Original Article

Blockade of transforming growth factor-beta (TGFβ) signaling inhibits osteoblastic tumorigenesis by a novel human prostate cancer cell line

  1. Sweta Mishra1,
  2. Yuping Tang1,
  3. Long Wang1,
  4. Linda deGraffenried2,
  5. I-Tien Yeh3,
  6. Sherry Werner3,
  7. Dean Troyer3,
  8. John A. Copland4,
  9. Lu-Zhe Sun1,5,*

Article first published online: 14 FEB 2011

DOI: 10.1002/pros.21361

Issue

The Prostate

The Prostate

Volume 71, Issue 13, pages 1441–1454, 15 September 2011

Additional Information

How to Cite

Mishra, S., Tang, Y., Wang, L., deGraffenried, L., Yeh, I.-T., Werner, S., Troyer, D., Copland, J. A. and Sun, L.-Z. (2011), Blockade of transforming growth factor-beta (TGFβ) signaling inhibits osteoblastic tumorigenesis by a novel human prostate cancer cell line. The Prostate, 71: 1441–1454. doi: 10.1002/pros.21361

Author Information

  1. 1

    Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas

  2. 2

    Department of Human Ecology, University of Texas, Austin, Texas

  3. 3

    Department of Pathology, University of Texas Health Science Center, San Antonio, Texas

  4. 4

    Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida

  5. 5

    Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas

*Department of Cellular and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7762, San Antonio, TX 78229-3900.

Publication History

  1. Issue published online: 10 AUG 2011
  2. Article first published online: 14 FEB 2011
  3. Manuscript Accepted: 19 JAN 2011
  4. Manuscript Received: 20 DEC 2010

Funded by

  • NIH. Grant Numbers: R01CA079683, R01CA075253, R01CA104505
  • NCI Cancer Center. Grant Number: P30CA054174

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Keywords:

  • metastasis;
  • TβRI kinase inhibitor;
  • BGERII;
  • osteoblastic lesion;
  • osteoclasts

Abstract

BACKGROUND

The skeleton is the most common site of prostate cancer metastasis, which often results in osteoblastic lesions. The role of transforming growth factor-beta (TGFβ) signaling in prostate cancer-induced osteoblastic metastasis is not clear. We investigated the role of TGFβ signaling in prostate cancer-induced bone metastasis using a novel human prostate cancer cell line, PacMetUT1.

METHODS

We injected PacMetUT1/Luc-GFP cells in male nude mice by intracardiac and intratibia injections and then investigated the effect of TGFβ signaling abrogation on osteoblastic tumor growth and incidence in vivo by using fluorescence and bioluminescence imaging analysis and quantifying bone and tumor volume by histomorphometry analysis. Osteoclasts were counted using TRAP assay.

RESULTS

Osteoblastic bone metastasis in skull, rib, and femur was detected after 10–16 weeks of intracardiac injection of the PacMetUT1 cells. Stable knockdown of TGFβ1 with an shRNA resulted in decreased tumor incidence and bone formation when the cells were directly injected into the tibiae. Systemic administration of either a small inhibitor of TGFβ type I receptor kinase or a pan TGFβ binding protein (BGERII) also decreased bone tumor growth and osteoblastic bone formation in vivo after 7 weeks of treatment.

CONCLUSIONS

Our results for the first time indicate that blockade of TGFβ signaling in the PacMetUT1 model significantly inhibits osteoblastic bone formation and tumor incidence. Thus, TGFβ signaling pathway may be a viable target for the prevention and treatment of prostate cancer-induced bone metastasis. Prostate 71:1441–1454, 2011. © 2011 Wiley-Liss, Inc.

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