IGF-1 contributes to the expansion of melanoma-initiating cells through an epithelial-mesenchymal transition process

Abstract

Melanoma is a particularly virulent human cancer, due to its resistance to conventional treatments and high frequency of metastasis. Melanomas contain a fraction of cells, the melanoma-initiating cells (MICs), responsible for tumor propagation and relapse. Identification of the molecular pathways supporting MICs is, therefore, vital for the development of targeted treatments. One factor produced by melanoma cells and their microenvironment, insulin-like growth factor-1 (IGF- 1), is linked to epithelial-mesenchymal transition (EMT) and stemness features in several cancers.We evaluated the effect of IGF-1 on the phenotype and chemoresistance of B16-F10 cells. IGF-1 inhibition in these cells prevented malignant cell proliferation, migration and invasion, and lung colony formation in immunodeficient mice. IGF-1 downregulation also markedly inhibited EMT, with low levels of ZEB1 and mesenchymal markers (N-cadherin, CD44, CD29, CD105) associated with high levels of E-cadherin and MITF, the major regulator of melanocyte differentiation. IGF-1 inhibition greatly reduced stemness features, including the expression of key stem markers (SOX2, Oct-3/4, CD24 and CD133), and the functional characteristics of MICs (melanosphere formation, aldehyde dehydrogenase activity, side population). These features were associated with a high degree of sensitivity to mitoxantrone treatment.In this study, we deciphered new connections between IGF-1 and stemness features and identified IGF-1 as instrumental for maintaining the MIC phenotype. The IGF1/IGF1-R nexus could be targeted for the development of more efficient anti-melanoma treatments. Blocking the IGF-1 pathway would improve the immune response, decrease the metastatic potential of tumor cells and sensitize melanoma cells to conventional treatments.

IGF-1 induces the epithelial-mesenchymal transition via Stat5 in hepatocellular carcinoma

“…It has been reported that IGF-1 inhibition repressed malignant cancer cell proliferation, migration and invasion in immunodeficient mice. IGF-1 inhibition also significantly inhibited the progression of EMT, with low expression of ZEB1 and N-cadherin and high expression of E-cadherin and MITF [ 14 ]. Yao C et al demonstrated the critical roles of IGF/STAT3/NANOG/Slug signaling pathways in the progression of CRC by regulating EMT and CSCs properties [ 15 ].…”

Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men

“…The insulin like growth factor 1 (IGF-1) molecule is another regulator various functions, including the frequently reported effect on cell migration for cardiac stem cells (O’Neill et al 2016), as well as vascular smooth muscle cells (Beneit et al 2016). Similar to some other factors described above, IGF-1 is extensively involved in tumor invasion (Le Coz et al 2016). …”

Interleukin 7-expressing fibroblasts promote breast cancer growth through sustenance of tumor cell stemness

“…Consistently, EYFP + CAFs showed higher expression of principal stem cell ligands and stemness-related genes ( Fig.5 D), several growth factors ( Fig.5 E) and a particular set of cancer-related cytokines and chemokines ( Fig.5F ). Elevated mRNA expression of the microenvironmental stemness regulators Cxcl12 , 27 , 28 Jag1 , 29 Postn , 16 Tnc 30 and Igf1 31 in EYFP + CAFs was validated by RT-PCR ( Fig.5 G). Moreover, upregulation of Il33, Fgf2, Tgfb2 and Vegfc expression was confirmed and Il7 , which was not identified as a differentially regulated gene in the microarray, was found to be elevated in EYFP + CAFs (Supplementary Fig.…”