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

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2634-2644
Number of pages11
JournalOncogene
Volume35
Issue number20
DOIs
StatePublished - May 19 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

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