Abstract:The results indicate that MMP-1 is independently associated with CSS in patients with colon cancer. Furthermore, a possible clinical implication is that MMP-1 protein expression in tumor-free mucosa could identify colon cancer patients with poor CSS in need of more intensified adjuvant treatment.
“…Untreated high density mono-cultures of HCT116 expressed MMP-13, however compared to HCT116 high density tumor microenvironment co-cultures, expression was markedly lower (Fig. 5:a). These results are in agreement with other studies that expression of MMPs is known to be up-regulated in the tumor microenvironment [17]–[19], [41], known to be regulated by transcription factor NF-κB [36], [42]. Treatment of HCT116 high density tumor microenvironment co-cultures with curcumin down-regulated the expression of MMP-13 (Fig.…”
Section: Resultssupporting
confidence: 93%
“…Cadherins, Integrins) [14]–[16]. Modulation of matrix metalloproteinase (MMP) expression in the tumor (micro)-environment is important as MMPs are known markers for CRC progression [17]–[19]. Tumor metastasis and invasion is further influenced by tumor cell interaction with epithelial and endothelial cells.…”
ObjectiveInteraction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially on cancer stem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment.MethodsColon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU.ResultsMonolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing CSCs to 5-FU treatment.ConclusionEnrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-β and EMT. Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis.
“…Untreated high density mono-cultures of HCT116 expressed MMP-13, however compared to HCT116 high density tumor microenvironment co-cultures, expression was markedly lower (Fig. 5:a). These results are in agreement with other studies that expression of MMPs is known to be up-regulated in the tumor microenvironment [17]–[19], [41], known to be regulated by transcription factor NF-κB [36], [42]. Treatment of HCT116 high density tumor microenvironment co-cultures with curcumin down-regulated the expression of MMP-13 (Fig.…”
Section: Resultssupporting
confidence: 93%
“…Cadherins, Integrins) [14]–[16]. Modulation of matrix metalloproteinase (MMP) expression in the tumor (micro)-environment is important as MMPs are known markers for CRC progression [17]–[19]. Tumor metastasis and invasion is further influenced by tumor cell interaction with epithelial and endothelial cells.…”
ObjectiveInteraction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially on cancer stem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment.MethodsColon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU.ResultsMonolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing CSCs to 5-FU treatment.ConclusionEnrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-β and EMT. Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis.
“…There are several works concerning the usefulness of the determination of MMP-1 in patients with colorectal cancer; however, the most recent researches demonstrate that it is an independent prognostic factor in patients with CRC. On the basis of our studies, it may appear that an increased concentration of its pro-enzyme (proMMP-1) indicates large tumor mass [28].…”
The aim of this study was the evaluation of clinical usage of metalloproteinase (MMP): proMMP-1, MMP-2, MMP-7, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in serum of patients with rectal cancer, as well as the selection of parameters of the greatest diagnostic sensitivity and the determination of their relation with clinicopathological features, what is more, the demonstration whether their concentrations may have a prognostic value in the assessment of disease-free survival (DFS) and overall survival (OS). The study comprised 100 patients with rectal cancer including 29 women and 71 men. The tested group was comprised of qualified patients without distant metastasis (M0). It was demonstrated that in patients with rectal cancer, the concentrations of MMP-9, MMP-7, and proMMP-1 as well as TIMP-1 were significantly higher in comparison to the reference group. On the basis of ROC curves, the greatest diagnostic sensitivity of MMP-9 was demonstrated. When evaluating the correlation of tested parameters with the size of the tumor (T1-T2 vs T3-T4), essential differences were shown for proMMP-1 concentrations. The highest percentage of patients with progression had an increased concentration of MMP-7 and TIMP-1. During a 5-year follow-up, univariate log-rank analysis had shown an essential dependence between the concentration of MMP-7 in men and DSF which was confirmed in Cox multivariate analysis. It was demonstrated that the pretreatment concentration of proMMP-1 may be clinically useful when evaluating the mass of the tumor, whereas MMP-7 may be a prognostic factor for DFS in men with rectal cancer without distant metastasis.
“…Eventually, 13 studies were included [10, 13, 15–17, 21–28]. The study conducted by Langenskiöld [23] was not included for analysis for the following reasons: (1) it had a great impact on the combined HR and accounted for 99% of the weight due to its small standard error of HR (0.005); (2) the study analysed colon cancer and rectal cancer separately; and (3) it is very difficult to get the small standard error in such a sample size (136). Therefore, 12 studies were eligible for this meta-analysis.Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Only one study investigated rectal cancer [22], and two investigated colon cancer [25, 27], whereas other studies investigated colorectal cancer. One study included stage III patients [22], and one study included stage I-III patients [23]. Other studies included patients with all stages of CRC.…”
BackgroundTransforming growth factor-beta (TGF-β) is associated with a higher incidence of distant metastasis and decreased survival. Whether TGF-β can be used as a prognostic indicator of colorectal cancer (CRC) remains controversial.MethodsThe Medline, EMBASE and Cochrane databases were searched from their inception to March 2016. The studies that focused on TGF-β as a prognostic factor in patients with CRC were included in this analysis. Overall survival (OS) and disease-free survival (DFS) were analysed separately. A meta-analysis was performed, and hazard ratios (HR) with 95% confidence intervals (CI) were calculated.ResultsTwelve studies were included in the analysis, of which 8 were used for OS and 7 for DFS. In all, 1622 patients with CRC undergoing surgery were included. Combined HRs suggested that high expression of TGF-β had a favourable impact on OS (HR = 1.68, 95% CI: 1.10–2.59) and DFS (HR = 1.11, 95% CI: 1.03–1.19) in CRC patients. For OS, the combined HRs of Asian studies and Western studies were 1.50 (95% CI: 0.61–3.68) and 1.80 (95% CI: 1.33–2.45), respectively. For DFS, the combined HRs of Asian studies and Western studies were 1.42 (95% CI: 0.61–3.31) and 1.11 (95% CI: 1.03–1.20), respectively.ConclusionsThis meta-analysis demonstrates that TGF-β can be used as a prognostic biomarker for CRC patients undergoing surgery, especially for CRC patients from Western countries.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3215-7) contains supplementary material, which is available to authorized users.
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