Metastatic colorectal cancer: mechanisms and emerging therapeutics

Shin, Alice E.; Giancotti, Filippo G.; Rustgi, Anil K.

doi:10.1016/j.tips.2023.01.003

Cited by 176 publications

(66 citation statements)

References 97 publications

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“…Identification of the complex mechanism underlying CRC metastasis is crucial for determining strategies to precisely target metastatic CRC. The invasion‐metastasis cascade has been described in CRC 31 . The first and primary step of this cascade in CRC is the detachment of CRC cells from adjacent normal cells through changes in the EMT‐associated proteins 32 .…”

Section: Discussionmentioning

confidence: 99%

Tumour‐associated macrophage‐derived DOCK7‐enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis

Chen,

Zhou,

Guan

et al. 2024

Clinical & Translational Med

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BackgroundMetastasis accounts for the majority of deaths among patients with colorectal cancer (CRC). Here, the regulatory role of tumour‐associated macrophages (TAMs) in CRC metastasis was explored.MethodsImmunohistochemical (IHC) analysis of the TAM biomarker CD163 was conducted to evaluate TAM infiltration in CRC. Transwell assays and an ectopic liver metastasis model were established to evaluate the metastatic ability of tumour cells. RNA sequencing (RNA‐seq) and liquid chromatography‒mass spectrometry (LC‒MS) were applied to identify the differentially expressed genes and proteins in CRC cells and in TAM‐derived extracellular vesicles (EVs). Cholesterol content measurement, a membrane fluidity assay and filipin staining were performed to evaluate cholesterol efflux in CRC cells.ResultsOur results showed that TAM infiltration is positively correlated with CRC metastasis. TAMs can facilitate the migration and invasion of MC‐38 and CT‐26 cells via EVs. According to the RNA‐seq data, TAM‐EVs increase cholesterol efflux and enhance membrane fluidity in CRC cells by regulating ABCA1 expression, thus affecting the motility of CRC cells. Mechanistically, DOCK7 packaged in TAM‐EVs can activate RAC1 in CRC cells and subsequently upregulate ABCA1 expression by phosphorylating AKT and FOXO1. Moreover, IHC analysis of ABCA1 in patients with liver‐metastatic CRC indicated that ABCA1 expression is significantly greater in metastatic liver nodules than in primary CRC tumours.ConclusionsOverall, our findings suggest that DOCK7 delivered via TAM‐EVs could regulate cholesterol metabolism in CRC cells and CRC cell metastasis through the RAC1/AKT/FOXO1/ABCA1 axis. DOCK7 could thus be a new therapeutic target for controlling CRC metastasis.

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Section: Discussionmentioning

confidence: 99%

Tumour‐associated macrophage‐derived DOCK7‐enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis

Chen,

Zhou,

Guan

et al. 2024

Clinical & Translational Med

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“…The process of tumor development is very complex. Therefore, targeted therapy for different types of gene mutations and the exploration of new drug molecular targets are important means to optimize cancer precision medicine [28]. Despite the fact that a few drugs are under clinical trials, effective therapies against Wnt are largely lacking [6].…”

Section: Discussionmentioning

confidence: 99%

The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/β‐catenin signaling in cancer

Wang,

Liu,

Zheng

et al. 2023

FEBS Letters

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The liver kinase B1 (LKB1)/AMP‐activated protein kinase (AMPK) axis pivotally controls cell metabolism and suppresses abnormal growth in various cancers. Wnt/β‐catenin is a frequently dysregulated signaling pathway that drives oncogenesis. Here, we discovered a crosstalk mechanism between the LKB1/AMPK axis and Wnt/β‐catenin signaling. Activated AMPK phosphorylates the deubiquitinase USP10 to potentiate the deubiquitination and stabilization of the key scaffold protein Axin1. This phosphorylation also strengthens the binding between USP10 and β‐catenin and supports the phase transition of β‐catenin. Both processes suppress Wnt/β‐catenin amplitude in parallel and inhibit colorectal cancer growth in a clinically relevant manner. Collectively, we established a crosstalk route by which LKB1/AMPK regulates Wnt/β‐catenin signaling in cancer. USP10 acts as the hub in this process, thus enabling LKB1/AMPK to suppress tumor growth via regulation of both metabolism and cell proliferation.

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“…EGF and other EGFR ligands compete with Cetuximab, a murine‐human chimeric monoclonal antibody, for the receptor's binding ability. Because of the potential for immunogenic reactions from completely humanized or chimeric murine‐human antibodies, the CRYSTAL trial demonstrated that Cetuximab reduced the risk of progression when added to chemotherapy 43,44 …”

Section: Tissue‐based Biomarkersmentioning

confidence: 99%

“…Because of the potential for immunogenic reactions from completely humanized or chimeric murine-human antibodies, the CRYSTAL trial demonstrated that Cetuximab reduced the risk of progression when added to chemotherapy. 43,44 Multiple studies found that Panitumumab's tolerance and effectiveness, particularly on the left, were similar to cetuximab dot's. EGFR expression is usually more abundant in malignancies than in cancers on the right side.…”

Section: Egfrmentioning

confidence: 99%

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance

Kusumaningrum,

Makaba,

Ali

et al. 2024

Cell Biochemistry & Function

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The majority of cancer cases are colorectal cancer, which is also the second largest cause of cancer‐related deaths worldwide. Metastasis is the leading cause of death for patients with colorectal cancer. Metastatic colorectal cancer incidence are on the rise due to a tiny percentage of tumors developing resistant to medicines despite advances in treatment tactics. Cutting‐edge targeted medications are now the go‐to option for customized and all‐encompassing CRC care. Specifically, multitarget kinase inhibitors, antivascular endothelial growth factors, and epidermal growth factor receptors are widely used in clinical practice for CRC‐targeted treatments. Rare targets in metastatic colorectal cancer are becoming more well‐known due to developments in precision diagnostics and the extensive use of second‐generation sequencing technology. These targets include the KRAS mutation, the BRAF V600E mutation, the HER2 overexpression/amplification, and the MSI‐H/dMMR. Incorporating certain medications into clinical trials has significantly increased patient survival rates, opening new avenues and bringing fresh viewpoints for treating metastatic colorectal cancer. These focused therapies change how cancer is treated, giving patients new hope and better results. These markers can significantly transform and individualize therapy regimens. They could open the door to precisely customized and more effective medicines, improving patient outcomes and quality of life. The fast‐growing body of knowledge regarding the molecular biology of colorectal cancer and the latest developments in gene sequencing and molecular diagnostics are directly responsible for this advancement.

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Metastatic colorectal cancer: mechanisms and emerging therapeutics

Cited by 176 publications

References 97 publications

Tumour‐associated macrophage‐derived DOCK7‐enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis

Tumour‐associated macrophage‐derived DOCK7‐enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis

The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/β‐catenin signaling in cancer

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance

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