{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T18:22:14Z","timestamp":1779214934077,"version":"3.51.4"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T00:00:00Z","timestamp":1651190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Surgery at BIDMC to BW","award":["NCI R21 CA169904"],"award-info":[{"award-number":["NCI R21 CA169904"]}]},{"name":"Department of Surgery at BIDMC to BW","award":["NCI R21 CA256720"],"award-info":[{"award-number":["NCI R21 CA256720"]}]},{"name":"Department of Surgery at BIDMC to BW","award":["NIDDK R01 DK104714"],"award-info":[{"award-number":["NIDDK R01 DK104714"]}]},{"name":"Department of Surgery at BIDMC to BW","award":["R01 DK125846"],"award-info":[{"award-number":["R01 DK125846"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Endometriosis, a painful gynecological condition accompanied by inflammation in women of reproductive age, is associated with an increased risk of ovarian cancer. We evaluated the role of peritoneal heme accumulated during menstrual cycling, as well as peritoneal and lesional macrophage phenotype, in promoting an oncogenic microenvironment. We quantified the heme-degrading enzyme, heme oxygenase-1 (HO-1, encoded by Hmox1) in normal peritoneum, endometriotic lesions and endometriosis-associated ovarian cancer (EAOC) of clear cell type (OCCC). HO-1 was expressed primarily in macrophages and increased in endometrioma and OCCC tissues relative to endometriosis and controls. Further, we compared cytokine expression profiles in peritoneal macrophages (PM) and peripheral blood mononuclear cells (PBMC) in women with endometriosis versus controls as a measure of a tumor-promoting environment in the peritoneum. We found elevated levels of HO-1 along with IL-10 and the pro-inflammatory cytokines (IL-1\u03b2, IL-16, IFN\u03b3) in PM but not in PBMC from endometriosis patients. Using LysM-Cre:Hmox1flfl conditional knockout mice, we show that a deficiency of HO-1 in macrophages led to the suppression of growth of ID8 ovarian tumors implanted into the peritoneum. The restriction of ID8 ovarian tumor growth was associated with an increased number of Mac3+ macrophage and B cells in LysM-Cre:Hmox1flfl mice compared to controls. Functional experiments in ovarian cancer cell lines show that HO-1 is induced by heme. Low levels of exogenous heme promoted ovarian cancer colony growth in soft agar. Higher doses of heme led to slower cancer cell colony growth in soft agar and the induction of HO-1. These data suggest that perturbation of heme metabolism within the endometriotic niche and in cancer cells themselves may be an important factor that influences tumor initiation and growth.<\/jats:p>","DOI":"10.3390\/cancers14092242","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T16:49:57Z","timestamp":1651250997000},"page":"2242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Labile Heme and Heme Oxygenase-1 Maintain Tumor-Permissive Niche for Endometriosis-Associated Ovarian Cancer"],"prefix":"10.3390","volume":"14","author":[{"given":"Jonathan L.","family":"Hecht","sequence":"first","affiliation":[{"name":"Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5113-9673","authenticated-orcid":false,"given":"Monika","family":"Janikova","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, 814 99 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reeham","family":"Choudhury","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of OB\/GYN, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Greater Baltimore Medical Center, 6569 Charles Street, Towson, MD 21204, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3318-4550","authenticated-orcid":false,"given":"Giacomo","family":"Canesin","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Vor Biopharma, 100 Cambridgepark Dr, Suite 400, Cambridge, MA 02140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lubica","family":"Janovicova","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, 814 99 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Csizmadia","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa M.","family":"Jorgensen","sequence":"additional","affiliation":[{"name":"Department of OB\/GYN, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharine M.","family":"Esselen","sequence":"additional","affiliation":[{"name":"Department of OB\/GYN, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5883-3580","authenticated-orcid":false,"given":"Peter","family":"Celec","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, 814 99 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth D.","family":"Swanson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0679-8765","authenticated-orcid":false,"given":"Barbara","family":"Wegiel","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrendo.2013.255","article-title":"Endometriosis: Pathogenesis and treatment","volume":"10","author":"Vercellini","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1056\/NEJMoa1614814","article-title":"Cancer-Associated Mutations in Endometriosis without Cancer","volume":"376","author":"Anglesio","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/path.5314","article-title":"Oncogenic mutations in histologically normal endometrium: The new normal?","volume":"249","author":"Lac","year":"2019","journal-title":"J. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ygyno.2011.10.001","article-title":"The association between endometriosis and ovarian cancer: A review of histological, genetic and molecular alterations","volume":"124","author":"Munksgaard","year":"2012","journal-title":"Gynecol. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.fertnstert.2016.07.1075","article-title":"Oxidative stress in the pelvic cavity and its role in the pathogenesis of endometriosis","volume":"106","author":"Donnez","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1179\/1351000215Y.0000000038","article-title":"Potential scenarios leading to ovarian cancer arising from endometriosis","volume":"21","author":"Kobayashi","year":"2016","journal-title":"Redox Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/S0015-0282(02)03346-0","article-title":"Iron overload in the peritoneal cavity of women with pelvic endometriosis","volume":"78","author":"Donnez","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1146\/annurev.pharmtox.010909.105600","article-title":"Mechanisms of cell protection by heme oxygenase-1","volume":"50","author":"Gozzelino","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3389\/fimmu.2020.00066","article-title":"Heme-Derived Metabolic Signals Dictate Immune Responses","volume":"11","author":"Canesin","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"108181","DOI":"10.1016\/j.celrep.2020.108181","article-title":"Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases","volume":"32","author":"Canesin","year":"2020","journal-title":"Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7009","DOI":"10.1158\/0008-5472.CAN-13-1075","article-title":"Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth","volume":"73","author":"Wegiel","year":"2013","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1038\/sj.bjc.6604081","article-title":"Nuclear translocation of haeme oxygenase-1 is associated to prostate cancer","volume":"97","author":"Sacca","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2765","DOI":"10.2174\/1381612811319150012","article-title":"Nuclear translocation of heme oxygenase-1 confers resistance to imatinib in chronic myeloid leukemia cells","volume":"19","author":"Tibullo","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1038\/onc.2014.464","article-title":"Signal peptide peptidase-mediated nuclear localization of heme oxygenase-1 promotes cancer cell proliferation and invasion independent of its enzymatic activity","volume":"34","author":"Hsu","year":"2015","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"20621","DOI":"10.1074\/jbc.M607954200","article-title":"Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress","volume":"282","author":"Lin","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1525-1438.2006.00754.x","article-title":"Risk of developing ovarian cancer among women with ovarian endometrioma: A cohort study in Shizuoka, Japan","volume":"17","author":"Kobayashi","year":"2007","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fimmu.2013.00009","article-title":"Endometriosis, a disease of the macrophage","volume":"4","author":"Capobianco","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.fertnstert.2013.05.010","article-title":"Reduced hemopexin levels in peritoneal fluid of patients with endometriosis","volume":"100","author":"Wolfler","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tai, C.S., Lin, Y.R., Teng, T.H., Lin, P.Y., Tu, S.J., Chou, C.H., Huang, Y.R., Huang, W.C., Weng, S.L., and Huang, H.D. (2017). Haptoglobin expression correlates with tumor differentiation and five-year overall survival rate in hepatocellular carcinoma. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171269"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1111\/j.1872-034X.2012.01044.x","article-title":"Clinical utility of serum fucosylated hemopexin in Japanese patients with hepatocellular carcinoma","volume":"42","author":"Kobayashi","year":"2012","journal-title":"Hepatol. Res."},{"key":"ref_21","first-page":"1828","article-title":"Haptoglobin is a serological biomarker for adenocarcinoma lung cancer by using the ProteomeLab PF2D combined with mass spectrometry","volume":"6","author":"Chang","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.4049\/jimmunol.1701443","article-title":"Deletion of Biliverdin Reductase A in Myeloid Cells Promotes Chemokine Expression and Chemotaxis in Part via a Complement C5a--C5aR1 Pathway","volume":"202","author":"Bisht","year":"2019","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41419-019-1342-6","article-title":"Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury","volume":"10","author":"Hedblom","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12451","DOI":"10.1073\/pnas.0703451104","article-title":"Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator","volume":"104","author":"Hever","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S1471-4906(03)00181-9","article-title":"Heme oxygenase-1: Unleashing the protective properties of heme","volume":"24","author":"Otterbein","year":"2003","journal-title":"Trends Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s00404-020-05445-1","article-title":"Association between endometriosis and gynecological cancers: A critical review of the literature","volume":"301","author":"Kalaitzopoulos","year":"2020","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"751571","DOI":"10.1155\/2015\/751571","article-title":"The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life","volume":"2015","author":"Grandi","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.fertnstert.2016.07.005","article-title":"Immune-inflammation gene signatures in endometriosis patients","volume":"106","author":"Ahn","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"941","DOI":"10.2741\/4431","article-title":"Inflammation and endometriosis","volume":"21","author":"Jiang","year":"2016","journal-title":"Front. Biosci (Landmark Ed.)"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1007\/s00262-020-02831-1","article-title":"Immunologic factors involved in the malignant transformation of endometriosis to endometriosis-associated ovarian carcinoma","volume":"70","author":"Leenen","year":"2021","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wendel, J.R.H., Wang, X., and Hawkins, S.M. (2018). The Endometriotic Tumor Microenvironment in Ovarian Cancer. Cancers, 10.","DOI":"10.3390\/cancers10080261"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.fertnstert.2004.12.004","article-title":"Elevated interleukin-16 levels in the peritoneal fluid of women with endometriosis may be a mechanism for inflammatory reactions associated with endometriosis","volume":"83","author":"Koga","year":"2005","journal-title":"Fertil. Steril."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e120596","DOI":"10.1172\/jci.insight.120596","article-title":"Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury","volume":"3","author":"Zhang","year":"2018","journal-title":"JCI Insight"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nm0311-285","article-title":"B cells and macrophages in cancer: Yin and yang","volume":"17","author":"Mantovani","year":"2011","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1073\/pnas.91.6.2305","article-title":"Molecular cloning and structure of a pre-B-cell growth-stimulating factor","volume":"91","author":"Nagasawa","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1084\/jem.20061609","article-title":"Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism","volume":"204","author":"Deshane","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5438","DOI":"10.1182\/blood-2010-07-296483","article-title":"Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2","volume":"117","author":"Muto","year":"2011","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ahmad, I.M., Dafferner, A.J., O'Connell, K.A., Mehla, K., Britigan, B.E., Hollingsworth, M.A., and Abdalla, M.Y. (2021). Heme Oxygenase-1 Inhibition Potentiates the Effects of Nab-Paclitaxel-Gemcitabine and Modulates the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma. Cancers, 13.","DOI":"10.3390\/cancers13092264"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5081","DOI":"10.1158\/0008-5472.CAN-10-4668","article-title":"Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer","volume":"71","author":"Konstantinopoulos","year":"2011","journal-title":"Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/9\/2242\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:04:39Z","timestamp":1760137479000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/9\/2242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,29]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["cancers14092242"],"URL":"https:\/\/doi.org\/10.3390\/cancers14092242","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,29]]}}}