The 78-kDa glucose-regulated protein (GRP78) accentuates the metastatic cancer progression via the modulation of myeloid-derived suppressor cells in cancer microenvironment

Abstract

Cancer cells create a cancer microenvironment for cancer growth and survival, and the interaction between cancer cells and cancer microenvionrment plays an important role in multiple aspects of cancer cells growth, invasion, metastasis, and the immune escape by the secretion of a variety of factors. We previously confirmed that metastatic murine breast cancer cells with high interleukin-6 (IL-6) expression recruited myeloid-derived suppressor cells (MDSCs) to the cancer site and the other metastatic organs, and recruited MDSCs induce metastasis to distant site through IL-6 trans-signaling. Cancer-derived IL-6 can recruit MDSCs to the cancer microenvironment of non-metastatic breast cancer cells, but it cannot induce MDSC-meditated metastasis. Therefore, I examined the additional cancer-derived factors that can activate MDSCs in the cancer microenvironment to induce metastasis to distant site. In this study, I characterized cancer-derived the 78 kDa glucose-regulated protein (GRP78) as additional MDSC-activating factors. Metastatic cancer cells expressed high levels of GRP78, and secreted GRP78 protein into the cancer microenvironment. Cancer-derived soluble GRP78 was accentuates the metastatic cancer progression via the modulation of MDSCs in cancer microenvironement. GRP78 stimulation showed the functional MDSCs which induced IL-6 production, up-regulated ER stress sensor proteins by ER stress, enhanced the immune suppressive functions, and increased the ADAM17 expression. When the metastatic cancer cells expressed low level of GRP78, these cells lose the aggressive phenotype, invasion, and drug resistance, and decreased cancer growth in vivo. Therefore, this study provides strong evidence that targeting GRP78 protein to inhibit the interaction of cancer cells and MDSCs in cancer microenvironment could be a novel approach to cancer therapy.