Which patients are prone to suffer liver metastasis? A review of risk factors of metachronous liver metastasis of colorectal cancer

Hao, Mengdi; Wang, Kun; Ding, Yuhan; Li, Huimin; Liu, Yin; Ding, Lei

doi:10.1186/s40001-022-00759-z

Cited by 11 publications

(7 citation statements)

References 149 publications

(168 reference statements)

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“…If the risk of MLM can be predicted, early intervention may significantly improve patient prognosis. However, there is still no effective method for alerting MLM patients, and MLM patients still use the same treatment as PC patients before occurrence (63)(64)(65). Our study is the first to offer a novel approach for pre-warning of the occurrence of MLM based on 5hmC features derived from portal venous blood.…”

Section: Discussionmentioning

confidence: 97%

5-hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target

Lin

Xu²,

Gao

et al. 2023

Preprint

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Metachronous liver metastases (MLM) are characterized by high incidence and high mortality in clinical colorectal cancer treatment. Currently traditional clinical methods cannot effectively predict and prevent the occurrence of metachronous liver metastasis in colorectal cancer. Based on 5hmC-Seal analysis of blood and tissue samples, this study found that portal venous blood was more relevant to tumor gDNA than peripheral blood. We performed a novel epigenetic liquid biopsy strategy using the 10 5hmC epigenetic alterations, to accurately distinguish MLM patients from patients without metastases. Among these epigenetic alterations, phosphodiesterase 4 (PDE4D) was highly increased in MLM patients and correlated with poor survival. Moreover, our studies demonstrated that PDE4D was a key metastasis-driven target for drug development. Interfering with the function of PDE4D significantly repressed liver metastases. Similarly, roflumilast, a PDE4 inhibitor approved for Chronic obstructive pulmonary disease (COPD) also inhibits liver metastases. Roflumilast treatment significantly inhibited the protein levels of HIF-1α, CCN2, p-AKT and p-ERK, thus suppressing metastases. To develop a more efficient PDE4D inhibitor and reduce the occurrence of adverse events, we also designed several new compounds based on 2-arylbenzofurans and discovered lead L11 with potent affinity for PDE4D and significant suppression of liver metastases. Interestingly, we further found that compound L11 was better tolerated in terms of emetic activity on beagle dogs than roflumilast. Summarily, our study provides a promising strategy for predicting metachronous liver metastasis and discovers roflumilast as a potential repurposed drug for inhibiting liver metastasis, which have the potential to benefit patients with CRC in the future.

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Section: Discussionmentioning

confidence: 97%

5-hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target

Lin

Xu²,

Gao

et al. 2023

Preprint

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“…The five-year survival rate of patients with CRC in stages CRC I and II reaches 90%, while in advanced stages decreases to 14% (23). For newly diagnosed CRC patients, clarifying potential risk factors for prognosis and prediction of therapy response is paramount as it could have important clinical implications (24).…”

Section: Muc13-mirna-4647 Axis In Colorectal Cancer: Prospects To Ide...mentioning

confidence: 99%

MUC13‑miRNA‑4647 axis in colorectal cancer: Prospects to identifications of risk factors and clinical outcomes

et al. 2022

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MUC13, a transmembrane mucin glycoprotein, is overexpressed in colorectal cancer (CRC), however, its regulation and functions are not fully understood. It has been shown that MUC13 protects colonic epithelial cells from apoptosis. Therefore, studying MUC13 and MUC13-regulated pathways may reveal promising therapeutic approaches for CRC treatment. Growing evidence suggests that microRNAs (miRs) are involved in the development and progression of CRC. In the present study, the MUC13-miR-4647 axis was addressed in association with survival of patients. miR-4647 is predicted in silico to bind to the MUC13 gene and was analyzed by RT-qPCR in 187 tumors and their adjacent non-malignant mucosa of patients with CRC. The impact of previously mentioned genes on survival and migration abilities of cancer cells was validated in vitro. Significantly upregulated MUC13 (P=0.02) in was observed tumor tissues compared with non-malignant adjacent mucosa, while miR-4647 (P=0.05) showed an opposite trend. Higher expression levels of MUC13 (log-rank P=0.05) were associated with worse patient's survival. The ectopic overexpression of studied miR resulted in decreased migratory abilities and worse survival of cells. Attenuated MUC13 expression levels confirmed the suppression of colony forming of CRC cells. In summary, the present data suggested the essential role of MUC13-miR-4647 in patients' survival, and this axis may serve as a novel therapeutic target. It is anticipated MUC13 may hold significant potential in the screening, diagnosis and treatment of CRC.

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“…The presence of metastases significantly shortens median survival time (MST), despite the use of aggressive therapeutic methods. Tumor metastasis is therefore a significant challenge in both biological and clinical research [ 3 ]. One of the therapeutic methods is limiting the mobility of tumor cells and, thus, reducing the possibility of cell migration, both in the tissue and to distant organs [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Cellular Localization of Selected Porphyrins and Their Effect on the In Vitro Motility of Human Colon Tumors and Normal Cells

et al. 2023

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Standard therapies for colorectal cancer cannot eliminate or sufficiently reduce the metastasis process. Photodynamic therapy (PDT) may be an alternative to minimizing this problem. Here, we examined the cellular localization of selected porphyrins and determined whether free-base and manganese (III) metallated porphyrins may limit colon cancer cells’ (HT29) or normal colon epithelial cells’ (CCD 841 CoTr) motility in vitro. White light irradiation was used to initiate the photodynamic effect. Porphyrin uptake by the cells was determined by porphyrin fluorescence measurements through the use of confocal microscopy. Free-base porphyrin was found in cells, where it initially localized at the edge of the cytoplasm and later in the perinuclear area. The concentrations of porphyrins had no effect on cancer cell migration but had a significant effect on normal cell motility. Due to the low concentrations of porphyrins used, no changes in F-actin filaments of the cellular cytoskeleton were detected. Signal transmission via connexons between neighbouring cells was limited to a maximum of 40 µm for HT29 and 30 µm for CCD 841 CoTr cells. The tested porphyrins differed in their activity against the tumor and normal cells’ migration capacity. Depending on the porphyrin used and the type of cells, their migration changed in relation to the control sample. The use of white light may change the activity of the porphyrins relative to the migratory capacity of the cells. The aim of the present study was to analyse the intracellular localization of tested porphyrins and their influence on the mobility of cells after irradiation with harmless white light.

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Which patients are prone to suffer liver metastasis? A review of risk factors of metachronous liver metastasis of colorectal cancer

Cited by 11 publications

References 149 publications

5-hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target

5-hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target

MUC13‑miRNA‑4647 axis in colorectal cancer: Prospects to identifications of risk factors and clinical outcomes

Cellular Localization of Selected Porphyrins and Their Effect on the In Vitro Motility of Human Colon Tumors and Normal Cells

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