The fundamental basis of pregnancy and cancer is to determine the fate of the survival or the death of humanity. However, the development of fetuses and tumors share many similarities and differences, making them two sides of the same coin. This review presents an overview of the similarities and differences between pregnancy and cancer. In addition, we will also discuss the critical roles that Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 may play in the immune system, cell migration, and angiogenesis, all of which are essential for fetal and tumor development. Even though the comprehensive understanding of ERAP2 lags that of ERAP1 due to the lack of an animal model, recent studies have shown that both enzymes are associated with an increased risk of several diseases, including pregnancy disorder pre-eclampsia (PE), recurrent miscarriages, and cancer. The exact mechanisms in both pregnancy and cancer need to be elucidated. Therefore, a deeper understanding of ERAP’s role in diseases can make it a potential therapeutic target for pregnancy complications and cancer and offer greater insight into its impact on the immune system.

Tissue fibrosis is a progressive pathological process induced by repeated tissue injury and inflammation resulting in excessive collagen deposition. The Wnt signaling pathway regulates cell proliferation and differentiation for tissue repair processes. Dickkopf1 (DKK1) is a quintessential inhibitory ligand of the Wnt pathway. M2-like macrophages, induced by type 2 cytokines such as IL-13, play a central role in tissue fibrosis. We found that DKK1 protein expression markedly increased in both lung tissues of human idiopathic pulmonary fibrosis (IPF) and lungs from the murine bleomycin (BLM)-induced fibrosis model. To investigate the role of DKK1 in lung fibrosis, we used the DKK1 hypomorphic doubleridge (Dkk1d/d) mouse model. Collagen mRNA and protein expressions were markedly decreased in the lungs of Dkk1d/d mice compared to those of WT mice upon BLM challenge. The infiltration of macrophages was significantly decreased in the lungs of Dkk1d/d mice upon lung injury. We tested whether DKK1 modulates the polarization of M2-like macrophages in vitro using mouse bone marrow-derived macrophages (BMDMs). Interestingly, DKK1 induced M2-like macrophage marker CD206 (mannose receptor) and Arginase 1 (Arg1) protein expression. The expression of CD206 and Arg1 was synergistically increased by DKK1 and IL-13. We demonstrated that DKK1 utilizes STAT6 and JNK to induce Arg1 and CD206. Taken together, our study demonstrates that DKK1 promotes pulmonary fibrosis by activation of M2-like macrophages. Our study will provide new mechanistic insights into DKK1-mediated lung fibrosis pathogenesis.