA, Yang L, Carbone DP (2007) Blood 110(2): 624-31
    › Primary publication · 17376891 (PubMed) · PMC1924481 (PubMed Central)
  10. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. Dikov MM, Ohm JE, Ray N, Tchekneva EE, Burlison J, Moghanaki D, Nadaf S, Carbone DP (2005) J Immunol 174(1): 215-22
    › Primary publication · 15611243 (PubMed)