Midkine enhances soft-tissue sarcoma growth: A possible novel therapeutictarget

Zeming Jin, Guy Lahat, Borys Korchin, Theresa Nguyen, Quan Sheng Zhu, Xuemei Wang, Alexander J. Lazar, Jonathan Trent, Raphael E. Pollock, Dina Lev

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Purpose: New therapeutic targets for soft-tissue sarcoma (STS) treatment are critically needed. Midkine (MK), a multifunctional cytokine, is expressed during midgestation but is highly restricted in normal adult tissues. Renewed MK expression was shown in several malignancies where protumorigenic properties were described/We evaluated the expression and function of MK in STS. Experimental Design: Immunohistochemistry, reverse transcription-PCR, and Western blotting (WB) evaluated MK expression in human STS tissues and cell lines.WB and flow cytometry analyzed MK receptor expression. Cell growth assays evaluated the effect of MK on STS cell growth, and WB assessed MK downstream signaling. MK knock-in and knockout experiments further evaluated MK function. The growth of parental versus MK-transfected human fibrosarcoma cells was studied in vivo. Results: MK was found to be overexpressed in a variety of human STS histologies. Using a rhabdomyosarcoma (RMS) tissue microarray, cytoplasmic and nuclear MK was identified; nuclear MK expression was significantly increased in metastases. Similarly, several STS cell lines expressed and secreted MK; RMS cells exhibited nuclear MK. STS cells also expressed the MK receptors protein tyrosine phosphatase ζ and lipoprotein receptor-related protein. MK significantly enhanced STS cell growth potentially via the Src and extracellular signal-regulated kinase pathways. STS cells stably transfected with MK exhibited increased growth in vitro and in vivo. MK-expressing human STS xenografts showed increased tumor-associated vasculature. Furthermore, MK knockdown resulted in decreased STS cell growth, especially in RMS cells. Conclusion: MK enhances STS tumor growth; our results support further investigation of MK and its receptors as therapeutic targets for human STS.

Original languageEnglish
Pages (from-to)5033-5042
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number16
DOIs
StatePublished - Aug 15 2008
Externally publishedYes

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Sarcoma
Growth
Rhabdomyosarcoma
midkine
Western Blotting
Lipoprotein Receptors
Cell Line
Neoplasms
Protein Tyrosine Phosphatases
Fibrosarcoma
Extracellular Signal-Regulated MAP Kinases
Heterografts
Reverse Transcription

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Jin, Z., Lahat, G., Korchin, B., Nguyen, T., Zhu, Q. S., Wang, X., ... Lev, D. (2008). Midkine enhances soft-tissue sarcoma growth: A possible novel therapeutictarget. Clinical Cancer Research, 14(16), 5033-5042. https://doi.org/10.1158/1078-0432.CCR-08-0092

Midkine enhances soft-tissue sarcoma growth : A possible novel therapeutictarget. / Jin, Zeming; Lahat, Guy; Korchin, Borys; Nguyen, Theresa; Zhu, Quan Sheng; Wang, Xuemei; Lazar, Alexander J.; Trent, Jonathan; Pollock, Raphael E.; Lev, Dina.

In: Clinical Cancer Research, Vol. 14, No. 16, 15.08.2008, p. 5033-5042.

Research output: Contribution to journalArticle

Jin, Z, Lahat, G, Korchin, B, Nguyen, T, Zhu, QS, Wang, X, Lazar, AJ, Trent, J, Pollock, RE & Lev, D 2008, 'Midkine enhances soft-tissue sarcoma growth: A possible novel therapeutictarget', Clinical Cancer Research, vol. 14, no. 16, pp. 5033-5042. https://doi.org/10.1158/1078-0432.CCR-08-0092
Jin, Zeming ; Lahat, Guy ; Korchin, Borys ; Nguyen, Theresa ; Zhu, Quan Sheng ; Wang, Xuemei ; Lazar, Alexander J. ; Trent, Jonathan ; Pollock, Raphael E. ; Lev, Dina. / Midkine enhances soft-tissue sarcoma growth : A possible novel therapeutictarget. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 16. pp. 5033-5042.
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abstract = "Purpose: New therapeutic targets for soft-tissue sarcoma (STS) treatment are critically needed. Midkine (MK), a multifunctional cytokine, is expressed during midgestation but is highly restricted in normal adult tissues. Renewed MK expression was shown in several malignancies where protumorigenic properties were described/We evaluated the expression and function of MK in STS. Experimental Design: Immunohistochemistry, reverse transcription-PCR, and Western blotting (WB) evaluated MK expression in human STS tissues and cell lines.WB and flow cytometry analyzed MK receptor expression. Cell growth assays evaluated the effect of MK on STS cell growth, and WB assessed MK downstream signaling. MK knock-in and knockout experiments further evaluated MK function. The growth of parental versus MK-transfected human fibrosarcoma cells was studied in vivo. Results: MK was found to be overexpressed in a variety of human STS histologies. Using a rhabdomyosarcoma (RMS) tissue microarray, cytoplasmic and nuclear MK was identified; nuclear MK expression was significantly increased in metastases. Similarly, several STS cell lines expressed and secreted MK; RMS cells exhibited nuclear MK. STS cells also expressed the MK receptors protein tyrosine phosphatase ζ and lipoprotein receptor-related protein. MK significantly enhanced STS cell growth potentially via the Src and extracellular signal-regulated kinase pathways. STS cells stably transfected with MK exhibited increased growth in vitro and in vivo. MK-expressing human STS xenografts showed increased tumor-associated vasculature. Furthermore, MK knockdown resulted in decreased STS cell growth, especially in RMS cells. Conclusion: MK enhances STS tumor growth; our results support further investigation of MK and its receptors as therapeutic targets for human STS.",
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T2 - A possible novel therapeutictarget

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AU - Lahat, Guy

AU - Korchin, Borys

AU - Nguyen, Theresa

AU - Zhu, Quan Sheng

AU - Wang, Xuemei

AU - Lazar, Alexander J.

AU - Trent, Jonathan

AU - Pollock, Raphael E.

AU - Lev, Dina

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N2 - Purpose: New therapeutic targets for soft-tissue sarcoma (STS) treatment are critically needed. Midkine (MK), a multifunctional cytokine, is expressed during midgestation but is highly restricted in normal adult tissues. Renewed MK expression was shown in several malignancies where protumorigenic properties were described/We evaluated the expression and function of MK in STS. Experimental Design: Immunohistochemistry, reverse transcription-PCR, and Western blotting (WB) evaluated MK expression in human STS tissues and cell lines.WB and flow cytometry analyzed MK receptor expression. Cell growth assays evaluated the effect of MK on STS cell growth, and WB assessed MK downstream signaling. MK knock-in and knockout experiments further evaluated MK function. The growth of parental versus MK-transfected human fibrosarcoma cells was studied in vivo. Results: MK was found to be overexpressed in a variety of human STS histologies. Using a rhabdomyosarcoma (RMS) tissue microarray, cytoplasmic and nuclear MK was identified; nuclear MK expression was significantly increased in metastases. Similarly, several STS cell lines expressed and secreted MK; RMS cells exhibited nuclear MK. STS cells also expressed the MK receptors protein tyrosine phosphatase ζ and lipoprotein receptor-related protein. MK significantly enhanced STS cell growth potentially via the Src and extracellular signal-regulated kinase pathways. STS cells stably transfected with MK exhibited increased growth in vitro and in vivo. MK-expressing human STS xenografts showed increased tumor-associated vasculature. Furthermore, MK knockdown resulted in decreased STS cell growth, especially in RMS cells. Conclusion: MK enhances STS tumor growth; our results support further investigation of MK and its receptors as therapeutic targets for human STS.

AB - Purpose: New therapeutic targets for soft-tissue sarcoma (STS) treatment are critically needed. Midkine (MK), a multifunctional cytokine, is expressed during midgestation but is highly restricted in normal adult tissues. Renewed MK expression was shown in several malignancies where protumorigenic properties were described/We evaluated the expression and function of MK in STS. Experimental Design: Immunohistochemistry, reverse transcription-PCR, and Western blotting (WB) evaluated MK expression in human STS tissues and cell lines.WB and flow cytometry analyzed MK receptor expression. Cell growth assays evaluated the effect of MK on STS cell growth, and WB assessed MK downstream signaling. MK knock-in and knockout experiments further evaluated MK function. The growth of parental versus MK-transfected human fibrosarcoma cells was studied in vivo. Results: MK was found to be overexpressed in a variety of human STS histologies. Using a rhabdomyosarcoma (RMS) tissue microarray, cytoplasmic and nuclear MK was identified; nuclear MK expression was significantly increased in metastases. Similarly, several STS cell lines expressed and secreted MK; RMS cells exhibited nuclear MK. STS cells also expressed the MK receptors protein tyrosine phosphatase ζ and lipoprotein receptor-related protein. MK significantly enhanced STS cell growth potentially via the Src and extracellular signal-regulated kinase pathways. STS cells stably transfected with MK exhibited increased growth in vitro and in vivo. MK-expressing human STS xenografts showed increased tumor-associated vasculature. Furthermore, MK knockdown resulted in decreased STS cell growth, especially in RMS cells. Conclusion: MK enhances STS tumor growth; our results support further investigation of MK and its receptors as therapeutic targets for human STS.

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