Tenascin-C Produced by Intestinal Myofibroblasts Promotes Colitis-associated Cancer Development Through Angiogenesis

Kawamura, Takafumi; Yamamoto, Masayoshi; Suzuki, K.; Suzuki, Yuhi; Kamishima, Megumu; Sakata, Mayu; Kurachi, Kiyotaka; Setoh, Mitsutoshi; Konno, Hiroyuki; Takeuchi, Hiroya

doi:10.1093/ibd/izy368

Cited by 19 publications

(20 citation statements)

References 40 publications

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“…Tenascin-C (TNC) is an extracellular matrix glycoprotein that is highly expressed in malignant solid tumours, including breast cancer tumours 13 . TNC has been implicated in the modulation of cell migration, proliferation, invasion and angiogenesis 14 – 16 . TNC is also well known for its function in arresting T-cell proliferation and activation to overcome immune surveillance.…”

Section: Introductionmentioning

confidence: 99%

Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation

et al. 2020

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Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8 + T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.

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Section: Introductionmentioning

confidence: 99%

Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation

et al. 2020

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“…Tumor-derived TNC promotes or enhances the process of angiogenesis in different tumor models (Hirata et al , 2009; Kawamura et al , 2018; Pezzolo et al , 2011; Rupp et al , 2016), but the mechanistic insight has not been fully elucidated. In our previous study, TNC level is much higher in high metastatic potential CRC cell line SW620 compared to the other four CRC cell lines, particularly in the conditioned medium (Li et al , 2016).…”

Section: Resultsmentioning

confidence: 99%

“…A total of 216 DEPs were identified, and then GO analysis and systematic pathway-based enrichment analysis was performed. Among the DEPs, many have been reported or predicted as potential targets for cancer antiangiogenic treatment (see Figure 1D and Supplementary Table S4), such as FBLN5 (Albig & Schiemann, 2004), CEACAM6 (Zang et al , 2015), S100A9 (Eisenblaetter et al , 2017; Zhang et al , 2017), THBS1 (Lawler, 2002), CANX (Demeure et al , 2016), TNC (Kawamura et al , 2018), HSP47 (Wu et al , 2016), CTTN (Ramos-Garcia & Gonzalez-Moles, 2018), MMP9 (Gupta et al , 2013), TGM2 (Lei et al , 2018), S100A7 (Padilla et al , 2017), LCN2 (Hu et al , 2018), RACK1 (Wang et al , 2011), PGK1 (Shichijo et al , 2004), EPO (Samoszuk et al , 1996), CD74 (Gai et al , 2018), GRP78 (Kao et al , 2018). For these candidate antiangiogenic targets, our results are consistent with previously published data.…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomic profiling of tumor-associated vascular endothelial cells in colorectal cancer

Wang

Yang

et al. 2019

Preprint

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Summery statement:We provided large-scale proteomic profiling of vascular endothelial cells in colorectal cancer with quantitative information, a number of potential antiangiogenic targets and a novel vision in the angiogenesis bio-mechanism of CRC. SummeryTo investigate the global proteomic profiles of vascular endothelial cells (VECs) in the tumor microenvironment and antiangiogenic therapy for colorectal cancer (CRC), matched pairs of normal (NVECs) and tumor-associated VECs (TVECs) were purified from CRC tissues by laser capture microdissection and subjected to iTRAQ based quantitative proteomics analysis. Here, 216 differentially expressed proteins (DEPs) were identified and performed bioinformatics analysis. Interestingly, these proteins were implicated in epithelial mesenchymal transition (EMT), ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, angiogenesis and HIF-1 signaling pathway, which may play important roles in CRC angiogenesis. Among these DEPs, Tenascin-C (TNC) was found to upregulated in the TVECs of CRC and be correlate with CRC multistage carcinogenesis and metastasis. Furthermore, the reduction of tumor-derived TNC could attenuate human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation through ITGB3/FAK/Akt signaling pathway. Based on the present work, we provided a large-scale proteomic profiling of VECs in CRC with quantitative information, a certain number of potential antiangiogenic targets and a novel vision in the angiogenesis bio-mechanism of CRC.

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“…TNC expression correlates with CRC malignancy [139] and may be considered a putative biomarker for metastasis [135,140]. Kawamura and colleagues demonstrated that TNC promotes colitis-associated cancer development through αvβ3-mediated angiogenesis and the disruption of this interaction is suggestive of promising therapeutic applications [141].…”

Section: Int J Mol Sci 2020 21 X For Peer Review 3 Of 34mentioning

confidence: 99%

Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis

Andreuzzi

Capuano

Poletto

et al. 2020

IJMS

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Gastrointestinal tumors are responsible for more cancer-related fatalities than any other type of tumors, and colorectal and gastric malignancies account for a large part of these diseases. Thus, there is an urgent need to develop new therapeutic approaches to improve the patients’ outcome and the tumor microenvironment is a promising arena for the development of such treatments. In fact, the nature of the microenvironment in the different gastrointestinal tracts may significantly influence not only tumor development but also the therapy response. In particular, an important microenvironmental component and a potential therapeutic target is the vasculature. In this context, the extracellular matrix is a key component exerting an active effect in all the hallmarks of cancer, including angiogenesis. Here, we summarized the current knowledge on the role of extracellular matrix in affecting endothelial cell function and intratumoral vascularization in the context of colorectal and gastric cancer. The extracellular matrix acts both directly on endothelial cells and indirectly through its remodeling and the consequent release of growth factors. We envision that a deeper understanding of the role of extracellular matrix and of its remodeling during cancer progression is of chief importance for the development of new, more efficacious, targeted therapies.

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Tenascin-C Produced by Intestinal Myofibroblasts Promotes Colitis-associated Cancer Development Through Angiogenesis

Cited by 19 publications

References 40 publications

Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation

Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation

Quantitative proteomic profiling of tumor-associated vascular endothelial cells in colorectal cancer

Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis

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