Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal/benign but not cancer-associated prostate stromal cells

Katsumi Shigemura, Wen Chin Huang, Xiangyan Li, Haiyen E. Zhau, Guodong Zhu, Akinobu Gotoh, Masato Fujisawa, Jingwu Xie, Fray F. Marshall, Leland W K Chung

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

BACKGROUND Sonic hedgehog (Shh) signaling plays a pivotal role in stromal-epithelial interaction during normal development but its role in tumor-stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma. METHODS Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4-2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF (cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4-2/NPF tumors. RESULTS We found that (1) Shh has minimal growth-stimulating effects on prostate cancer cells, but it stimulated the growth of NPF but not CPF; (2) active Shh signaling was found between AI C4-2 cells and NPF but not CPF; and (3) osteonectin (ON) is a Gli1 target gene in NPF and not in CPF, and ON up-regulation in NPF can be blocked by cyclopamine CONCLUSIONS Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells.

Original languageEnglish (US)
Pages (from-to)1711-1722
Number of pages12
JournalProstate
Volume71
Issue number16
DOIs
StatePublished - Dec 2011
Externally publishedYes

Fingerprint

Hedgehogs
Stromal Cells
Androgens
Prostatic Neoplasms
Osteonectin
Prostate
Neoplasms
Bone Neoplasms
Polymerase Chain Reaction
Growth
Coculture Techniques
Mesenchymal Stromal Cells
Genes
Cultured Cells
Transcription Factors
Up-Regulation
Fibroblasts
Hormones
Apoptosis
Staining and Labeling

Keywords

  • androgen independent prostate cancer
  • bone marrow stroma
  • prostate stroma
  • Sonic hedgehog
  • tumor-stromal interaction

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal/benign but not cancer-associated prostate stromal cells. / Shigemura, Katsumi; Huang, Wen Chin; Li, Xiangyan; Zhau, Haiyen E.; Zhu, Guodong; Gotoh, Akinobu; Fujisawa, Masato; Xie, Jingwu; Marshall, Fray F.; Chung, Leland W K.

In: Prostate, Vol. 71, No. 16, 12.2011, p. 1711-1722.

Research output: Contribution to journalArticle

Shigemura, K, Huang, WC, Li, X, Zhau, HE, Zhu, G, Gotoh, A, Fujisawa, M, Xie, J, Marshall, FF & Chung, LWK 2011, 'Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal/benign but not cancer-associated prostate stromal cells', Prostate, vol. 71, no. 16, pp. 1711-1722. https://doi.org/10.1002/pros.21388
Shigemura, Katsumi ; Huang, Wen Chin ; Li, Xiangyan ; Zhau, Haiyen E. ; Zhu, Guodong ; Gotoh, Akinobu ; Fujisawa, Masato ; Xie, Jingwu ; Marshall, Fray F. ; Chung, Leland W K. / Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal/benign but not cancer-associated prostate stromal cells. In: Prostate. 2011 ; Vol. 71, No. 16. pp. 1711-1722.
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abstract = "BACKGROUND Sonic hedgehog (Shh) signaling plays a pivotal role in stromal-epithelial interaction during normal development but its role in tumor-stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma. METHODS Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4-2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF (cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4-2/NPF tumors. RESULTS We found that (1) Shh has minimal growth-stimulating effects on prostate cancer cells, but it stimulated the growth of NPF but not CPF; (2) active Shh signaling was found between AI C4-2 cells and NPF but not CPF; and (3) osteonectin (ON) is a Gli1 target gene in NPF and not in CPF, and ON up-regulation in NPF can be blocked by cyclopamine CONCLUSIONS Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells.",
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AU - Shigemura, Katsumi

AU - Huang, Wen Chin

AU - Li, Xiangyan

AU - Zhau, Haiyen E.

AU - Zhu, Guodong

AU - Gotoh, Akinobu

AU - Fujisawa, Masato

AU - Xie, Jingwu

AU - Marshall, Fray F.

AU - Chung, Leland W K

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N2 - BACKGROUND Sonic hedgehog (Shh) signaling plays a pivotal role in stromal-epithelial interaction during normal development but its role in tumor-stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma. METHODS Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4-2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF (cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4-2/NPF tumors. RESULTS We found that (1) Shh has minimal growth-stimulating effects on prostate cancer cells, but it stimulated the growth of NPF but not CPF; (2) active Shh signaling was found between AI C4-2 cells and NPF but not CPF; and (3) osteonectin (ON) is a Gli1 target gene in NPF and not in CPF, and ON up-regulation in NPF can be blocked by cyclopamine CONCLUSIONS Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells.

AB - BACKGROUND Sonic hedgehog (Shh) signaling plays a pivotal role in stromal-epithelial interaction during normal development but its role in tumor-stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma. METHODS Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4-2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF (cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4-2/NPF tumors. RESULTS We found that (1) Shh has minimal growth-stimulating effects on prostate cancer cells, but it stimulated the growth of NPF but not CPF; (2) active Shh signaling was found between AI C4-2 cells and NPF but not CPF; and (3) osteonectin (ON) is a Gli1 target gene in NPF and not in CPF, and ON up-regulation in NPF can be blocked by cyclopamine CONCLUSIONS Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells.

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KW - prostate stroma

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