Aspirin use and endometrial cancer risk and survival Tsuyoshi Takiuchi, Erin A. Blake, Koji Matsuo, Anil K. Sood, Theodore M. Brasky  Gynecologic Oncology  Volume 148, Issue 1, Pages 222-232 (January 2018) DOI: 10.1016/j.ygyno.2017.10.026 Copyright © 2017 Elsevier Inc. Terms and Conditions

Fig. 1 Impact of obesity in endometrial cancer progression. Excess estrogen from peripheral conversion of androgens to estrogen, mainly androstenedione in adipose tissue, causes continued stimulation of the endometrium to develop endometrial cancer. Adipose tissue also secretes a variety of both anti- and pro-inflammatory cytokines classified as adipokines (TNF-α, IL-6, and leptin), which cause a state of chronic systemic inflammation. Chronic inflammation promotes cellular proliferation, mainly by releasing pro-inflammatory cytokines, enhancing insulin resistance, suppressing the immune system, and generating reactive oxygen species for DNA damage. Abbreviations: TNF-α, tumor necrosis factor alpha; IL-6, Interleukin-6; and ROS, reactive oxygen species. Gynecologic Oncology 2018 148, 222-232DOI: (10.1016/j.ygyno.2017.10.026) Copyright © 2017 Elsevier Inc. Terms and Conditions

Fig. 2 Aspirin: mechanism of action against cyclooxygenase pathway. Aspirin exerts its anti-inflammatory effects mainly by inhibiting COX, a key enzyme responsible for PG biosynthesis from AA. Two major isoforms of COX, COX-1 and COX-2, catalyze the conversion of AA to prostanoids which are metabolized by tissue-specific synthases to different prostanoids. COX-1 is constitutively expressed in most tissues and is highly expressed in platelets, where it is involved with platelet activation via the generation of TXA2, and gastric epithelial cells where it protects gastric mucosa via the generation of PGE2. COX-2 is expressed in several tissues and is induced in response to pro-inflammatory cytokines, which can lead to PGE2 production. Aspirin irreversibly inactivates both COX-1 and COX-2 and has several different pharmacological effects ranging from anti-platelet action at low doses to anti-inflammatory action at high doses is dependent on drug availability in the target tissue and recovery of COX activity through de novo enzyme synthesis. Abbreviations: AA, arachidonic acid; PG, prostaglandin; COX, cyclooxygenase; TXA2, thromboxane A2; and GI, gastrointestinal. Gynecologic Oncology 2018 148, 222-232DOI: (10.1016/j.ygyno.2017.10.026) Copyright © 2017 Elsevier Inc. Terms and Conditions

Fig. 3 Low-dose aspirin: decrease in plasma concentration after the first pass through the liver. Aspirin concentration is significantly different between pre-systemic circulation and systemic circulation. Low-dose aspirin (green circle) is absorbed in the upper intestine and circulated to the liver via portal vein. Low-dose aspirin concentration decreases after it is metabolized in the liver and further is diluted in the systemic circulation. The low-dose aspirin plasma concentration in the portal vein is sufficient for the inactivation of the platelet COX-1. Low-dose aspirin concentration is represented by the width of the green bar. Gynecologic Oncology 2018 148, 222-232DOI: (10.1016/j.ygyno.2017.10.026) Copyright © 2017 Elsevier Inc. Terms and Conditions

Fig. 4 PGE2 promotes cancer progression. PGE2 is a known factor for enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis, stimulation of invasion, induction of the transition from EMT, regulation of stem cell homeostasis, and suppression of immune response. PGE2 also stimulates aromatase expression and thereby regulates estrogen production. Abbreviations: PG, prostaglandin; and EMT, epithelial-mesenchymal transition. Gynecologic Oncology 2018 148, 222-232DOI: (10.1016/j.ygyno.2017.10.026) Copyright © 2017 Elsevier Inc. Terms and Conditions

Fig. 5 Aspirin and the PI3K/AKT/mTOR pathway in endometrial cancer. The activation of RTK induced by adipokines leads to activation of the PI3K/AKT/mTOR pathway in endometrial cancer. The direct association between ER and RTK also stimulates the PI3K/AKT/mTOR pathway. The PIK3CA mutations activate the kinase activity of PI3K, which is antagonized by PTEN through its phosphatase function. Up-regulation of PI3K enhances COX-2 activity and PGE2 synthesis in the setting of obesity. Thus, suppression of PGE2 production as would theoretically be achieved with use of aspirin, could be a promising strategy for the treatment of endometrial cancer. Dashed lines represent the suggested pathways in endometrial cancer. Abbreviations: RTK, receptor tyrosine kinase; PG, prostaglandin; COX, cyclooxygenase; PI3K, phosphatidylinositol 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; mTOR, mammalian target of rapamycin; TNF-α, tumor necrosis factor alpha; IL-6, interleukin-6; ER, estrogen receptor; and PTEN, phosphatase and tensin homolog. Gynecologic Oncology 2018 148, 222-232DOI: (10.1016/j.ygyno.2017.10.026) Copyright © 2017 Elsevier Inc. Terms and Conditions

Fig. 6 Low-dose aspirin: proposed anti-tumor mechanisms in endometrial cancer. Activated platelets are integral to the process of metastasis. Low-dose aspirin treatment inhibits activation of platelet, leading to suppression of tumor-promoting mechanisms. Increase in PGE2 is strongly associated with several pathways which contribute to endometrial cancer progression. Low-dose aspirin treatment may suppress endometrial cancer progression by inhibition of activated platelet. Abbreviations: PG, prostaglandin; PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; and MMR, mismatch repair. Gynecologic Oncology 2018 148, 222-232DOI: (10.1016/j.ygyno.2017.10.026) Copyright © 2017 Elsevier Inc. Terms and Conditions