Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy

Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies. Various regulatory mechanisms are involved in the development of a fertilized egg into an embryo to ensure that it proceeds normally. Meanwhile, cancer cells also exhibit several embryo-like characteristics that enhance multidrug resistance. (A) The level of corpus-secreted progesterone can be mediated by the inner or outer environment and lead to embryonic diapause. (a) Cancer cells are able to transition to a dormant state after treatment. (B) Wnt, Notch, Hedgehog, and Hippo signaling pathways contribute to development by driving the proliferation and differentiation of embryonic cells. (b) Cancer stem cells are considered drug-resistant cells associated with some embryonic developmental signaling pathways. (C) Preimplantation embryo was reported to drive the formation of immunosuppressive microenvironment to evade attack from maternal immune system. (c) The immune microenvironment components of cancer cells can confer resistance to immune checkpoint blockades (ICBs). (D) To export environmental toxins and provide a favorable condition for development, ABC transporters are usually overexpressed in the blood-embryo barrier. (d) ABC transporter overexpression in cancer cells results in the development of multidrug resistance.image