Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance
Since the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance sys...
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MDPI AG
2022-08-01
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| author | Shigeru Hashimoto Ari Hashimoto Ryuta Muromoto Yuichi Kitai Kenji Oritani Tadashi Matsuda |
| author_facet | Shigeru Hashimoto Ari Hashimoto Ryuta Muromoto Yuichi Kitai Kenji Oritani Tadashi Matsuda |
| author_sort | Shigeru Hashimoto |
| collection | DOAJ |
| description | Since the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance system and protumor immunity due to cancer-related inflammation is responsible for cancer malignancy. The majority of inflammatory signals affect tumorigenesis by activating signal transducer and activation of transcription 3 (STAT3) and nuclear factor-κB. Persistent STAT3 activation in malignant cancer cells mediates extremely widespread functions, including cell growth, survival, angiogenesis, and invasion and contributes to an increase in inflammation-associated tumorigenesis. In addition, intracellular STAT3 activation in immune cells causes suppressive effects on antitumor immunity and leads to the differentiation and mobilization of immature myeloid-derived cells and tumor-associated macrophages. In many cancer types, STAT3 does not directly rely on its activation by oncogenic mutations but has important oncogenic and malignant transformation-associated functions in both cancer and stromal cells in the tumor microenvironment (TME). We have reported a series of studies aiming towards understanding the molecular mechanisms underlying the proliferation of various types of tumors involving signal-transducing adaptor protein-2 as an adaptor molecule that modulates STAT3 activity, and we recently found that AT-rich interactive domain-containing protein 5a functions as an mRNA stabilizer that orchestrates an immunosuppressive TME in malignant mesenchymal tumors. In this review, we summarize recent advances in our understanding of the functional role of STAT3 in tumor progression and introduce novel molecular mechanisms of cancer development and malignant transformation involving STAT3 activation that we have identified to date. Finally, we discuss potential therapeutic strategies for cancer that target the signaling pathway to augment STAT3 activity. |
| first_indexed | 2024-03-09T04:35:48Z |
| format | Article |
| id | doaj.art-589fb69d76aa44dbb2f6f62a8c8f1fd6 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T04:35:48Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-589fb69d76aa44dbb2f6f62a8c8f1fd62023-12-03T13:27:30ZengMDPI AGCells2073-44092022-08-011116261810.3390/cells11162618Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and ImmunosurveillanceShigeru Hashimoto0Ari Hashimoto1Ryuta Muromoto2Yuichi Kitai3Kenji Oritani4Tadashi Matsuda5Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, JapanDepartment of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, JapanDepartment of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, JapanDepartment of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, JapanDepartment of Hematology, International University of Health and Welfare, Narita 286-8686, JapanDepartment of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, JapanSince the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance system and protumor immunity due to cancer-related inflammation is responsible for cancer malignancy. The majority of inflammatory signals affect tumorigenesis by activating signal transducer and activation of transcription 3 (STAT3) and nuclear factor-κB. Persistent STAT3 activation in malignant cancer cells mediates extremely widespread functions, including cell growth, survival, angiogenesis, and invasion and contributes to an increase in inflammation-associated tumorigenesis. In addition, intracellular STAT3 activation in immune cells causes suppressive effects on antitumor immunity and leads to the differentiation and mobilization of immature myeloid-derived cells and tumor-associated macrophages. In many cancer types, STAT3 does not directly rely on its activation by oncogenic mutations but has important oncogenic and malignant transformation-associated functions in both cancer and stromal cells in the tumor microenvironment (TME). We have reported a series of studies aiming towards understanding the molecular mechanisms underlying the proliferation of various types of tumors involving signal-transducing adaptor protein-2 as an adaptor molecule that modulates STAT3 activity, and we recently found that AT-rich interactive domain-containing protein 5a functions as an mRNA stabilizer that orchestrates an immunosuppressive TME in malignant mesenchymal tumors. In this review, we summarize recent advances in our understanding of the functional role of STAT3 in tumor progression and introduce novel molecular mechanisms of cancer development and malignant transformation involving STAT3 activation that we have identified to date. Finally, we discuss potential therapeutic strategies for cancer that target the signaling pathway to augment STAT3 activity.https://www.mdpi.com/2073-4409/11/16/2618STAT3tumorigenesisimmune evasionSTAP-2ARID5A |
| spellingShingle | Shigeru Hashimoto Ari Hashimoto Ryuta Muromoto Yuichi Kitai Kenji Oritani Tadashi Matsuda Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance Cells STAT3 tumorigenesis immune evasion STAP-2 ARID5A |
| title | Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance |
| title_full | Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance |
| title_fullStr | Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance |
| title_full_unstemmed | Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance |
| title_short | Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance |
| title_sort | central roles of stat3 mediated signals in onset and development of cancers tumorigenesis and immunosurveillance |
| topic | STAT3 tumorigenesis immune evasion STAP-2 ARID5A |
| url | https://www.mdpi.com/2073-4409/11/16/2618 |
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