Emerging Role of Fascin-1 in the Pathogenesis, Diagnosis, and Treatment of the Gastrointestinal Cancers

Abstract

Gastrointestinal (GI) cancers, including esophageal, gastric, colorectal, liver, and pancreatic cancers, remain as one of the leading causes of death worldwide, with a large proportion accounting for fatalities related to metastatic disease. Invasion of primary cancer occurs by the actin cytoskeleton remodeling, including the formation of the filopodia, stereocilia, and other finger-like membrane protrusions. The crucial step of actin remodeling in the malignant cells is mediated by the fascin protein family, with fascin-1 being the most active. Fascin-1 is an actin-binding protein that cross-links filamentous actin into tightly packed parallel bundles, giving rise to finger-like cell protrusions, thus equipping the cell with the machinery necessary for adhesion, motility, and invasion. Thus, fascin-1 has been noted to be a key component for determining patient diagnosis and treatment plan. Indeed, the overexpression of fascin-1 in GI tract cancers has been associated with a poor clinical prognosis and metastatic progression. Moreover, fascin-1 has received attention as a potential therapeutic target for metastatic GI tract cancers. In this review, we provide an up-to-date literature review of the role of fascin-1 in the initiation of GI tract cancers, metastatic progression, and patients’ clinical outcomes.

In colon cancer cells, fascin1 functions as a mechanosensor that transforms adherens junction mechanotransduction

“…Even though fascin1 has been identified as a driver and prognostic marker of metastatic CRCs a systematic characterization of fascin1 function in the etiology of CRCs is lacking. (Ristic et al, 2021) Fascin1 expression is very significantly upregulated in SSLs and fascin1 has been identified as a potential biomarker of SSLs. (Ashktorab et al, 2019;Kanth et al, 2019;Kanth et al, 2016) Herr et al, 2015) Here we show that in BRAF V600E CRC cells, AJ and TJ remodeling is phenocopied by fascin1 upregulation and we identify fascin1 as a major driver of this BRAF V600E -mutant CRC phenotype.…”

“…(Li et al, 2014) In multivariate analysis, fascin1 has been identified as an independent factor for CRCs, and fascin1 positive CRCs exhibit a greater ability to invade lymph nodes and develop extra-nodal tumor extensions, and have a higher likelihood of recurrence with a lower rate of disease-free and overall survival. (Hashimoto et al, 2006;Ristic et al, 2021;Tampakis et al, 2021) It is generally assumed that fascin1 drives tumor cell migration and invasion by assembling filopodia and invadopodia. However, there is emerging evidence that fascin1 also has cell migration-independent functions linked to tumor cell proliferation, oncogenesis, metastatic colonization, anoikis resistance, chemoresistance, and cancer stemness although the molecular mechanism underlying these non-canonical functions of fascin1 remain unclear.…”

“…(Hashimoto et al, 2006; Shi et al, 2020; Tan et al, 2013; Vignjevic et al, 2007) Moreover, in multivariate analysis, fascin1 has been identified as an independent factor for CRCs, and fascin1 positive CRCs exhibit a greater ability to invade lymph nodes, to develop extra-nodal tumor extensions, and have a higher likelihood of recurrence with a lower rate of disease-free and overall survival. (Hashimoto et al ., 2006; Ristic et al, 2021; Tampakis et al, 2021) It is assumed that fascin1 drives colorectal tumor cell migration and invasion by assembling filopodia and invadopodia. (Lin et al, 2021; Liu et al, 2021) However, fascin1’s function in CRCs has not been directly investigated.…”

“…There is emerging evidence from other cancer cells that fascin1 also has cell migration-independent functions linked to tumor cell proliferation, oncogenesis, metastatic colonization, anoikis resistance, chemoresistance, and cancer stemness although the molecular mechanism underlying these non-canonical functions of fascin1 remain unclear. (Barnawi et al, 2016; Li et al, 2014; Ristic et al ., 2021) Consequently, the mechanism by which fascin1 promotes metastatic CRCs also remains unknown. The functional characterization of fascin1 could shed light on the biology driving metastatic CRCs.…”

Epithelial Mesenchymal Transition (EMT) and Associated Invasive Adhesions in Solid and Haematological Tumours

“…Formation of filopodia [ 70 , 71 ] downstream of activation of TWIST1 and SNAIL1 [ 72 ] and the expression of formins [ 73 , 74 ] regulate the migration of cancer cells undergoing EMT. Additionally, the upregulation of formins contributes to metastasis formation [ 75 ], and high levels of fascin correlate with poor prognosis in a number of cancers including breast, lung, gastrointestinal and oral squamous cell carcinoma [ 64 , 76 , 77 ], suggesting that their role in EMT contributes to cell invasion and the formation of secondary tumour foci. Increased expression of fascin is also associated with the development of EMT-mediated drug resistance in hepatocellular carcinoma [ 78 ].…”