Strong suppression of tumor growth by insulin‐like growth factor‐binding protein‐related protein 1/tumor‐derived cell adhesion factor/mac25

Abstract

Insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) has been shown to induce cellular senescence or apoptosis of breast and prostate cancer cell lines in vitro. To examine whether IGFBP-rP1 acts as a tumor-suppressive protein in vivo, we established two model systems. Expression of IGFBP-rP1 in the human bladder carcinoma cell line EJ-1 was blocked by RNA interference. Human colon cancer cell line DLD-1, which did not express endogenous IGFBP-rP1, was transfected with an IGFBP-rP1 expression vector. When injected intraperitoneally or subcutaneously into nude mice, the IGFBP-rP1-expressing EJ-1 and DLD-1 cell lines grew poorly, whereas the IGFBP-rP1 non-producers grew rapidly and produced large tumors. In monolayer culture the IGFBP-rP1 producers and nonproducers grew similarly in each model, whereas in soft agar culture the former produced far less colonies than the latter. The IGFBP-rP1 producers had IGFBP-rP1 bound to the cell surface, and adhered more efficiently to fibronectin and laminin-5 than the respective non-producers. Expression of IGFBP-rP1 did not affect the efficiency of insulin signaling. These results demonstrate that IGFBP-rP1 strongly suppresses tumor growth by an insulin-independent or insulin-like growth factor-independent mechanism. Cell surface IGFBP-rP1 may reduce the anchorage-independent growth ability, leading to the marked loss of tumorigenicity. (Cancer Sci 2007; 98: 1055-1063)

Insulin-like growth factor-binding protein 7 alters the sensitivity to interferon-based anticancer therapy in hepatocellular carcinoma cells

“…Considering that IGFBP7-suppressed cells showed a smaller percentage of apoptosis than control cells, the acquired resistance was thought to result from the impediment of apoptosis. The suppression of apoptosis by downregulation of IGFBP7 was consistent with that found in previous studies (Burger et al, 1998;Landberg et al, 2001;Mutaguchi et al, 2003;Sato et al, 2007;Lin et al, 2008;Wajapeyee et al, 2008). In addition to resistance to IFN-a, IGFBP7-suppressed cells showed modest but significant resistance to other drugs.…”

“…In this study, gene expression profiling identified significant suppression of IGFBP7 in PLC-Rs compared with PLC-P. Insulinlike growth factor-binding protein 7, also known as IGFBP-rP1 and MAC25, can inhibit the proliferation of cancer cells, and its expression is downregulated in certain cancers (Burger et al, 1998;Landberg et al, 2001;Mutaguchi et al, 2003;Sato et al, 2007;Lin et al, 2008;Wajapeyee et al, 2008). It is also reported that IGFBP7 suppression is associated with rapid tumour growth and tumour invasiveness (Burger et al, 1998;Sato et al, 2007;Lin et al, 2008).…”

“…It is also reported that IGFBP7 suppression is associated with rapid tumour growth and tumour invasiveness (Burger et al, 1998;Sato et al, 2007;Lin et al, 2008). However, there are no reports of the association between IGFBP7 expression and sensitivity to chemotherapeutic drugs.…”

“…As IGFBP7 has been shown to suppress tumour activity through induction of apoptosis (Landberg et al, 2001;Mutaguchi et al, 2003;Sato et al, 2007;Wajapeyee et al, 2008), we evaluated the extent of apoptosis induced at 24 h after treatment of PLC-P/ shRNA with 1000 IU ml À1 IFN-a. Annexin V assay using flow cytometry showed a significantly lower percentage of early apoptotic cells in PLC-P/shRNA than in PLC-P/shRNA-NC ( Figure 3C).…”

“…The microarray analysis identified that insulin-like growth factor (IGF)-binding protein 7 (IGFBP7), which has been reported to have a tumour-suppressive activity through the induction of apoptosis in some cancers, was a key gene related to the response to this therapy (Burger et al, 1998;Landberg et al, 2001;Mutaguchi et al, 2003;Sato et al, 2007;Lin et al, 2008;Wajapeyee et al, 2008). Furthermore, we confirmed that IGFBP7 significantly correlated with the response to IFN-a/5-FU therapy in genetic manipulation experiments and to the clinical response in HCC tissue samples.…”