scholarly journals Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Takashi Nishina ◽  
Yutaka Deguchi ◽  
Daisuke Ohshima ◽  
Wakami Takeda ◽  
Masato Ohtsuka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Human Cancer ◽  
Tumor Development ◽  
Gene Signature ◽  
Free Survival ◽  
Expression Of Genes ◽  
Reporter Mice ◽  
Interleukin 11

AbstractInterleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generate Il11 reporter mice. IL-11+ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11+ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+ fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.

scholarly journals Interleukin-11 is a Marker for Both Cancer- and Inflammation-Associated Fibroblasts that Contribute to Colorectal Cancer Progression

2020 ◽  
Author(s):  
Takashi Nishina ◽  
Yutaka Deguchi ◽  
Wakami Takeda ◽  
Masato Ohtsuka ◽  
Daisuke Ohshima ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Human Cancer ◽  
Tumor Development ◽  
Disease Free Survival ◽  
Reporter Mice ◽  
Stat3 Phosphorylation ◽  
Colorectal Cancer Progression ◽  
Cancer And Inflammation

SUMMARYInterleukin (IL)-11 is a member of the IL-6 family of cytokines and involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generated Il11 reporter mice. IL-11+ cells appeared in the colon of three murine tumor models, and a murine acute colitis model. Il11ra1 or Il11 deletion attenuated the development of colitis-associated colorectal cancer. IL-11+ cells expressed fibroblast markers, and genes associated with cell proliferation and tissue repair. IL-11 induced STAT3 phosphorylation in colonic fibroblasts, suggesting the activation of IL-11+ fibroblasts. Analysis using the human cancer database revealed that genes enriched in IL-11+ fibroblasts were elevated in human colorectal cancer, and correlated with reduced disease-free survival. Together, our results suggested that tumor cells induced IL-11+ fibroblasts, and that a feed-forward loop between IL-11 and IL-11+ fibroblasts might contribute to tumor development.

scholarly journals Targeting OLFML3 in Colorectal Cancer Suppresses Tumor Growth and Angiogenesis, and Increases the Efficacy of Anti-PD1 Based Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4625
Author(s):  
Jimmy Stalin ◽  
Beat A. Imhof ◽  
Oriana Coquoz ◽  
Rachel Jeitziner ◽  
Philippe Hammel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Molecular Subtype ◽  
Human Cancer ◽  
Tumor Development ◽  
Tumor Grade ◽  
Tissue Expression ◽  
In Vivo Studies

The role of the proangiogenic factor olfactomedin-like 3 (OLFML3) in cancer is unclear. To characterize OLFML3 expression in human cancer and its role during tumor development, we undertook tissue expression studies, gene expression analyses of patient tumor samples, in vivo studies in mouse cancer models, and in vitro coculture experiments. OLFML3 was expressed at high levels, mainly in blood vessels, in multiple human cancers. We focused on colorectal cancer (CRC), as elevated expression of OLFML3 mRNA correlated with shorter relapse-free survival, higher tumor grade, and angiogenic microsatellite stable consensus molecular subtype 4 (CMS4). Treatment of multiple in vivo tumor models with OLFML3-blocking antibodies and deletion of the Olfml3 gene from mice decreased lymphangiogenesis, pericyte coverage, and tumor growth. Antibody-mediated blockade of OLFML3 and deletion of host Olfml3 decreased the recruitment of tumor-promoting tumor-associated macrophages and increased infiltration of the tumor microenvironment by NKT cells. Importantly, targeting OLFML3 increased the antitumor efficacy of anti-PD-1 checkpoint inhibitor therapy. Taken together, the results demonstrate that OLFML3 is a promising candidate therapeutic target for CRC.

scholarly journals TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Sha Zhou ◽  
Jianhong Peng ◽  
Liuniu Xiao ◽  
Caixia Zhou ◽  
Yujing Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Free Survival ◽  
Free Survival ◽  
Epigenetic Regulator ◽  
Crc Management ◽  
Disease Free ◽  
Resistance To Chemotherapy

AbstractResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

scholarly journals Genome-Wide Scan for Copy Number Alteration Association with Relapse-Free Survival in Colorectal Cancer with Liver Metastasis Patients

2018 ◽  
Vol 7 (11) ◽  
pp. 446 ◽  
Author(s):  
Po-Sheng Yang ◽  
Hsi-Hsien Hsu ◽  
Tzu-Chi Hsu ◽  
Ming-Jen Chen ◽  
Cin-Di Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Gene Signature ◽  
Comparative Genomic ◽  
Relapse Free Survival ◽  
Cgh Array ◽  
Free Survival

Predicting a patient’s risk of recurrence after the resection of liver metastases from colorectal cancer is critical for evaluating and selecting therapeutic approaches. Clinical and pathologic parameters have shown limited accuracy thus far. Therefore, we combined the clinical status with a genomic approach to stratify relapse-free survival in colorectal cancer liver metastases patients. To identify new molecular and genetic signatures specific to colorectal cancer with liver metastasis (CRCLM) patients, we conducted DNA copy number profiling on a cohort of 21 Taiwanese CRCLM patients using a comparative genomic hybridization (CGH) array. We identified a three-gene signature based on differential copy number alteration between patients with different statuses of (1) recurrence and (2) synchronous metastasis. In relapse hotspot regions, only three genes (S100PBP, CSMD2, and TGFBI) were significantly associated with the synchronous liver metastasis factor. A final set of three genes—S100PBP, CSMD2, TGFBI—significantly predicted relapse-free survival in our cohort (p = 0.04) and another CRCLM cohort (p = 0.02). This three-gene signature is the first genomic signature validated for relapse-free survival in post-hepatectomy CRCLM patients. Our three-gene signature was developed using a whole-genome CGH array and has a good prognostic position for the relapse-free survival of CRCLM patients after hepatectomy.

scholarly journals Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior

2017 ◽  
Vol 114 (4) ◽  
pp. 758-763 ◽  
Author(s):  
Kyoichi Hashimoto ◽  
Yosuke Yamada ◽  
Katsunori Semi ◽  
Masaki Yagi ◽  
Akito Tanaka ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Tumor Cells ◽  
Critical Role ◽  
Tumor Development ◽  
Cell Lineage ◽  
Genetic Rescue ◽  
Cellular Behavior ◽  
Cellular Context ◽  
Context Dependent

The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect for genetic aberrations. However, the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated. We reprogrammed colon tumor cells in an ApcMin/+ (adenomatous polyposis coli) mouse model, in which the loss of the Apc gene plays a critical role in tumor development and subsequently, established reprogrammed tumor cells (RTCs) that exhibit pluripotent stem cell (PSC)-like signatures of gene expression. We show that the majority of the genes in RTCs that were affected by Apc mutations did not overlap with the genes affected in the intestine. RTCs lacked pluripotency but exhibited an increased expression of Cdx2 and a differentiation propensity that was biased toward the trophectoderm cell lineage. Genetic rescue of the mutated Apc allele conferred pluripotency on RTCs and enabled their differentiation into various cell types in vivo. The redisruption of Apc in RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine, but the majority of the intestinal lesions remained as pretumoral microadenomas. These results highlight the significant influence of cellular context on gene regulation, cellular plasticity, and cellular behavior in response to the loss of the Apc function. Our results also imply that the transition from microadenomas to macroscopic tumors is reprogrammable, which underscores the importance of epigenetic regulation on tumor promotion.

scholarly journals MRN (MRE11-RAD50-NBS1) Complex in Human Cancer and Prognostic Implications in Colorectal Cancer

2019 ◽  
Vol 20 (4) ◽  
pp. 816 ◽  
Author(s):  
Yiling Situ ◽  
Liping Chung ◽  
Cheok Lee ◽  
Vincent Ho
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Human Cancer ◽  
Progression Free Survival ◽  
Current Evidence ◽  
Treatment Target ◽  
Free Survival ◽  
Mrn Complex ◽  
Prognostic Implications ◽  
Relationship Of

The MRE11-RAD50-NBS1 (MRN) complex has been studied in multiple cancers. The identification of MRN complex mutations in mismatch repair (MMR)-defective cancers has sparked interest in its role in colorectal cancer (CRC). To date, there is evidence indicating a relationship of MRN expression with reduced progression-free survival, although the significance of the MRN complex in the clinical setting remains controversial. In this review, we present an overview of the function of the MRN complex, its role in cancer progression, and current evidence in colorectal cancer. The evidence indicates that the MRN complex has potential utilisation as a biomarker and as a putative treatment target to improve outcomes of colorectal cancer.

scholarly journals Human Cancer Cells Express Slug-based Epithelial-Mesenchymal Transition Gene Signature Obtained in Vivo

2011 ◽  
Author(s):  
Jessica Kandel ◽  
Dimitris Anastassiou ◽  
Viktoria Rumjantseva ◽  
Wei-yi Cheng ◽  
Jianzhong Huang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Gene Signature ◽  
Mesenchymal Transition ◽  
Human Cancer Cells

Circ_0007031 enhances tumor progression and promotes 5-fluorouracil resistance in colorectal cancer through regulating miR-133b/ABCC5 axis

2020 ◽  
Vol 29 (4) ◽  
pp. 531-542
Author(s):  
Xiaowen He ◽  
Jun Ma ◽  
Mingming Zhang ◽  
Jianhua Cui ◽  
Hao Yang
Keyword(s):  
Colorectal Cancer ◽  
Colony Formation ◽  
Human Cancer ◽  
Animal Experiments ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Cell Progression ◽  
Rna Immunoprecipitation

Colorectal cancer (CRC) remains one of the most commonly diagnosed malignancies worldwide. Circular RNAs (circRNAs) are being found to play crucial roles in human cancer, including CRC. The purpose of this study was to explore the function and mechanism of circ_0007031 on CRC progression and 5-fluorouracil (5-FU) resistance. The levels of circ_0007031, ATP-binding cassette subfamily C member 5 (ABCC5) and miR-133b were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Cell survival and proliferation were detected by the 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Cell colony formation was evaluated using a standard colony formation assay. Transwell assays were performed to determine cell migration and invasion. Targeted correlations among circ_0007031, miR-133b and ABCC5 were verified by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pulldown assays. Animal experiments were performed to observe the role of circ_0007031 in vivo. Our data indicated that circ_0007031 up-regulation was associated with CRC resistance to 5-FU. Circ_0007031 knockdown repressed CRC cell proliferation, migration and invasion and enhanced 5-FU sensitivity. Circ_0007031 directly interacted with miR-133b. Moreover, circ_0007031 knockdown regulated CRC cell progression and 5-FU sensitivity by miR-133b. ABCC5 was a direct target of miR-133b, and circ_0007031 mediated ABCC5 expression via acting as a miR-133b sponge. Furthermore, miR-133b overexpression regulated CRC cell progression and sensitivity to 5-FU by down-regulating ABCC5. Additionally, circ_0007031 knockdown suppressed tumor growth in vivo. Our current work had led to the identification of circ_0007031 knockdown that repressed CRC cell malignant progression and enhanced 5-FU sensitivity via regulating ABCC5 expression by sponging miR-133b.

scholarly journals Recurrence-associated gene signature optimizes recurrence-free survival prediction of colorectal cancer

2017 ◽  
Vol 11 (11) ◽  
pp. 1544-1560 ◽  
Author(s):  
Xianglong Tian ◽  
Xiaoqiang Zhu ◽  
Tingting Yan ◽  
Chenyang Yu ◽  
Chaoqin Shen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Signature ◽  
Survival Prediction ◽  
Recurrence Free Survival ◽  
Free Survival

scholarly journals Assessment of circulating tumor cells in peripheral blood using flow cytometry in patients with surgery for colorectal cancer – review

2020 ◽  
Vol 28 (4) ◽  
pp. 365-379
Author(s):  
Ana-Maria Muşină ◽  
Ionuţ Huţanu ◽  
Mihaela Zlei ◽  
Mădălina Ştefan ◽  
Mihaela Mentel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Flow Cytometry ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Peripheral Blood ◽  
Disease Free Survival ◽  
Final Analysis ◽  
Immunomagnetic Separation ◽  
Free Survival ◽  
Pubmed Database

AbstractIntroduction: Colorectal cancer (CRC) is the third most common neoplasia in the world. Circulating tumor cells (CTC) have a prognostic value and can be useful in monitoring solid neoplasia. Only one method for CTC identification has received the approval and this is the CellSearch® system based on the immunomagnetic separation. Multiple markers are used in CTC identification, as epithelial markers and cytokeratines. CTC identification in peripheral blood is associated with a worse prognostic and reduced free survival in CRC.Material and methods: We performed a systematic search in PubMed database for articles that reports the circulating tumor cells in CRC until July 2019. We selected studies in English and French and the main words used for search were ‘circulating tumor cells’, ‘colorectal cancer’, ‘colon cancer’, ‘rectal cancer’, ‘flow cytometry’, ‘peripheral blood’. We included studies with more than 10 patients, where samples were collected from the blood in relation with surgery and flow cytometry was used as analyzing technique.Results: We included 7 studies in final analysis, that showed in flow cytometry analysis a cut-off value of CTC that can vary from 2-4 CTC/ 7.5 ml peripheral blood with a sensitivity of 50.8% and specificity of 95%. Patients with positive CTC were associated with higher T stage and positive lymph nodes, with a worse overall survival (OS) and disease free survival (DFS) comparing with negative patients.Conclusion: CTC are considered to be a prognostic factor who needs more validation studies in order to be included in the clinical practice.

Sign in / Sign up

Export Citation Format

Share Document