Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling

E. Sanchez-Lopez, E. Flashner-Abramson, S. Shalapour, Z. Zhong, K. Taniguchi, A. Levitzki, M. Karin

研究成果: Article

67 引用 (Scopus)

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The tumor microenvironment (TME) exerts critical pro-tumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility and invasion. Insulin-like growth factor-1 (IGF-1) and signal transducer and activator of transcription 3 (STAT3) stimulate colorectal cancer development and progression via cell autonomous and microenvironmental effects. Using a unique inhibitor, NT157, which targets both IGF-1 receptor (IGF-1R) and STAT3, we show that these pathways regulate many TME functions associated with sporadic colonic tumorigenesis in CPC-APC mice, in which cancer development is driven by loss of the Apc tumor suppressor gene. NT157 causes a substantial reduction in tumor burden by affecting cancer cells, cancer-associated fibroblasts (CAF) and myeloid cells. Decreased cancer cell proliferation and increased apoptosis were accompanied by inhibition of CAF activation and decreased inflammation. Furthermore, NT157 inhibited expression of protumorigenic cytokines, chemokines and growth factors, including IL-6, IL-11 and IL-23 as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1 and TGFâ; decreased cancer cell migratory activity and reduced their proliferation in the liver. NT157 represents a new class of anticancer drugs that affect both the malignant cell and its supportive microenvironment.

元の言語English
ページ(範囲)2634-2644
ページ数11
ジャーナルOncogene
35
発行部数20
DOI
出版物ステータスPublished - 2016 5 19

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Sanchez-Lopez, E., Flashner-Abramson, E., Shalapour, S., Zhong, Z., Taniguchi, K., Levitzki, A., & Karin, M. (2016). Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling. Oncogene, 35(20), 2634-2644. https://doi.org/10.1038/onc.2015.326