Targeting Migration inducting gene-7 inhibits carcinoma cell invasion, early primary tumor growth, and stimulates monocyte oncolytic activity

Abstract

Expression of Migration inducting gene-7 (Mig-7) is limited to tumor cells and to date not found in normal tissues. Multiple tumor microenvironment factors, such as epidermal and hepatocyte growth factors, in concert with αvβ5 integrin ligation, induce Mig-7 mRNA expression. Gain or loss of Mig-7 protein studies shows that Mig-7 promotes invasion of colon and endometrial carcinoma cells. These data led us to hypothesize that targeting Mig-7 through various methods could decrease invasion, enhance monocyte cell killing of tumor cells, and inhibit disease progression. To begin testing this hypothesis, an in vitro chemoinvasion assay of endometrial carcinoma cells treated with Mig-7-specific or control antibodies was used. Mig-7 antibody significantly reduced invasion by >60% compared with controls. In another approach to test this hypothesis, an in vitro analysis of peptidestimulated human peripheral blood monocyte cells and their killing of MCF-7 breast carcinoma cells was used. Mig-7 peptide treatment increased monocyte cell tumor necrosis factor expression and killing of MCF-7 cells 30-fold over no peptide stimulation and 3-fold over MUC-1 or control peptide treatments. Furthermore, stably expressing Mig-7-specific short hairpin RNA resulted in significantly reduced Mig-7 protein levels and early primary tumor growth in a xenograft nude mouse model. Reduced phosphorylation of ERK1/2, Akt, and S6 kinase as well as decreased membrane-type 1 matrix metalloproteinase activity were mechanisms through which Mig-7 protein caused these effects. Based on these collective data, Mig-7 expression could be a potential candidate for future targeted cancer therapies.

MIG-7 Controls COX-2/PGE2-Mediated Lung Cancer Metastasis

“…MIG-7 activates MT1-MMP to regulate EMT and has been reported to be required for metastasis (19,(36)(37)(38). Our results show that MIG-7 protein facilitates EMT and metastasis of lung cancer cells resulting in the death of animals bearing these cancer cells (Fig.…”

“…Transduction of MIG-7 in carcinoma cells results in invasion by carcinoma cells in 3-dimensional culture in vitro (17). Stably expressing MIG-7-specific shRNA, on the other hand, reduces phosphorylation of Akt and ERK1/2 and attenuates membrane-type 1 matrix metalloproteinase (MT1-MMP) activity in endometrial carcinoma cell lines (19). Whether or not this holds true for lung cancer has not been examined and functional association between MIG-7 and COX-2/PGE2 signaling in promoting lung cancer invasion/metastasis remains elusive.…”

Mig-7 expression and vasculogenic mimicry in malignant ovarian tumors

“…The alternative network of blood supply to the tumor is provided even though the rapid cancer growth may not be precisely synchronized with tumor angiogenesis. Some tumors cells may form abnormal vessel-like vascular channels by excretion of extracellular matrix which helps to form blood cells transporting system [9,20]. Identification of specific genes that are expressed in a cancer cell and which are capable of VM formation may be further used to find specific molecular markers that can be used clinically in the detection and disease progression assessment.…”

“…Reverse transcription of total RNA was performed with the use of the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems) according to the supplier's instructions. Each target was amplified in triplicate with a MIG-7-specific primer probe set as described by Petty et al [20] and designed by "Primer 3" v. 0.2 software. The following primer sequences were used in this part of the study: forward, 5'-CACCTGCCTCTGGTCGTTAGG-3'; reverse 5'-TACTG-GATTCCTCTAGCTTTGGTGTT-3'; probe 5'-AAACTCTCAGT-GATCTCT-3' .…”

“…Immunohistochemical (IHC) studies performed with MIG-7 antibodies revealed expression of this marker in circulating tumor cells, proposing its potential as an early marker for metastatic carcinomas [18,19]. The use of peptides specific to MIG-7 treatment has induced increased monocyte expression of tumor necrosis factor (TNF) and killing of breast carcinoma cells in vitro [20]. Another hypothesis is that MIG-7 stimulates vascular mimicry prior to tumor angiogenesis, thus contributing to early growth and metastasis of ovarian cancer [21].…”