High expression of TMEM180, a novel tumour marker, is associated with poor survival in stage III colorectal cancer

Abstract Background Transmembrane protein 180 (TMEM180) is a newly identified colorectal cancer (CRC)-specific molecule that is expressed very rarely in normal tissue and up-regulated under hypoxic conditions. We developed a monoclonal antibody (mAb) against TMEM180 and decided to examine the medical significance using the mAb. Methods A total of 157 patients (86 men and 71 women; median age 63.0 years) with stage III CRC who underwent curative surgery were analyzed for TMEM180 expression as a retrospective cohort design. Immunohistochemistry with anti-TMEM180 mAb was conducted on frozen sections, and the data were evaluated for any correlation with clinicopathological indices or prognosis. SW480 CRC cells were examined to investigate the relationship between the expression of TMEM180 and tumourigenesis of xenografts. Results In total, 92 cases had low TMEM expression and 65 had high TMEM180 expression. For disease-free survival, hazard ratio in high-TMEM180 cases was 1.449 (95% confidential interval = 0.802–2.619) higher than in low-TMEM180 cases, but the difference was not significant (p = 0.219). For cancer specific survival, hazard ratio in high-TMEM180 cases was 3.302 (95% confidential interval = 1.088–10.020), significantly higher than in low-TMEM180 cases (p = 0.035). In an assay examining in vitro colony-forming activity in soft agar, SW480-WT cells clearly formed colonies, but neither KD1 nor KD2 cells did. The in vivo tumour-initiating activity of SW480 cell lines was positively correlated with the level of TMEM180 expression. Conclusion These results indicate that TMEM180 is a useful marker for clinical prognosis in patients with CRC. We believe that these fundamental data warrant further basic and translational studies of TMEM180, and its mAb, for development of therapeutics against CRC.

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Clinical significance of tumor budding in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.422 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 422-422

Author(s):

Jae-Im Lee ◽

Chang Hyeok An ◽

Hyung Jin Kim ◽

Sang Chul Lee ◽

Seong-Taek Oh

Keyword(s):

Colorectal Cancer ◽

Clinical Significance ◽

Univariate Analysis ◽

Survival Rates ◽

Disease Free Survival ◽

Venous Invasion ◽

Hazard Ratio ◽

Tumor Budding ◽

Curative Surgery ◽

Invasive Margin

422 Background: Tumor budding was defined as an isolated single cancer cell or a small cluster of cancer cells at the invasive margins. We assessed the clinical significance of tumor budding, as a predictor of outcomes in patients with non-metastatic colorectal cancer. Methods: We studied a total of 148 patients with colorectal cancer who underwent curative resection. Tumor budding was assessed on slides stained with hematoxylin and eosin (H&E). Tissue specimens including the entire invasive margin from largest cut sections of the whole tumor were examined. Tumor budding was not classified according to previously described classification. The actual number of tumor budding along the entire invasive margin was counted at a magnification of x200 with the use of light microscopy. We determined cut-off point of tumor budding, lymph node ratio and carcinoembryonic antigen (CEA) with receiver operating characteristic (ROC) curve. Results: Univariate analysis revealed that poorly differentiation (p=0.009), lymphatic invasion (p=0.035) venous invasion (p=0.007), CEA >6.3 (p=0.0007) and tumor budding >13 (p=0.0006) were significantly related to poor survival. Cumulative five survival rates differed significantly between patients with tumor budding ≤13 (92.3%) and those with tumor budding >13 (73.1 %). Multivariate analysis with Cox’s regression analysis demonstrated that tumor budding >13 (hazard ratio=4.925, p=0.003), poorly differentiation (hazard ratio=3.696, p=0.01) and CEA >6.3 (hazard ratio=3.085, p=0.024) were independent prognostic factors for overall survival. CEA >6.3 (hazard ratio=2.361, p=0.034) and tumor budding >20 (hazard ratio=3.293, p=0.008) were significant prognostic predictors for disease free survival Conclusions: Tumor budding is useful for prognosis and identifying patients with colorectal cancer who have a high-risk of disease recurrence after curative surgery. The proper cut-off level of tumor budding is 13.

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The Combination of Inflammation and Nutrition Factors Reinforces the Prognostic Prediction for Stage III Colorectal Cancer Patients After Curative Resection

10.21203/rs.3.rs-1226522/v1 ◽

2022 ◽

Author(s):

Shinya Kato ◽

Norikatsu Miyoshi ◽

Shiki Fujino ◽

Soichiro Minami ◽

Chu Matsuda ◽

...

Keyword(s):

Colorectal Cancer ◽

Cox Regression ◽

Prognostic Score ◽

Disease Free Survival ◽

Albumin Level ◽

Stage Iii ◽

Curative Surgery ◽

Validation Set ◽

Prognostic Prediction ◽

Colorectal Cancer Patients

Abstract Purpose Inflammation and nutritional status are known to be associated with the prognosis of several malignancies. Herein, we attempted to develop inflammation–nutrition scores and predict the prognosis of stage III colorectal cancer (CRC). Methods This retrospective study included 262 patients with stage III CRC who underwent curative surgery and were divided into two groups: a training set (TS) of 162 patients and a validation set (VS) of 100 patients. In the TS, clinicopathological factors were tested using a Cox regression model, and the Kansai prognostic score (KPS) was assessed by 1 point each for <3.5 g/dL albumin level, >450 monocyte counts, and <1.65 × 105 platelet counts, which were associated with disease-free survival (DFS). Using KPS, DFS and overall survival (OS) were validated in VS. Results The C-indices of KPS to predict DFS and OS in TS were 0.707 and 0.772. It was validated in VS that the C-indices of KPS to predict DFS and OS were 0.618 and 0.708, respectively. A high KPS was a significant predictor of DFS and OS. Conclusion KPS serves as a new model for the prognosis of patients with stage III CRC.

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Predictive Values of EGFR expression for the Fluoropyrimidine Metronomic Maintenance Therapy in Patients with Stage III Colorectal Cancer after Radical Resection and Adjuvant Oxaliplatin-Based Chemotherapy

10.20944/preprints201912.0246.v1 ◽

2019 ◽

Author(s):

Ching-Wen Huang ◽

Cheng-Jen Ma ◽

Yi-Ting Chen ◽

Hsiang-Lin Tsai ◽

Yung-Sung Yeh ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Maintenance Therapy ◽

Disease Free Survival ◽

Radical Resection ◽

Stage Iii ◽

Independent Predictive Factor ◽

Predictive Values ◽

Egfr Expression

Background: This retrospective study evaluates the survival effects of metronomic maintenance therapy with fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. Methods: We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockdout of EGFR gene, we analyzed the capacities of cell proliferation and migration. Results: Postoperative relapse and mortality were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent predictive factor of postoperative relapse and mortality, as well as a prognostic factor of disease-free survival and overall survival. The significant differences of survival between the two groups were only observed in patients with positive EGFR expression. Conclusions: The present study suggested EGFR expression as the prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. By analyzing EGFR expression, we can identify the potential candidates with optimal survival benefit from metronomic maintenance therapy in patients with stage III CRC.

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The Survival Impact of Fluoropyrimidine Metronomic Maintenance Therapy Following Adjuvant Oxaliplatin-based Chemotherapy in Patients with Stage III Colorectal Cancer after Radical Resection: Functional Roles of EGFR as a Potential Predictor

10.20944/preprints201909.0036.v1 ◽

2019 ◽

Author(s):

Ching-Wen Huang ◽

Cheng-Jen Ma ◽

Yi-Ting Chen ◽

Hsiang-Lin Tsai ◽

Yung-Sung Yeh ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Maintenance Therapy ◽

Disease Free Survival ◽

Radical Resection ◽

Stage Iii ◽

Independent Predictive Factor ◽

Egfr Expression

Background: This retrospective study evaluate the survival effects of metronomic maintenance therapy with fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. Methods: We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockdout of EGFR gene, we analyzed the capacities of cell proliferation and migration. Results: Postoperative relapse and mortality were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent predictive factor of postoperative relapse and mortality, as well as a prognostic factor of disease-free survival and overall survival. We also demonstrated that EGFR-knockout Caco2 cells are more sensitive to the inhibition effect of fluoropyrimidine than the control those. Conclusions: The present study suggested EGFR expression as the prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. By analyzing EGFR expression and treatment strategies, we can identify the potential candidates with optimal survival benefit from metronomic maintenance therapy in patients with stage III CRC.

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Prognostic Value of EGFR Expression for Patients with Stage III Colorectal Cancer Receiving Fluoropyrimidine Metronomic Maintenance Therapy After Radical Resection and Adjuvant Oxaliplatin-Based Chemotherapy

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504020x15986099915822 ◽

2020 ◽

Author(s):

Ching-Wen Huang ◽

Cheng-Jen Ma ◽

Wei-Chih Su ◽

Yi-Ting Chen ◽

Hsiang-Lin Tsai ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Maintenance Therapy ◽

Growth Factor Receptor ◽

Disease Free Survival ◽

Radical Resection ◽

Stage Iii ◽

Egfr Expression

This study evaluated the survival effects of metronomic maintenance therapy with oral fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy with oral capecitabine (daily dose of 850 mg/m2, twice daily, on days 1–14 days every 3 weeks for 6 months) on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockout of the EGFR gene, we analyzed the capacities of cell proliferation and migration. Relapse and survival were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent associated factor of relapse and survival as well as a prognostic factor of disease-free survival and overall survival. Significant intergroup differences in survival were only observed in patients with positive EGFR expression. Thus, our findings suggest EGFR expression is a prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. Analysis of EGFR expression in these patients helps identify potential candidates who may receive the optimal survival benefit from metronomic maintenance therapy.

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TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

Cell Death and Disease ◽

10.1038/s41419-021-03734-4 ◽

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.

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Retrospective analysis of the effect of CAPOX and mFOLFOX6 dose intensity on survival in colorectal patients in the adjuvant setting

Current Oncology ◽

10.3747/co.23.3059 ◽

2016 ◽

Vol 23 (3) ◽

pp. 171 ◽

Cited By ~ 2

Author(s):

A. Mamo ◽

J. Easaw ◽

F. Ibnshamsah ◽

A. Baig ◽

Y.S. Rho ◽

...

Keyword(s):

Colorectal Cancer ◽

Dose Reduction ◽

Real Life ◽

Disease Free Survival ◽

Dose Intensity ◽

Sensory Neuropathy ◽

Stage Iii ◽

Cancer Centre ◽

Peripheral Sensory ◽

Disease Free

Background Despite lack of a true comparative study, the FOLFOX (5-fluorouracil–leucovorin–oxaliplatin) and CAPOX (capecitabine–oxaliplatin) regimens are believed to be similar in their efficacy and tolerability in the treatment of stage III colorectal cancer. However, that belief has been disputed, because real-life data suggest that the CAPOX regimen is more toxic, leading to more frequent reductions in the delivered dose intensity—thus raising questions about the effect of dose intensity on clinical outcomes.Methods A retrospective data review for two Canadian institutions, the Segal Cancer Centre and the Tom Baker Cancer Centre, considered patients diagnosed with stage III colorectal cancer during 2006–2013. Primary endpoints were dose intensity and toxicity, with a secondary endpoint of disease-free survival.Results The study enrolled 180 eligible patients (80 at the Segal Cancer Centre, 100 at the Tom Baker Cancer Centre). Of those 180 patients, 75 received CAPOX, and 105 received mFOLFOX6. In the CAPOX group, a significant dose reduction was identified for capecitabine compared with 5-fluorouracil in mFOLFOX6 group (p = 0.0014). Similarly, a significant dose reduction was observed for oxaliplatin in mFOLFOX6 compared with oxaliplatin in CAPOX (p = 0.0001). Compared with the patients receiving CAPOX, those receiving mFOLFOX6 were twice as likely to experience a treatment delay of more than 1 cycle-length (p = 0.03855). Toxicity was more frequent in patients receiving mFOLFOX6 (nausea: 30% vs. 18%; diarrhea: 47% vs. 24%; peripheral sensory neuropathy: 32% vs. 3%). At a median follow-up of 40 months, preliminary data showed no difference in disease-free survival (p = 0.598). Pooled data from both institutions were also separately analyzed, and no significant differences were found.Conclusions Our results support the use of CAPOX despite a lack of head-to-head randomized trial data.

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GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma

BMC Cancer ◽

10.1186/s12885-021-08898-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jung Hyun Jo ◽

Sun A Kim ◽

Jeong Hoon Lee ◽

Yu Rang Park ◽

Chanyang Kim ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cancer Progression ◽

Biomarker Discovery ◽

Disease Free Survival ◽

Tumor Formation ◽

Ductal Adenocarcinoma ◽

Curative Surgery ◽

In Vitro Proliferation

Abstract Background Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear. Method In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication. Results PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19–9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19–9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery. Conclusion Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.

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ORMDL1 is upregulated and associated with favorable outcome in colorectal cancer

10.1101/2020.12.10.420497 ◽

2020 ◽

Author(s):

Qian Wang ◽

Wanjun Liu ◽

Si Chen ◽

Qianxin Luo ◽

Yichen Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Colony Formation ◽

Transmembrane Protein ◽

Cohort Analysis ◽

Negative Regulator ◽

Morphologic Change ◽

Mesenchymal Transition

AbstractBackgroundORMDL1 gene encodes a transmembrane protein for endoplasmic reticulum and is known as crucial negative regulator for sphingolipid biogenesis. However, it has been rarely studied in tumor-related context. Therefore, its prognostic value and functional significance in colorectal cancer (CRC) remain to be explored.MethodsTCGA CRC cohort analysis, qRT-PCR, and immunohistochemistry (IHC) were used to examine the ORMDL1 expression level. The association between ORMDL1 expression and various clinical characteristics were analyzed by Chi-square tests. CRC patients’ overall survival (OS) was analyzed by Kaplan-Meier analysis. In vitro and in vivo cell-based assays were performed to explore the role of ORMDL1 in cell proliferation, invasion and migration. Transcriptional changes of cells either with ORMDL1 knockdowned or overexpressed were compared and analyzed.ResultsORMDL1 was upregulated in CRC tissues either in TCGA cohort or in our cohort. Interestingly, its expression was significantly lower in patients with metastasis compared to patients without metastasis, and high expression group had longer OS than low expression group. Knockdown of ORMDL1 expression can promote proliferation, colony formation and invasion, while attenuate migration in CRC cell lines. In opposite, forced overexpression of ORMDL1 reduced cell proliferation, colony formation and invasion, while enhanced cell migration. Epithelial-to-mesenchymal transition (EMT) related genes were enriched among differentially expressed genes when ORMDL1 was knockdowned in cells, which was consistent with morphologic change by microscopy observation. Finally, stable knockdown of ORMDL1 can promote cancer cell proliferation in vivo to some extent.ConclusionORMDL1 is upregulated and may serve as biomarker to predict favourable outcome in colorectal cancer.

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Necroptosis regulates tumor repopulation after radiotherapy via RIP1/RIP3/MLKL/JNK/IL8 pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1423-5 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 5

Author(s):

Yiwei Wang ◽

Minghui Zhao ◽

Sijia He ◽

Yuntao Luo ◽

Yucui Zhao ◽

...

Keyword(s):

Colorectal Cancer ◽

Growth Stimulation ◽

Underlying Mechanism ◽

Promoting Effect ◽

Clinical Prognosis ◽

Associated Proteins ◽

Radiation Induced ◽

Colorectal Cancer Patients

Abstract Background Tumor cell repopulation after radiotherapy is a major cause for the tumor radioresistance and recurrence. This study aims to investigate the underlying mechanism of tumor repopulation after radiotherapy, with focus on whether and how necroptosis takes part in this process. Methods Necroptosis after irradiation were examined in vitro and in vivo. And the growth-promoting effect of necroptotic cells was investigated by chemical inhibitors or shRNA against necroptosis associated proteins and genes in in vitro and in vivo tumor repopulation models. Downstream relevance factors of necroptosis were identified by western blot and chemiluminescent immunoassays. Finally, the immunohistochemistry staining of identified necroptosis association growth stimulation factor was conducted in human colorectal tumor specimens to verify the relationship with clinical outcome. Results Radiation-induced necroptosis depended on activation of RIP1/RIP3/MLKL pathway, and the evidence in vitro and in vivo demonstrated that the inhibition of necroptosis attenuated growth-stimulating effects of irradiated tumor cells on living tumor reporter cells. The JNK/IL-8 were identified as downstream molecules of pMLKL during necroptosis, and inhibition of JNK, IL-8 or IL-8 receptor significantly reduced tumor repopulation after radiotherapy. Moreover, the high expression of IL-8 was associated with poor clinical prognosis in colorectal cancer patients. Conclusions Necroptosis associated tumor repopulation after radiotherapy depended on activation of RIP1/RIP3/MLKL/JNK/IL-8 pathway. This novel pathway provided new insight into understanding the mechanism of tumor radioresistance and repopulation, and MLKL/JNK/IL-8 could be developed as promising targets for blocking tumor repopulation to enhance the efficacy of colorectal cancer radiotherapy.

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