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      The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17

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          Abstract

          PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells. To explore the role of PAX8 in these tissues, we purified the PAX8 protein complex from nonmalignant fallopian tube cells and high-grade serous ovarian carcinoma cell lines. We found that PAX8 was a member of a large chromatin remodeling complex and preferentially interacted with SOX17, another developmental transcription factor. Depleting either PAX8 or SOX17 from cancer cells altered the expression of factors involved in angiogenesis and functionally disrupted tubule and capillary formation in cell culture and mouse models. PAX8 and SOX17 in ovarian cancer cells promoted the secretion of angiogenic factors by suppressing the expression of SERPINE1 , which encodes a proteinase inhibitor with anti a ngiogenic effects. The findings reveal a non–cell-autonomous function of these transcription factors in regulating angiogenesis in ovarian cancer.

          Abstract

          A complex of the transcription factors PAX8 and SOX17 in ovarian tumors mediates proangiogenic effects.

          A PAX8-SOX17 duo in tumor angiogenesis

          The transcription factor PAX8 is essential for the development of the female reproductive tract but is frequently amplified in and supports the growth of ovarian cancers. By comparing ovarian cancer and nonmalignant fallopian tube cells and tissues, Chaves-Moreira et al. found that PAX8 interacted with another transcription factor, SOX17, and that this complex in cancer cells transcriptionally promoted a proangiogenic secretome, which involved a decrease in plasminogen activator inhibitor 1 and an increase in factors like VEGF. Repressing the complex inhibited tumor cell–induced angiogenesis in both cell culture and in vivo models. The findings may facilitate antiangiogenic strategies for treating ovarian cancer.

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          Cancer statistics, 2022

          Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2022)
          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.
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            Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods

            J Ferlay, M Colombet, I Soerjomataram … (2018)
            Estimates of the worldwide incidence and mortality from 36 cancers and for all cancers combined for the year 2018 are now available in the GLOBOCAN 2018 database, compiled and disseminated by the International Agency for Research on Cancer (IARC). This paper reviews the sources and methods used in compiling the cancer statistics in 185 countries. The validity of the national estimates depends upon the representativeness of the source information, and to take into account possible sources of bias, uncertainty intervals are now provided for the estimated sex- and site-specific all-ages number of new cancer cases and cancer deaths. We briefly describe the key results globally and by world region. There were an estimated 18.1 million (95% UI: 17.5-18.7 million) new cases of cancer (17 million excluding non-melanoma skin cancer) and 9.6 million (95% UI: 9.3-9.8 million) deaths from cancer (9.5 million excluding non-melanoma skin cancer) worldwide in 2018.
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              Ovarian cancer statistics, 2018

              Lindsey A Torre, Britton Trabert, Carol DeSantis … (2018)
              In 2018, there will be approximately 22,240 new cases of ovarian cancer diagnosed and 14,070 ovarian cancer deaths in the United States. Herein, the American Cancer Society provides an overview of ovarian cancer occurrence based on incidence data from nationwide population-based cancer registries and mortality data from the National Center for Health Statistics. The status of early detection strategies is also reviewed. In the United States, the overall ovarian cancer incidence rate declined from 1985 (16.6 per 100,000) to 2014 (11.8 per 100,000) by 29% and the mortality rate declined between 1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. Ovarian cancer encompasses a heterogenous group of malignancies that vary in etiology, molecular biology, and numerous other characteristics. Ninety percent of ovarian cancers are epithelial, the most common being serous carcinoma, for which incidence is highest in non-Hispanic whites (NHWs) (5.2 per 100,000) and lowest in non-Hispanic blacks (NHBs) and Asians/Pacific Islanders (APIs) (3.4 per 100,000). Notably, however, APIs have the highest incidence of endometrioid and clear cell carcinomas, which occur at younger ages and help explain comparable epithelial cancer incidence for APIs and NHWs younger than 55 years. Most serous carcinomas are diagnosed at stage III (51%) or IV (29%), for which the 5-year cause-specific survival for patients diagnosed during 2007 through 2013 was 42% and 26%, respectively. For all stages of epithelial cancer combined, 5-year survival is highest in APIs (57%) and lowest in NHBs (35%), who have the lowest survival for almost every stage of diagnosis across cancer subtypes. Moreover, survival has plateaued in NHBs for decades despite increasing in NHWs, from 40% for cases diagnosed during 1992 through 1994 to 47% during 2007 through 2013. Progress in reducing ovarian cancer incidence and mortality can be accelerated by reducing racial disparities and furthering knowledge of etiology and tumorigenesis to facilitate strategies for prevention and early detection. CA Cancer J Clin 2018;68:284-296. © 2018 American Cancer Society.
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                Author and article information

                Contributors
                Daniele Chaves-Moreira: (View ORCID Profile)
                Cristina Arruza: (View ORCID Profile)
                Priyanka Rawat: (View ORCID Profile)
                Simone Sidoli: (View ORCID Profile)
                Jessica Reddy: (View ORCID Profile)
                Rosario I. Corona: (View ORCID Profile)
                Isaac A. Klein: (View ORCID Profile)
                Benjamin A. Garcia: (View ORCID Profile)
                Donita C. Brady: (View ORCID Profile)
                Kate Lawrenson: (View ORCID Profile)
                Ronny Drapkin: (View ORCID Profile)
                Journal
                Title: Science Signaling
                Abbreviated Title: Sci. Signal.
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Print): 1945-0877
                ISSN (Electronic): 1937-9145
                Publication date Created: April 05 2022
                Publication date (Print): April 05 2022
                Volume: 15
                Issue: 728
                Affiliations
                [1 ]Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 1224, Philadelphia, PA 19104, USA.
                [2 ]Epigenetics Institute, Department of Biochemistry and Biophysics, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, Suite 9-124, Philadelphia, PA 19104, USA.
                [3 ]Women’s Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
                [4 ]Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
                [5 ]Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
                [6 ]Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
                [7 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
                [8 ]Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA.
                [9 ]Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN 55455, USA.
                [10 ]Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
                [11 ]Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 612, Philadelphia, PA 19104, USA.
                [12 ]Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 612, Philadelphia, PA 19104, USA.
                [13 ]Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
                Article
                DOI: 10.1126/scisignal.abm2496
                PubMed ID: 35380877
                SO-VID: dff6823d-e5dd-4d55-838a-8935677dc65b
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