Fig. 4

Sex hormones and pancreatic carcinogenesis and cancer progression. a In the cytoplasm of pancreatic acinar cells, the increased estrogen levels lead to the elevation of TAGs and total lipids in the pancreas, contributing to fatty infiltration. b Tamoxifen can play an anticancer role by antagonizing estrogen receptors and agonizing GPER, and the latter can mitigate fibrosis and hypoxia in the TME by targeting PSCs, while it also ameliorates the immunosuppressive infiltration of macrophages and hinders cancer progression. c According to the description of Kanda et al. ¹⁹⁵, the tumorigenic cytokine IL-6 can activate both STAT3 and MAPK signaling in PC cells, while extracellular androgen and oncogenic c-Src can also enhance AR and MAPK signaling and trigger the transactivation of nuclear ARs. Meanwhile, AHR, ARNT, and ARE interact with AR in a testosterone-dependent manner and translocate into the nucleus to increase the transcription of ADAM10, MMP9, TGFβ, and VEGF. ADAM10 and MMP-9 increase the expression of MICA and MICB and hamper the immune response of NK cells and T cells against cancer cells. In combination with the enhanced cell proliferation and invasion favored by the activation of EGF and MMP-9, TGF-β and VEGF also jointly promote angiogenesis and cell proliferation. ADAM10 a disintegrin and metalloprotease 10, AHR aryl hydrocarbon (or dioxin) receptor, AR androgen receptor, ARE androgen-responsive element, ARNT AHR nuclear translocator, ECM extracellular matrix, EGF epidermal growth factor, ERK extracellular signal-regulated kinase, GPER G-protein-coupled estrogen receptor, IL-6 interleukin 6, MAPK mitogen-activated protein kinase, MEK mitogen extracellular kinase, MICA/B major histocompatibility complex class I chain-related gene A/B, MMP-9 matrix metalloprotease 9, NK natural killer, PC pancreatic cancer, PSC pancreatic stellate cell, RAF Raf proto-oncogene, STAT3 signal transducer and activator of transcription 3, TAGs triglycerides, TAM tumor-associated macrophage, TCR T-cell receptor, TGF-β transforming growth factor β, TME tumor microenvironment, VEGF vascular endothelial growth factor. Panel c in this figure was adapted from a previous publication¹⁹⁵