Zienab Etwebi1, Jason R Goldsmith1, Mayassa Bou-Dargham1, Yuhua Tian2, Ryan Hood1, Nina Spitofsky1, Mingyue Li3, Honghong Sun1, Yunwei Lou4, Suxia Liu5, Christopher Lengner2, Youhai H Chen1,6. 1. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 2. Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA. 3. Wistar Institute, Philadelphia PA, USA. 4. Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, China. 5. Institute of Immunology, Shandong University School of Medicine, Jinan, China. 6. Faculty of Pharmaceutical Sciences, CAS Shenzhen Institute of Advanced Technology, Shenzhen, China.
Abstract
BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer in the United States, and inflammatory bowel disease patients have an increased risk of developing CRC due to chronic intestinal inflammation with it being the cause of death in 10% to 15% of inflammatory bowel disease patients. TIPE2 (TNF-alpha-induced protein 8-like 2) is a phospholipid transporter that is highly expressed in immune cells and is an important regulator of immune cell function. METHODS: The azoxymethane/dextran sulfate sodium murine model of colitis-associated colon cancer (CAC) was employed in Tipe2 -/- and wild-type mice, along with colonoid studies, to determine the role of TIPE2 in CAC. RESULTS: Early on, loss of TIPE2 led to significantly less numbers of visible tumors, which was in line with its previously described role in myeloid-derived suppressor cells. However, as time went on, loss of TIPE2 promoted tumor progression, with larger tumors appearing in Tipe2 -/- mice. This was associated with increased interleukin-22/STAT3 phosphorylation signaling. Similar effects were also observed in primary colonoid cultures, together demonstrating that TIPE2 also directly regulated colonocytes in addition to immune cells. CONCLUSIONS: This work demonstrates that TIPE2 has dual effects in CAC. In the colonocytes, it works as a tumor suppressor. However, in the immune system, TIPE2 may promote tumorigenesis through suppressor cells or inhibit it through IL-22 secretion. Going forward, this work suggests that targeting TIPE2 for CRC therapy requires cell- and pathway-specific approaches and serves as a cautionary tale for immunotherapy approaches in general in terms of colon cancer, as intestinal inflammation can both promote and inhibit cancer.
BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer in the United States, and inflammatory bowel disease patients have an increased risk of developing CRC due to chronic intestinal inflammation with it being the cause of death in 10% to 15% of inflammatory bowel disease patients. TIPE2 (TNF-alpha-induced protein 8-like 2) is a phospholipid transporter that is highly expressed in immune cells and is an important regulator of immune cell function. METHODS: The azoxymethane/dextran sulfate sodium murine model of colitis-associated colon cancer (CAC) was employed in Tipe2 -/- and wild-type mice, along with colonoid studies, to determine the role of TIPE2 in CAC. RESULTS: Early on, loss of TIPE2 led to significantly less numbers of visible tumors, which was in line with its previously described role in myeloid-derived suppressor cells. However, as time went on, loss of TIPE2 promoted tumor progression, with larger tumors appearing in Tipe2 -/- mice. This was associated with increased interleukin-22/STAT3 phosphorylation signaling. Similar effects were also observed in primary colonoid cultures, together demonstrating that TIPE2 also directly regulated colonocytes in addition to immune cells. CONCLUSIONS: This work demonstrates that TIPE2 has dual effects in CAC. In the colonocytes, it works as a tumor suppressor. However, in the immune system, TIPE2 may promote tumorigenesis through suppressor cells or inhibit it through IL-22 secretion. Going forward, this work suggests that targeting TIPE2 for CRC therapy requires cell- and pathway-specific approaches and serves as a cautionary tale for immunotherapy approaches in general in terms of colon cancer, as intestinal inflammation can both promote and inhibit cancer.
Authors: Samuel Huber; Nicola Gagliani; Lauren A Zenewicz; Francis J Huber; Lidia Bosurgi; Bo Hu; Matija Hedl; Wei Zhang; William O'Connor; Andrew J Murphy; David M Valenzuela; George D Yancopoulos; Carmen J Booth; Judy H Cho; Wenjun Ouyang; Clara Abraham; Richard A Flavell Journal: Nature Date: 2012-10-17 Impact factor: 49.962
Authors: Lauren A Peters; Jacqueline Perrigoue; Arthur Mortha; Alina Iuga; Won-Min Song; Eric M Neiman; Sean R Llewellyn; Antonio Di Narzo; Brian A Kidd; Shannon E Telesco; Yongzhong Zhao; Aleksandar Stojmirovic; Jocelyn Sendecki; Khader Shameer; Riccardo Miotto; Bojan Losic; Hardik Shah; Eunjee Lee; Minghui Wang; Jeremiah J Faith; Andrew Kasarskis; Carrie Brodmerkel; Mark Curran; Anuk Das; Joshua R Friedman; Yoshinori Fukui; Mary Beth Humphrey; Brian M Iritani; Nicholas Sibinga; Teresa K Tarrant; Carmen Argmann; Ke Hao; Panos Roussos; Jun Zhu; Bin Zhang; Radu Dobrin; Lloyd F Mayer; Eric E Schadt Journal: Nat Genet Date: 2017-09-11 Impact factor: 38.330