Epithelial–mesenchymal transition and metastasis of colon cancer cells induced by the FAK pathway in cancer-associated fibroblasts

Xuefeng, Xuefeng; Hou, Mingxing; Yang, Zhiwen; Agudamu, Agudamu; Wang, Feng; Su, Xiulan; Li, Xian; Shi, Lin; Terigele, Terigele; Bao, Lili; Wu, Xiaohong

doi:10.1177/0300060520931242

Cited by 20 publications

(14 citation statements)

References 46 publications

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“…Moreover, studies have shown that CAFs secrete the fibroblast growth factor 1 (FGF1) to increase CRC cell invasion via FGFR3 signaling (Henriksson et al, 2011), as well as the stromal cell-derived factor-1 (SDF-1) to promote CRC metastasis to distant organs via the C-X-C chemokine receptor type 4 (CXCR4) axis (Peng et al, 2018). Combining another research which shows that by secreting the LOXL2, CAFs stimulate the focal adhesion kinase (FAK) pathway and consequently induce the EMT and metastasis of CRC cells (Xuefeng et al, 2020), those research progresses characterize these signaling as vital mediators in transducing CAFs' notorious effects on malignant behaviors of CRC. Other CAF-secreted factors that have recently been shown to promote the EMT, migration and invasion of CRC include the CLEC3B (Zhu et al, 2019), activin A (Bauer et al, 2020), and Wnt2 (Aizawa et al, 2019).…”

Section: Epithelial-to-mesenchymal Transition Migration Invasion and Metastasismentioning

confidence: 99%

The Versatile Roles of Cancer-Associated Fibroblasts in Colorectal Cancer and Therapeutic Implications

Deng

Jiang

Zeng

et al. 2021

Front. Cell Dev. Biol.

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The tumor microenvironment (TME) is populated by abundant cancer-associated fibroblasts (CAFs) that radically influence the disease progression across many cancers, including the colorectal cancer (CRC). In theory, targeting CAFs holds great potential in optimizing CRC treatment. However, attempts to translate the therapeutic benefit of CAFs into clinic practice face many obstacles, largely due to our limited understanding of the heterogeneity in their origins, functions, and mechanisms. In recent years, accumulating evidence has uncovered some cellular precursors and molecular markers of CAFs and also revealed their versatility in impacting various hallmarks of CRC, together helping us to better define the population of CAFs and also paving the way toward their future therapeutic targeting for CRC treatment. In this review, we outline the emerging concept of CAFs in CRC, with an emphasis on their origins, biomarkers, prognostic significance, as well as their functional roles and underlying mechanisms in CRC biology. At last, we discuss the prospect of harnessing CAFs as promising therapeutic targets for the treatment of patients with CRC.

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Section: Epithelial-to-mesenchymal Transition Migration Invasion and Metastasismentioning

confidence: 99%

The Versatile Roles of Cancer-Associated Fibroblasts in Colorectal Cancer and Therapeutic Implications

Deng

Jiang

Zeng

et al. 2021

Front. Cell Dev. Biol.

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“…TM has been demonstrated to inhibit angiogenesis in tumours by targeting multiple pathways including the suppression of NF-κB, HIF1α, LOX and SOD1 activities (Brewer, 2003). More recently, it has been shown that TM can inhibit MEK1/2 kinase activity by reducing the levels of intracellular Cu, and eventually suppressing BRAF-driven tumorigenesis in melanoma, thyroid and colon cancers (Kim et al, 2020;Xuefeng et al, 2020). TM can also enhance the cytotoxicity of BRAF-specific inhibitors like sorafenib.…”

Section: Copper Chelators and Ionophores In Cancermentioning

confidence: 99%

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Kannappan

Ali

Small

et al. 2021

Front. Mol. Biosci.

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Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.

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“…FAK is required for the activation of the Wnt/β-catenin pathway through phosphorylation of GSK3β Y216 , which is crucial for intestinal tumorigenesis [ 43 ]. In Xue’s study, LOXL2 secreted by CAFs activated the FAK signaling pathway and then induced EMT in human colon cancer LOVO cells, thereby promoting the invasion and metastasis of colon cancer ( 44 ). By seeding OSCC cells on the collagen with different stiffness, we found that collagen with a stiffer surface mediated by CAFs-derived LOX can trigger the EMT process, which was consistent with cell morphological changes.…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated fibroblasts promote oral squamous cell carcinoma progression through LOX-mediated matrix stiffness

et al. 2021

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Background Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, have prominent roles in the development of solid tumors as stromal targets. However, the underlying mechanism of CAFs’ function in oral squamous cell carcinoma (OSCC) development remains unclear. Here, we investigated the role of lysyl oxidase (LOX) expression in CAFs in tumor stromal remodeling and the mechanism of its effect on OSCC progression. Methods Multiple immunohistochemistry (IHC) staining was performed to detect the correlation of CAFs and LOX in the stroma of OSCC specimens, as well as the correlation with clinicopathological parameters and prognosis. The expression of LOX in CAFs were detected by RT-qPCR and western blot. The effects of LOX in CAFs on the biological characteristics of OSCC cell line were investigated using CCK-8, wound-healing and transwell assay. CAFs were co-cultured with type I collagen in vitro, and collagen contraction test, microstructure observation and rheometer were used to detect the effect of CAFs on remodeling collagen matrix. Then, collagen with different stiffness were established to investigate the effect of matrix stiffness on the progression of OSCC. Moreover, we used focal adhesion kinase (FAK) phosphorylation inhibitors to explored whether the increase in matrix stiffness promote the progression of OSCC through activating FAK phosphorylation pathway. Results LOX was colocalized with CAFs in the stroma of OSCC tissues, and its expression was significantly related to the degree of malignant differentiation and poor prognosis in OSCC. LOX was highly expressed in CAFs, and its knockdown impaired the proliferation, migration, invasion and EMT process of OSCC cells. The expression of LOX in CAFs can catalyze collagen crosslinking and increase matrix stiffness. Furthermore, CAFs-derived LOX-mediated increase in collagen stiffness induced morphological changes and promoted invasion and EMT process in OSCC cells by activating FAK phosphorylation pathway. Conclusions Our findings suggest that CAFs highly express LOX in the stroma of OSCC and can remodel the matrix collagen microenvironment, and the increase in matrix stiffness mediated by CAFs-derived LOX promotes OSCC development through FAK phosphorylation pathway. Thus, LOX may be a potential target for the early diagnosis and therapeutic treatment of OSCC.

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Epithelial–mesenchymal transition and metastasis of colon cancer cells induced by the FAK pathway in cancer-associated fibroblasts

Cited by 20 publications

References 46 publications

The Versatile Roles of Cancer-Associated Fibroblasts in Colorectal Cancer and Therapeutic Implications

The Versatile Roles of Cancer-Associated Fibroblasts in Colorectal Cancer and Therapeutic Implications

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Cancer-associated fibroblasts promote oral squamous cell carcinoma progression through LOX-mediated matrix stiffness

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