Abstract

): The investigators hypothesize that the angiostatic factor IP-10 is an endogenous inhibitor of tumor-derived angiogenesis. In this proposal, they will test this hypothesis by characterizing the role of IP-10 in regulating overall tumor-derived angiogenic activity in an animal model of human non-small cell lung cancer (NSCLC). They will demonstrate that underexpression of IP-10 imparts increased angiogenic activity to NSCLC cell lines. Next, they will reconstitute IP-10 production in NSCLC cell lines, thus restoring the angiostatic balance, using two methods. (1) In vitro treatment of NSCLC cells with interferon gamma (IFNgamma) to induce IP-10 expression, and (2) Gene transfer technology to indirectly (IFNgamma) or directly (IP-10) augment IP-10 expression. They will then show that IFNgamma and IP-10 gene transfected cells have reduced in vitro angiogenic activity and reduced tumorigenicity in SCID mice. Finally, they will treat established NSCLC tumors in SCID mice with locally administered IFNgamma or IP-10 and show that IFNgamma inhibits tumor growth via an IP-10 dependent increase in angiostatic activity. These studies will lead to important new information about the pathogenesis of NSCLC, and enable the Principal Investigator to acquire the necessary skills to develop into an independent investigator.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA072543-03
Application #
2882464
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
1997-03-07
Project End
2002-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

White, Eric S; Flaherty, Kevin R; Carskadon, Shannon et al. (2003) Macrophage migration inhibitory factor and CXC chemokine expression in non-small cell lung cancer: role in angiogenesis and prognosis. Clin Cancer Res 9:853-60
White, E S; Strieter, R M; Arenberg, D A (2002) Chemokines as therapeutic targets in non-small cell lung cancer. Curr Med Chem Anticancer Agents 2:403-17
White, E S; Strom, S R; Wys, N L et al. (2001) Non-small cell lung cancer cells induce monocytes to increase expression of angiogenic activity. J Immunol 166:7549-55
Arenberg, D A; White, E S; Burdick, M D et al. (2001) Improved survival in tumor-bearing SCID mice treated with interferon-gamma-inducible protein 10 (IP-10/CXCL10). Cancer Immunol Immunother 50:533-8
Arenberg, D A; Zlotnick, A; Strom, S R et al. (2001) The murine CC chemokine, 6C-kine, inhibits tumor growth and angiogenesis in a human lung cancer SCID mouse model. Cancer Immunol Immunother 49:587-92
White, E S; Livant, D L; Markwart, S et al. (2001) Monocyte-fibronectin interactions, via alpha(5)beta(1) integrin, induce expression of CXC chemokine-dependent angiogenic activity. J Immunol 167:5362-6
Addison, C L; Arenberg, D A; Morris, S B et al. (2000) The CXC chemokine, monokine induced by interferon-gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis. Hum Gene Ther 11:247-61
Belperio, J A; Keane, M P; Arenberg, D A et al. (2000) CXC chemokines in angiogenesis. J Leukoc Biol 68:8-Jan
Arenberg, D A; Keane, M P; DiGiovine, B et al. (2000) Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines. Cancer Immunol Immunother 49:63-70
Moore, B B; Arenberg, D A; Stoy, K et al. (1999) Distinct CXC chemokines mediate tumorigenicity of prostate cancer cells. Am J Pathol 154:1503-12

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