Abstract

TGF-? plays a central role in bone metastases. lt is released in high concentrations from bone during osteoclastic bone resorption, a process that is active in all bone metastases. TGF-? enhances tumor factors that increase osteolytic bone destruction. The actions of TGF-? on osteoblasts &osteoclasts &consequent contributions to tumor growth in bone are less well characterized. We hypothesize that, in addition to its effects on tumor cells, TGF-? acts on osteoblasts to regulate factors, such as Wnt ligands and BMP antagonists, which have differing effects on the growth of osteolytic vs. osteoblastic tumor types. In addition, TGF-? activates osteoclasts to increase bone resorption in all types of skeletal metastases. Dr. Neil Bhowmick, Vanderbilt University Tumor Microenvironment Network (VUTMEN), &Dr. Theresa Guise, Indiana University, will study the role of TGF-? signaling in osteoblasts &osteoclasts in the bone microenvironment and the effect on bone metastases. The PIs will test: Hypothesis 1: TGF-? signaling in osteoblasts regulates tumor growth in bone, &the responses are dependent on whether the tumor is predominantly osteolytic or osteoblastic.
Aim 1. Determine the role of osteoblastic responsiveness to TGF-? in the establishment and progression of bone metastases of all types: Mice with osteoblasts-targeted deletion or activation of TGF-? signaling will be generated &the effect on bone metastases by osteolytic, osteoblastic or mixed tumors of breast, prostate, &melanoma will be studied. Hypothesis 2: TGF-? signaling in osteoclasts increases bone resorption, favoring tumor growth in bone, independent of the type of bone metastasis.
Aim 2. Determine the role of osteoclastic responsiveness to TGF-? in the establishment and progression of all types of bone metastases. Mice with osteoclast targeted deletion or activation of TGF-? signaling will be generated &the effect on bone metastases will be studied as in Aim 1. Hypothesis 3: Osteoblasts respond to TGF-? via secretion of factors, in a Stat3-dependent manner, to alter tumor behavior in bone.
Aim 3. Identify mechanisms of TGF-?-mediated paracrine regulation of metastatic tumor growth in bone: the role of Stat3 regulation of wnt5a and chordin will be studied in mouse models and human tissue.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA143057-01A1
Application #
8034058
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (O1))
Program Officer
Mohla, Suresh
Project Start
2011-04-07
Project End
2016-03-31
Budget Start
2011-04-07
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$551,442
Indirect Cost

  Institution

Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202

  Publications

Esposito, Mark; Guise, Theresa; Kang, Yibin (2018) The Biology of Bone Metastasis. Cold Spring Harb Perspect Med 8:
Juárez, Patricia; Fournier, Pierrick G J; Mohammad, Khalid S et al. (2017) Halofuginone inhibits TGF-?/BMP signaling and in combination with zoledronic acid enhances inhibition of breast cancer bone metastasis. Oncotarget 8:86447-86462
Singh, Pratibha; Hoggatt, Jonathan; Kamocka, Malgorzata M et al. (2017) Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells. J Clin Invest 127:4527-4540
Regan, Jenna N; Trivedi, Trupti; Guise, Theresa A et al. (2017) The Role of TGF? in Bone-Muscle Crosstalk. Curr Osteoporos Rep 15:18-23
Trivedi, Trupti; Zheng, Yu; Fournier, Pierrick G J et al. (2017) The vitamin D receptor is involved in the regulation of human breast cancer cell growth via a ligand-independent function in cytoplasm. Oncotarget 8:26687-26701
Wright, Laura E; Harhash, Ahmed A; Kozlow, Wende M et al. (2017) Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo. Oncotarget 8:8406-8419
Ross, Michael H; Esser, Alison K; Fox, Gregory C et al. (2017) Bone-Induced Expression of Integrin ?3 Enables Targeted Nanotherapy of Breast Cancer Metastases. Cancer Res 77:6299-6312
Regan, Jenna N; Mikesell, Carter; Reiken, Steven et al. (2017) Osteolytic Breast Cancer Causes Skeletal Muscle Weakness in an Immunocompetent Syngeneic Mouse Model. Front Endocrinol (Lausanne) 8:358
Tripathi, Manisha; Nandana, Srinivas; Billet, Sandrine et al. (2017) Modulation of cabozantinib efficacy by the prostate tumor microenvironment. Oncotarget 8:87891-87902
Zhang, Peng; Xing, Caihong; Rhodes, Steven D et al. (2016) Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice. Stem Cell Reports 6:914-925

Showing the most recent 10 out of 37 publications