ATF3 function in cancer cells: oncogene vs. tumor suppressor
The mouse homolog of ATF3 (named TI-241) was identified by differential hybridization due to its high expression in the extremely metastatic melanoma cell line B16-F10, and absence in the related but non-metastatic cell line B16-F1. While characterizing the ATF3 mouse homolog, it was found that over-expression of ATF3 in the non-metastatic B16-F1cells converted them into highly metastatic cells, therefore, suggesting that ATF3 functions as an oncogene in melanoma. Subsequently, the same group described an oncogenic role of ATF3 in a human colon cancer cell line; wherein knock-down of ATF3 in the cancer cells reduced tumor growth in vivo and increased survival of the mice. However, …show more content…
The tumor incidence and the resultant stromal changes themselves are a stress to the cells of the host (organism bearing the tumor). The host cells’ response to this stress and the ensuing cross talk between the transformed cancer cells and the untransformed host cells (both within the tumor microenvironment as well as distant tissues) eventually determines the outcome of disease. Since ATF3 plays a central role during cellular response to stress and in cell-cell communication, it is probable that stromal ATF3 expression is functionally significant for cancer development. Supporting this notion, we and others have found that ATF3 is highly expressed in the stromal compartment of several types of cancers including melanoma, breast, colon and lung cancer. Thus far, there are three reports in literature that examine the function of ATF3 in different stromal cells—fibroblasts, pericytes, and tumor-associated macrophages; and I will recapitulate them here. 1) Buganim et.al. reported that ATF3 over-expression in cancer-associated fibroblasts (CAFs) promoted tumor growth of co-injected cancer cells in mice. ATF3 expression in CAFS transcriptionally represses CLDN1 and induces CXCL12 and RGS4 thereby mediating its pro-tumor effect. 2) Xue et.al. reported that platelet-derived growth factor PDGF-BB acts on stromal cells, pericytes or vascular mesenchymal cells that express the PDGF-BB receptor PDGFR-β, to expand the stromal compartment and induce erythropoietin (EPO) expression, leading to enhanced tumor angiogenesis. The PDGF-BB–PDGFR-b signaling system activates the EPO promoter within the stromal
The mouse homolog of ATF3 (named TI-241) was identified by differential hybridization due to its high expression in the extremely metastatic melanoma cell line B16-F10, and absence in the related but non-metastatic cell line B16-F1. While characterizing the ATF3 mouse homolog, it was found that over-expression of ATF3 in the non-metastatic B16-F1cells converted them into highly metastatic cells, therefore, suggesting that ATF3 functions as an oncogene in melanoma. Subsequently, the same group described an oncogenic role of ATF3 in a human colon cancer cell line; wherein knock-down of ATF3 in the cancer cells reduced tumor growth in vivo and increased survival of the mice. However, …show more content…
The tumor incidence and the resultant stromal changes themselves are a stress to the cells of the host (organism bearing the tumor). The host cells’ response to this stress and the ensuing cross talk between the transformed cancer cells and the untransformed host cells (both within the tumor microenvironment as well as distant tissues) eventually determines the outcome of disease. Since ATF3 plays a central role during cellular response to stress and in cell-cell communication, it is probable that stromal ATF3 expression is functionally significant for cancer development. Supporting this notion, we and others have found that ATF3 is highly expressed in the stromal compartment of several types of cancers including melanoma, breast, colon and lung cancer. Thus far, there are three reports in literature that examine the function of ATF3 in different stromal cells—fibroblasts, pericytes, and tumor-associated macrophages; and I will recapitulate them here. 1) Buganim et.al. reported that ATF3 over-expression in cancer-associated fibroblasts (CAFs) promoted tumor growth of co-injected cancer cells in mice. ATF3 expression in CAFS transcriptionally represses CLDN1 and induces CXCL12 and RGS4 thereby mediating its pro-tumor effect. 2) Xue et.al. reported that platelet-derived growth factor PDGF-BB acts on stromal cells, pericytes or vascular mesenchymal cells that express the PDGF-BB receptor PDGFR-β, to expand the stromal compartment and induce erythropoietin (EPO) expression, leading to enhanced tumor angiogenesis. The PDGF-BB–PDGFR-b signaling system activates the EPO promoter within the stromal