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      Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells

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          Abstract

          Introduction

          Inflammation has been implicated in cancer aggressiveness. As transglutaminase 2 (TG2), which has been associated with inflammatory signaling, has been suggested to play a role in tumor behavior, we propose that TG2 may be an important linker inducing interleukin (IL)-6-mediated cancer-cell aggressiveness, including distant hematogenous metastasis.

          Methods

          To investigate the role for TG2 and IL-6, TG2-knocked-down and IL-6-knocked-down cancer cells were generated by using shRNA. Human breast cancer cell xenograft model in highly immunocompromised mice and human advanced breast cancer primary tumor tissue microarrays were used in this study.

          Results

          IL-6 production in human breast cancer cells was dependent on their TG2 expression level. In vitro tumor-sphere formation was dependent on TG2 and downstream IL-6 production from cancer cells. Primary tumor growth in the mammary fat pads and distant hematogenous metastasis into the lung was also dependent on TG2 and downstream IL-6 expression levels. The effect of TG2 expression on human breast cancer distant metastasis was investigated by analyzing a tissue microarray of primary tumors from 412 patients with their clinical data after 7 years. TG2 expression in primary tumor tissue was inversely correlated with recurrence-free survival ( P = 0.019) and distant metastasis-free survival (DMFS) ( P = 0.006) in patients with advanced breast cancer. Furthermore, by using public datasets that included a total of 684 breast cancer patients, we found that the combined high expression of TG2 and IL-6 was associated with shorter DMFS, compared with the high expression of IL-6 only ( P = 0.013).

          Conclusions

          We provide evidence that TG2 is an important link in IL-6-mediated tumor aggressiveness, and that TG2 could be an important mediator of distant metastasis, both in a xenograft animal model and in patients with advanced breast cancer.

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          Most cited references31

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          Epithelial-mesenchymal transitions in development and disease.

          Jean Paul Thiery, Hervé Acloque, Ruby Y J Huang … (2009)
          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.

            V Shankaran, H. Ikeda, A. T. Bruce … (2001)
            Lymphocytes were originally thought to form the basis of a 'cancer immunosurveillance' process that protects immunocompetent hosts against primary tumour development, but this idea was largely abandoned when no differences in primary tumour development were found between athymic nude mice and syngeneic wild-type mice. However, subsequent observations that nude mice do not completely lack functional T cells and that two components of the immune system-IFNgamma and perforin-help to prevent tumour formation in mice have led to renewed interest in a tumour-suppressor role for the immune response. Here we show that lymphocytes and IFNgamma collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity. The immune response thus functions as an effective extrinsic tumour-suppressor system. However, this process also leads to the immunoselection of tumour cells that are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals.
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              Tumor self-seeding by circulating cancer cells.

              Mi-Young Kim, Thordur Oskarsson, Swarnali Acharyya … (2009)
              Cancer cells that leave the primary tumor can seed metastases in distant organs, and it is thought that this is a unidirectional process. Here we show that circulating tumor cells (CTCs) can also colonize their tumors of origin, in a process that we call "tumor self-seeding." Self-seeding of breast cancer, colon cancer, and melanoma tumors in mice is preferentially mediated by aggressive CTCs, including those with bone, lung, or brain-metastatic tropism. We find that the tumor-derived cytokines IL-6 and IL-8 act as CTC attractants whereas MMP1/collagenase-1 and the actin cytoskeleton component fascin-1 are mediators of CTC infiltration into mammary tumors. We show that self-seeding can accelerate tumor growth, angiogenesis, and stromal recruitment through seed-derived factors including the chemokine CXCL1. Tumor self-seeding could explain the relationships between anaplasia, tumor size, vascularity and prognosis, and local recurrence seeded by disseminated cells following ostensibly complete tumor excision. Copyright 2009 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Breast Cancer Res
                Title: Breast Cancer Research : BCR
                Publisher: BioMed Central
                ISSN (Print): 1465-5411
                ISSN (Electronic): 1465-542X
                Publication date (Print): 2011
                Publication date (Electronic): 3 October 2011
                Volume: 13
                Issue: 5
                Page: R96
                Affiliations
                [1 ]Laboratory of Immunology, Interdisciplinary Program of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-799, Korea
                [2 ]Transplantation Research Institute, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-799, Korea
                [3 ]Department of Surgery, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-799, Korea
                [4 ]Dongnam Institute of Radiological & Medical Sciences, 40 Jwadong-gil Jangan-eup, Gijang-gun, Busan 619-953, Korea
                [5 ]Department of Pathology, Hanil Hospital, 388-1 Sangmon3-dong Dobong-gu, Seoul 132-703, Korea
                [6 ]College of Pharmacy, Sunchon National University, 255 Jungangno, Suncheon, Jeonnam 540-742, Korea
                Article
                Publisher ID: bcr3034
                DOI: 10.1186/bcr3034
                PMC ID: 3262209
                PubMed ID: 21967801
                SO-VID: f100e501-17ba-4c64-bec0-b66dee877cf5
                Copyright © Copyright ©2011 Oh et al.; licensee BioMed Central Ltd.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 24 February 2011
                Date revision received : 18 August 2011
                Date accepted : 3 October 2011
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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