Colorectal carcinoma (CRC) is the third most lethal malignancy in the United States for both women and men, with an overall 5-year survival rate of around 60% . 106,680 cases of colon and 41,930 cases of rectal cancer are expected to occur in 2006. It is estimated that 55,170 deaths from CRC will occur in 2006, accounting for 10% of all cancer deaths . At present, the only curative treatment is surgical resection: however, it is often impossible to remove all cancer cells, especially those that have invaded the surrounding tissues. The penetration of tumor cells into lymphoid vessels and blood vessels leads to tumor metastasis and ultimately the tumor becomes fatal . The current major method for assessing the risk of metastatic recurrence and need for adjuvant chemotherapy is to examine tumor resection specimens for evidence of metastasis to local lymph nodes. However, this approach may be of limited prognostic value as a sizeable fraction of colorectal carcinomas have innate resistance to chemotherapy and 25% to 30% of the patients presenting with lymph-node negative tumors also develop fatal disease . Therefore, there is an urgent need for more accurate and informative methods of individual risk assessment for patients with CRC, some of which might be based on the molecular properties of the primary tumor itself .
Tumor invasion and metastasis are the result of highly coordinated processes that involve multiple intracellular and extracellular factors [6–8]. In part, carcinoma cell migration is enabled by the altered differentiation status of the epithelial cells that includes changes in cell-cell and cell-matrix adhesion properties and in the organization of the actin cytoskeleton [9–12]. With regard to the composition of the cytoskeleton of carcinoma cells, the actin-bundling protein, fascin, has become of great interest due to its functional involvement in cell adhesion and motility [13, 14]. Fascin is expressed in mature dendritic cells, mesenchymal cells, endothelial cells and neurons during development and in the adult [15, 16]. It is absent from most normal epithelia, but is expressed in multiple epithelial neoplasms, including carcinomas of the pancreas, lung, esophagus, stomach and breast [17–24]. Most strikingly, fascin expression has been associated with a poorer prognosis in carcinomas of the lung, esophagus, stomach and breast [19–21, 23]. In node-negative, invasive hereditary breast carcinomas, fascin is frequently expressed by BRCA1-associated tumors . Fascin has also been identified as a component of a gene signature that correlates clinically with breast cancer metastasis to the lung .
In cell culture, expression of recombinant fascin in fascin-negative colonic adenocarcinoma cells correlated with increased proliferation, altered beta1 integrin distribution, increased invasive capacity and altered differentiation status . Similar findings have been obtained in other epithelial cells, suggesting that fascin may contribute to a more aggressive tumor phenotype by facilitating carcinoma cell migration and invasion [20, 27]. However, with regard to colorectal cancer, an initial study of tumor specimens examined only 10 cases without regard to tumor stage or clinical annotation . Thus, the clinical relevance of fascin expression in CRC remains unclear and it is also unknown whether fascin plays any role in the early development of colorectal carcinoma.
Studies of fascin in multiple cell types have established that its actin-binding properties are regulated by extracellular cues acting both through adhesion receptors and receptor tyrosine kinases [14, 16, 28–30]. Furthermore, several studies have indicated that fascin expression may be related to the proliferative status of carcinomas. In mouse xenografts, cells from fascin-positive human ovarian carcinomas were more tumorigenic than fascin-negative lines . Colonic epithelial cells engineered to over-express fascin proliferated faster in culture than control cells . Despite these findings, the relationship between fascin expression and cell proliferation in human cancers is currently unclear. In non-small cell lung carcinoma, highly fascin-positive tumors tended to be highly proliferative, as established by Ki67 antibody staining. However, it was also noted that individual Ki67-positive cells stained less strongly for fascin than surrounding tumor cells . In gastric carcinoma, the reverse trend was observed, with a higher Ki67 index in fascin-positive areas compared to fascin-negative areas .
Here, we have examined the clinicopathological significance of fascin and Ki67, singly and in combination, in a series of colorectal tumor specimens. By examining whole paraffin-embedded sections, we closely reviewed the localization and topographic relationship of fascin and Ki67 in colonic adenomas and colorectal adenocarcinomas. The potential prognostic significance of fascin expression was assessed by using clinically-annotated samples in a CRC tissue microarray of 158 colorectal adenocarcinomas and 15 adenomas. We report that fascin and Ki67 are most frequently inversely correlated at the cellular level. Fascin is upregulated at the adenoma stage and is of potential prognostic significance as a marker of aggressive colorectal adenocarcinomas.