Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells

Abstract

Abstract. Ovarian cancer (OC), of which epithelial ovarian cancer (EOC) is the most common, is the deadliest gynecological tumor because of the difficulties in detection at early stages, and metastasis and chemoresistance at advanced stages. Tumor-associated macrophages (TAMs) differentiate through alternative pathways and play important roles in tumor growth and metastasis. However, the underlying mechanism remains unclear. Here, we established a mouse TAM model using bone marrow monocytes and conditioned medium (CM) of TAMs to culture ID8 mouse EOC cells. The results showed that TAM CM accelerated the proliferation and migration of ID8 cells. In a previous study, gene chip analysis showed that human TAMs expressed significantly higher levels of insulinlike growth factor-1 (IGF1) than undifferentiated M0 myeloid cells. In the present study, we observed that the IGF1 level was higher in human EOC specimens than that in benign ovarian tumor specimens, and further analysis showed that a higher level of IGF1 was related to more advanced clinical stage and liver metastasis. Therefore, we hypothesized that TAMs may accelerate the proliferation and migration of EOC cells by upregulating IGF1. As expected, increased IGF1 expression at both the mRNA and protein levels was observed in ID8 cells cultured with TAM CM, whereas blockade of the IGF1 pathway in ID8 cells with an IGF1 neutralizing antibody effectively reversed the promotion of proliferation and migration. Finally, we inhibited the phosphorylation of insulin-like growth factor-1 receptor (IGF1R) and its downstream molecules Akt and Erk with the IGF1R inhibitor linsitinib, and observed that the treatment effectively suppressed the proliferation and migration of ID8 cells exposed to TAM CM. Thus, we demonstrated that TAMs may promote the growth and metastasis of EOC via the activation of the IGF1 pathway; thus, targeting the IGF1 pathway may be promising for EOC therapy.

Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C

“…Other factors, including EGF, IGF1, and CHI3L1, have been proposed to be involved in the migration-promoting function of macrophages [22][23][24] , but these mediators are not among the proteins upregulated in the pro-migratory MDM secretomes identified by our approach. Several reasons are likely to contribute to these differences.…”

“…For example, it is suggested that TAM and tumor cells cooperate in extracellular matrix (ECM) remodeling, which is a prerequisite for tumor cell adhesion and invasion 7,13,14 . Consistent with this model, it has been reported that TAM secrete migration-promoting factors like insulin-like growth factor 1 (IGF1), epidermal growth factor (EGF), and CHI3L1 pointing to a presumably central role of TAM in cancer cell migration, adhesion, and invasion [22][23][24] .…”

A Population-Based Study on Liver Metastases in Women With Newly Diagnosed Ovarian Cancer

“…Further basic research manifested the IGF1 promoted the proliferation and migration of ovarian cancer cells and inhibition of IGF1 receptor and the downstream molecules effectively suppressed the malignant phenotype of tumor cells. Therefore, targeting the IGF1 pathway may be promising for the treatment for ovarian cancer patients with liver metastases(12). Joelle et al found that the cell surface glycoprotein CD44 contributed to the spheroid formation, mesothelial adhesion and mesenteric metastasis in epithelial ovarian carcinoma.…”

Plasmodium infection inhibits tumor angiogenesis through effects on tumor-associated macrophages in a murine implanted hepatoma model

“…However, our present study showed no significant decrease in the VEGF levels of the TAMs in the [14,15,41,42]. IGF-1 has been shown to signal intracellularly through the PI3 and MAPK pathways after binding to IGF-1R on the cell surface, and IGF-1 thereby increases the enzymatic activity of MMP-2 and MMP-9 and enhances the proliferation and migration of tumor cells [14,15,[43][44][45]. Noticeably, IGF-1 derived from polarized macrophages can maintain the M2-type activation profile in these 15 macrophages by activating the PI3-K and MAPK pathways [43,46].…”