Association of fascin-1 with mortality, disease progression and metastasis in carcinomas: a systematic review and meta-analysis

Abstract

BackgroundFascin-1 is an actin-bundling protein expressed in many human carcinomas, although absent from most normal epithelia. Fascin-1 promotes filopodia formation, migration and invasion in carcinoma cells; in mouse xenograft tumor models it contributes to metastasis. Fascin-1 is an interesting candidate biomarker for aggressive, metastatic carcinomas but data from individual studies of human tumors have not yet been pooled systematically.MethodsThis systematic review was conducted in accordance with PRISMA guidelines, using fixed and random effects models, as appropriate, to undertake meta-analysis.ResultsA total of 26 immunohistochemical studies of 5 prevalent human carcinomas were identified for meta-analysis. Fascin-1 was associated with increased risk of mortality for breast (pooled hazard ratio, (HR) = 2.58; 95% confidence interval (CI) 1.48 to 4.52; P = 0.001), colorectal (HR = 1.60 (1.37 to 1.86; P <0.001) and esophageal carcinomas (HR = 1.35; CI 1.13 to 1.60; P = 0.001). There was no evidence of association of fascin-1 with mortality in gastric and lung carcinomas. Fascin-1 was associated with increased risk of disease progression in breast (HR = 2.48; CI 1.38 to 4.46; P = 0.002) and colorectal carcinomas (HR = 2.12; CI 1.00 to 4.47; P = 0.05), but not with progression of lung carcinomas (HR = 0.95; CI 0.49 to 1.85; P = 0.9). Fascin-1 was associated with increased risk of lymph node metastasis in colorectal (pooled risk ratio (RR) = 1.47; CI 1.26 to 1.71; P <0.001) and gastric carcinomas (RR = 1.43; CI 1.21 to 1.70; P <0.001). There was no evidence of association of fascin-1 with lymph node metastasis in lung or esophageal carcinomas. Fascin-1 was associated with increased risk of distant metastasis in colorectal (RR = 1.70; CI 1.18 to 2.45; P = 0.004) and gastric carcinomas (RR = 1.93; CI 1.21 to 3.33; P = 0.02). No association with distant metastasis in esophageal carcinomas was observed. Pooling across all the carcinomas provided strong evidence for association of fascin-1 with increased risk of mortality (HR = 1.44; CI 1.24 to 1.68; P <0.001; n = 3,645), lymph node metastasis (RR = 1.36; CI 1.18 to 1.55; P <0.001; n = 2,906) and distant metastasis (1.76; 1.34 to 2.32; P <0.001; n = 1,514).ConclusionsFascin-1 is associated consistently with increased risk of mortality in breast, colorectal and esophageal carcinomas and with metastasis in colorectal and gastric carcinomas. The results were stable to various sensitivity analyses and did not vary by predefined subgroups. These data will assist rational decision making for focusing investigations of fascin-1 as a biomarker or therapeutic target onto the most relevant carcinomas.

Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization

“…Elevated fascin expression is associated with increased risk of metastasis and mortality from patient studies, and increased numbers of filopodia are correlated to increased invasiveness, aggressivity and decreased survival rate 17,18,30 . To develop therapeutics for metastatic cancer treatment, we developed an HTS method, screened chemical libraries and identified smallmolecule compounds that specifically inhibit the actin-bundling function of fascin.…”

“…A recent systematic review and meta-analysis of 26 immunohistochemical studies (total B9,000 patients) of the five prevalent human carcinomas (breast, colorectal, gastric, lung and oesophageal carcinomas) revealed that, in breast, colorectal and oesophageal carcinomas, high levels of fascin are associated with increased risk of mortality and disease progression 30 . Pooled analysis of all carcinomas indicate that high levels of fascin are associated with increased risk of mortality, lymph node metastasis and distant metastasis, and may provide a novel biomarker for early diagnosis of aggressive and metastatic tumours 30 .…”

“…Pooled analysis of all carcinomas indicate that high levels of fascin are associated with increased risk of mortality, lymph node metastasis and distant metastasis, and may provide a novel biomarker for early diagnosis of aggressive and metastatic tumours 30 . Furthermore, another systematic review and meta-analysis of resected cholangiocarcinoma from 73 immunohistochemical studies (total 4,126 patients) uncovered several biomarkers prognostic of overall survival consisting of fascin, EGFR, MUC1, MUC4 and p27 (ref.…”

“…Fascin holds 10-30 parallel actin filaments together to form filopodia 60-200 nm in diameter 13 . Elevated levels of fascin have been found in many types of metastatic tumours and are correlated with clinically aggressive phenotypes, poor prognosis and shorter survival [28][29][30] . Human fascin expression is low or absent in normal adult epithelial cells, but highly expressed in embryonic stages 31,32 .…”

Fascin expression predicts an aggressive clinical course in patients with advanced breast cancer

“…The additional forms of fascin, fascin-2 and -3, are expressed in retinal photoreceptor cells and the testes, respectively (16). Published data has demonstrated that fascin is upregulated or highly expressed in the human cancer of various organs, including the oesophagus (17), breast (18), colon (19), lung (20), stomach (21) and urinary bladder (22), as well as in individual tissues, and that the expression of fascin is associated with aggressive behaviour (23). Previous studies of breast cancer have identified that fascin overexpression is associated with factors representing aggressive tumor behaviour, for example hormonal receptor negativity, a triple-negative subtype and/or a basal-like phenotype (24)(25)(26).…”