Impairing tumor vasculature (anti-angiogenesis) is important in cancer therapy. We and others have demonstrated that Stat3, which is constitutively-activated in tumor cells and required for tumor cell survival, is indispensable for production of numerous angiogenic and invasive factors, suggesting that Stat3 is a promising target for anti-angiogenesis therapy. However, the tumor stroma, which includes diverse hematopoietic cells, also produces a wide range of angiogenic and invasive factors. Therefore, effective anti-angiogenic therapy must also target tumor stromal hematopoietic cells. We recently showed that Stat3 is persistently-activated in tumor stromal hematopoietic cells, including macrophages, neutrophils and Gr1+ myeloid cells, among others. Furthermore, preliminary data indicated that tumor stromal Gr1+ myeloid cells produce angiogenic factors in a Stat3-dependent manner, suggesting that inhibiting Stat3 may block a large array of angiogenic and invasive factors produced by various tumor hematopoietic cells. Additionally, blocking Stat3 either in tumor cells or endothelial cells abrogates tumor milieu-induced angiogenesis. Prompted by these preliminary data, we hypothesize that tumor and tumor stromal cells resonate through activated Stat3, producing angiogenic and invasive factors, including those that activate Stat3 in tumor stromal cells, to promote tumor angiogenesis and thereby strengthen the survival of a tumor and its resistance to therapy. As a result, inhibiting Stat3 will target the tumor and its microenvironment, leading to efficient impairment of tumor vasculature. We have generated extensive biological systems and reagents to test this hypothesis: mouse models to induce Stat3 ablation in hematopoietic cells at various stages of tumor development; a Stat3-specific inhibitor; a long-lived form of Stat3 RNAi coupled with nanoparticles to systemically target tumor cells; and an autochthonous mouse prostate tumor model that allows Stat3 ablation in prostate when androgen surges, and in which the hematopoietic system can also be reconstituted with Stat3-null bone marrow supplementation. With these and other biological systems and reagents, the proposed studies will define whether Stat3 is an effective target for modulating tumor microenvironment and inhibiting angiogenesis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115815-03
Application #
7490948
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2006-09-27
Project End
2011-07-31
Budget Start
2008-08-06
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$291,276
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Yang, Chunmei; Lee, Heehyoung; Pal, Sumanta et al. (2013) B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS One 8:e64159
Deng, Jiehui; Liu, Yong; Lee, Heehyoung et al. (2012) S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell 21:642-54
Lee, Heehyoung; Zhang, Peng; Herrmann, Andreas et al. (2012) Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. Proc Natl Acad Sci U S A 109:7765-9
Lee, Heehyoung; Deng, Jiehui; Xin, Hong et al. (2011) A requirement of STAT3 DNA binding precludes Th-1 immunostimulatory gene expression by NF-?B in tumors. Cancer Res 71:3772-80
Anders, Kathleen; Buschow, Christian; Herrmann, Andreas et al. (2011) Oncogene-targeting T cells reject large tumors while oncogene inactivation selects escape variants in mouse models of cancer. Cancer Cell 20:755-67
Scuto, A; Krejci, P; Popplewell, L et al. (2011) The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia 25:538-50
Xin, Hong; Herrmann, Andreas; Reckamp, Karen et al. (2011) Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res 71:6601-10
Lee, Heehyoung; Deng, Jiehui; Kujawski, Maciej et al. (2010) STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat Med 16:1421-8
Yang, Fan; Jove, Veronica; Xin, Hong et al. (2010) Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways. Mol Cancer Res 8:35-45
Kortylewski, Marcin; Swiderski, Piotr; Herrmann, Andreas et al. (2009) In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol 27:925-32

Showing the most recent 10 out of 14 publications