Second although HO expression in the stromal macrophages has

Second, although HO-1 expression in the stromal macrophages has been seen in the other cancer tissues [21], the impact of HO-1 expression on EAOC progression has not been explored. We have found that the CD163+ M2-like beta-Nicotinamide mononucleotide receptor were HO-1+ in OE, but malignant transformation may be associated with, and at least partly due to, reduced number of M2 phenotypes expressing HO-1. Endometriotic cyst fluid contains much higher levels of iron-related compounds, such as hemoglobin species, heme and free iron, compared with EAOC sample [22]. Repeated episodes of hemorrhage in OE induce excess oxidative stress and trigger DNA damage, mutations and genome instability, demonstrating the dichotomy between cytotoxicity and proliferation in endometriotic cells [1,2,19,23]. Thus, stimuli in environment create increased cellular susceptibility to oxidant-mediated cell killing or carcinogenesis. In benign OE, autoxidation and Fenton reaction of hemoglobin from the ferrous Fe2+ (oxyhemoglobin) state to the ferric Fe3+ (methemoglobin) state lead to production of excess reactive oxygen species (ROS), such as O2− and ∙OH, that are major sources of DNA damage and mutation [24]. HO-1 is strongly and rapidly induced in response to oxidative cytotoxic conditions, such as excessive production of ROS. The ferric Fe3+ rich in OE can induce a high expression of HO-1 [25], supporting the finding that the number of HO-1+ cells was significantly higher in the OE group than in the EAOC group. In contrast, EAOC showed lower oxidant activity than OE, due to the decreased expression of ferric Fe3+ (methemoglobin) and increased expression of ferrous Fe2+ (oxyhemoglobin) [2]. EAOC appears to be associated with an antioxidant environment and decreased response to oxidative stress. Our findings support that M2 phenotypes no longer produce HO-1 in the EAOC microenvironment. EAOC macrophages demonstrate sustained downregulation of an antioxidant marker, HO-1, possibly due to decreased oxidative stress. Taken together, the pattern of redox balance supports that reduced oxidative stress may be involved in the pathogenesis of malignant transformation. Third, the expression of HO-1 in macrophages was decreased in some cancers such as lung cancer [26]. Theoretically, HO-1 downregulation leads to the increase of ROS and DNA damage in cells, which may promote the initiation of carcinogenesis [27]. Conversely, HO-1 has been detected in tumor-infiltrating macrophages and shows the impact on cancer progression, aggressiveness, invasion, metastasis, and poor prognosis [27,28]. At late phase of tumorigenesis, HO-1 overexpression may promote cancer progression through inducing the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF) [29]. Several lines of evidence have highlighted the role of HO-1 in cancer progression through modulating tumor microenvironment [27]. Thus, the function of HO-1 in the pathogenesis of cancer progression remains controversial.
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INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate of 8%. Surgical resection is the most viable therapeutic option, however, even in patients with no lymph node or extrapancreatic metastasis, the 5-year survival rate only increases to 30%–75%. To date, chemotherapies contribute to many treatment-limiting adverse events and fail to significantly extend the life span of patients with advanced PDAC. Gemcitabine is one of the standard-of-care for the treatment of PDAC. However, the efficacy of gemcitabine is limited due to inherent resistance of PDAC cells and less than 20% of patients respond to this first line therapy. Tumor hypoxia is a characteristic feature of PDAC and arises from an intense stromal desmoplasia leading to poor tumor perfusion. The hypoxic environment favors the outgrowth of aggressive clones and the development of inherent drug resistance, as well as expression of various growth factors that promote cell proliferation and facilitate cell migration. One such well supported, hypoxia-activated transcription factor is hypoxia-inducible factor-1α (HIF-1α). Studies have shown that cells with constitutive expression of HIF-1α are more resistant to hypoxia-induced apoptosis. Hypoxia may reprogram gene expression and mediate many of its effects by upregulating molecules such heme oxygenase-1 (HO-1), which can support PDAC cells during conditions of oxidative stress.