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

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 (CRC) 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 pro-tumorigenic cytokines, chemokines and growth factors, including IL-6, IL-11 and IL-23 as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1 and TGFβ; decreased cancer cell migratory activity and reduced their proliferation in the liver. NT157 represents a new class of anti-cancer drugs that affect both the malignant cell and its supportive microenvironment.

Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways

“…For this reason, we examined the expression of several chemokines in CRC and preliminarily verified the upregulation of CXCL5 in CRC. Previous studies have reported that CXCL5 produced by fibroblasts plays a prominent role in the progression, growth and spread of various types of cancer [15, 21]. However, in our study, we revealed that CRC cells, rather than fibroblasts, are able to secrete CXCL5.…”

Let‐7e enhances the radiosensitivity of colorectal cancer cells by directly targeting insulin‐like growth factor 1 receptor

“…In various studies, overactivated IGF‐1R is identified in the progression, development, and targeted agent resistance of various human cancers including CRC (Afshar et al, ; Denduluri et al, ; Moreno‐Acosta et al, ; Simpson, Petnga, Macaulay, Weyer‐Czernilofsky, & Bogenrieder, ). For instance, study by Sanchez‐Lopez () have demonstrated that IGF‐1R plays key roles in different mechanisms including cellular growth, proliferation, angiogenesis, and metastasis in CRC, and thus could be a valid candidate for the therapy of human CRC. Furthermore, in another study, it has been suggested that IGF‐1R significantly associated with poor overall survival and then resistance to chemotherapy in metastatic tumors compared to primary ones (Codony‐Servat et al, ).…”

Single nucleotide polymorphisms in the IGF‐IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE‐3 trial

“…Among NT compounds, NT157 showed to prevent colorectal tumor development and caused durable regression of established tumors and attenuated metastatic growth in murine models and in human CRC cells. 28 .…”