IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma

Tohru Hosoyama, Mohammed Imran Aslam, Jinu Abraham, Suresh I. Prajapati, Koichi Nishijo, Joel E Michalek, Lee Ann Zarzabal, Laura D. Nelon, Denis C. Guttridge, Brian P. Rubin, Charles Keller

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Purpose: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor α (IL-4Rα) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression. Experimental Design: By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL-4R-mediated mitogenesis, myodifferentiation, and tumor progression. Results: IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt, or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically engineered mouse model of ARMS, we have shown that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting in significant survival extension in vivo. Conclusions: Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach.

Original languageEnglish (US)
Pages (from-to)2757-2766
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number9
DOIs
StatePublished - May 1 2011

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Interleukin-4 Receptors
Alveolar Rhabdomyosarcoma
Rhabdomyosarcoma
Interleukin-13
Neoplasm Metastasis
Interleukin-4
Neoplasms
MyoD Protein
Lymph Nodes
Myogenin
Neutralizing Antibodies
Sarcoma
Cell Biology
Research Design
Cell Culture Techniques
Ligands
Cell Line
Muscles
Lung
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hosoyama, T., Aslam, M. I., Abraham, J., Prajapati, S. I., Nishijo, K., Michalek, J. E., ... Keller, C. (2011). IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma. Clinical Cancer Research, 17(9), 2757-2766. https://doi.org/10.1158/1078-0432.CCR-10-3445

IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma. / Hosoyama, Tohru; Aslam, Mohammed Imran; Abraham, Jinu; Prajapati, Suresh I.; Nishijo, Koichi; Michalek, Joel E; Zarzabal, Lee Ann; Nelon, Laura D.; Guttridge, Denis C.; Rubin, Brian P.; Keller, Charles.

In: Clinical Cancer Research, Vol. 17, No. 9, 01.05.2011, p. 2757-2766.

Research output: Contribution to journalArticle

Hosoyama, T, Aslam, MI, Abraham, J, Prajapati, SI, Nishijo, K, Michalek, JE, Zarzabal, LA, Nelon, LD, Guttridge, DC, Rubin, BP & Keller, C 2011, 'IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma', Clinical Cancer Research, vol. 17, no. 9, pp. 2757-2766. https://doi.org/10.1158/1078-0432.CCR-10-3445
Hosoyama, Tohru ; Aslam, Mohammed Imran ; Abraham, Jinu ; Prajapati, Suresh I. ; Nishijo, Koichi ; Michalek, Joel E ; Zarzabal, Lee Ann ; Nelon, Laura D. ; Guttridge, Denis C. ; Rubin, Brian P. ; Keller, Charles. / IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 9. pp. 2757-2766.
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AU - Aslam, Mohammed Imran

AU - Abraham, Jinu

AU - Prajapati, Suresh I.

AU - Nishijo, Koichi

AU - Michalek, Joel E

AU - Zarzabal, Lee Ann

AU - Nelon, Laura D.

AU - Guttridge, Denis C.

AU - Rubin, Brian P.

AU - Keller, Charles

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N2 - Purpose: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor α (IL-4Rα) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression. Experimental Design: By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL-4R-mediated mitogenesis, myodifferentiation, and tumor progression. Results: IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt, or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically engineered mouse model of ARMS, we have shown that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting in significant survival extension in vivo. Conclusions: Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach.

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