The present study demonstrated that fascin-1 expression correlates with aggressive clinical features, poor 3-year-PFS, and 5-year OS regardless of TNM stage, tumor grade, vascular and perineural invasion. Moreover, patients with early-stage CRC encountered poor 5-year OS when fascin-1 displayed moderate to high expression.
Similar results have been supported previously in the literature. A meta-analysis 19 of solid tumors about fascin expression demonstrated an increased risk of mortality in breast, colorectal, and esophageal cancer. More specifically for CRC patients, two studies 20–21 in this meta-analysis 19 referring to advanced disease investigated the correlation between fascin expression and time-to disease progression with a total of 354 CRC patients. The pooled random effects hazard ratio was estimated at 2.12 (p = 0.05) for mortality, recurrence, or metastasis. However, a moderate to substantial heterogeneity existed among these two cohort studies (I2 = 73%, p = 0.06). A strong correlation 19 of fascin expression with lymph node (RR estimate of 1.47, p < 0.001 for N = 833 patients) and distant metastasis (RR estimate of 1.70, p = 0.004 for N = 684 patients) was, also, revealed. Interesting to note is the arguable smaller range of heterogeneity (I2 = 6.4%, p = 0.38 and I2 = 0%, p = 0.83 respectively) among the included studies of the meta-analysis. Chan et al. 22 suggested that there was a stronger correlation with poor overall survival when fascin expression exists in the central region of the tumor rather than the invasive front. Finally, Hashimoto et al. 23 demonstrated the presence of correlation among fascin and Ki-67 in adenomas of the colon, suggesting, therefore, a potential role of fascin in the neoplastic transformation from a low-grade dysplastic lesion to frankly invasive cancer. In our study, fascin-1 expression was significantly higher as the anatomic disease extent progressed.
Although fascin seems to be associated with aggressive clinical features in CRC, the exact mechanisms that mediate fascin dependent cell invasion remain unclear. Studies investigating the role of fascin have established that extracellular signaling pathways regulate its acting-binding properties by acting both through adhesion receptors and receptor tyrosine kinases24. Besides, in mouse xenografts, cells from human ovarian cancer cells displaying fascin expression were more tumorigenic, indicating an association of fascin with the proliferative status of the cancer 25. Jayo and colleagues 26 suggested a role for fascin as a mechano-transducer of cytoplasmic forces that couples F-actin to the nuclear envelope protein nesprin-2. More specifically, this "coupling" regulates nuclear localization and deformation, which contribute to the migration of cells in confined spaces suggesting, therefore, a fascin-mediated structural remodeling of the cytoskeleton. The latter is further enhanced as Jawhari et al. 27 enhance the latter by presenting that fascin positive epithelial cells promote local motility and invasion by altering the organization of actin-based protrusions and focal cell-matrix adhesions.
In the present study, fascin-1 expression was associated with lymph node and distant metastasis and with high-grade tumors. Previous reports demonstrated that high fascin expression correlates with low E-cadherin expression, suggesting, therefore, that as cells progress through the epithelial to mesenchymal transition (EMT), they gain fascin while losing E-cadherin 28–29. In addition, the wnt activated LEF-TCF transcriptional signaling pathway constitutes a significant promoter of the EMT pathway and regulates fascin expression 30. Machesky et al. 14 assumed that when fascin upregulation occurs as part of the EMT pathway, it confers special motility and invasion properties on cancer cells. Furthermore, fascin, via actin stabilization, provides cells powerful invasive properties which enhance their capability to promote metastasis. A stem-cell-like state could potentially explain the aggressive clinical profile of the fascin-1 positive patients. Subsequently, fascin-1 positive cancer cells appear to acquire properties of progenitor cells in colorectal cancer.
Disease recurrence and metastasis are the primary cause of cancer-associated morbidity and mortality. Approximately by 10% of the patients with stage I and 20% of the patients with stage II colon colonic cancer occurs disease recurrence 31. The effectiveness of adjuvant chemotherapy by balancing toxicity profiles simultaneously for patients with stage II colonic cancer remains controversial as it has been demonstrated to provide minimal survival benefit and is often considered not to be worth of the toxicity of the drugs 32. Furthermore, previous studies that aimed to identify the subgroup of patients with stage II cancer that are at increased risk of recurrence are not vigorous enough 33 to warrant a clear indication of chemotherapy. In the present study, patients exhibiting high fascin-1 expression displayed a poor overall survival even in early-stage cancer. A stem-cell-like phenotype of fascin-1 positive cancer cells could potentially explain the poor overall survival even in early-stage CRC.
There are limitations to the present study. The retrospective nature of the study requires prospective confirmation with a specific protocol of interventions. In addition, immunohistochemical analysis might underestimate the presence of heterogeneity of fascin expression within the tumor. Nevertheless, our findings do represent a solid basis for the formulation of sound working hypotheses, capitalizing on reliable clinical data.