Immunohistochemical Validation of a Novel Epithelial and a Novel Stromal Marker of Pancreatic Ductal Adenocarcinoma Identified by Global Expression Microarrays

Abstract

We extended the results of a previous microarray analysis by immunohistochemical validation of differential protein expression in a series of 57 surgically resected infiltrating ductal pancreatic adenocarcinomas. Two representative genes were examined: sea urchin fascin homolog (overexpressed in both cell lines and primary tumors) and heat shock protein 47 (HSP47; overexpressed in primary tumors only). Protein expression also was evaluated in the precursor lesions of pancreatic cancer pancreatic intraepithelial neoplasia (PanIN), and normal ductal epithelium. Fascin expression was seen in the neoplastic cells of 54 (95%) of 57 ductal adenocarcinomas but not in 49 (94%) of 52 adjacent nonneoplastic epithelium. In the multistep pathogenesis of ductal adenocarcinomas, fascin expression seemed to be a late event, usually present in PanINs 2 and 3. HSP47 expression was almost universal and most intense in the ductal adenocarcinoma-associated stromal desmoplasia (57/57), although 37 cases (65%) also expressed HSP47 in the neoplastic epithelium. HSP47 expression was absent in the majority of nonneoplastic pancreata (46 [88%]). Fascin and HSP47 are novel tumor markers with potential diagnostic and therapeutic implications for pancreatic carcinoma. These results establish the usefulness of global expression platforms to identify novel tumor markers.

Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization

“…Moreover, it has been suggested that upregulation of fascin is part of the programme of epithelial-to-mesenchymal transition that confers motility and invasion properties on tumour cells 29 . Therefore, fascin has been suggested as a therapeutic target for blocking tumour cell migration, invasion and metastasis 31,32,[35][36][37][38][39][40][41][42][43] .…”

Independent prognostic value of fascin immunoreactivity in stage III–IV colonic adenocarcinoma

“…Moreover, the protein promotes cell locomotion (Yamashiro et al, 1998) and participates in the mechanical organisation of stress fibres (Adams, 1997). A definite overexpression of fascin has been reported in carcinomas of different organs, including oesophagus (Hashimoto et al, 2005a;Xie et al, 2005;Zhang et al, 2006), stomach (Hashimoto et al, 2004), colon (Jawhari et al, 2003;Hashimoto et al, 2006), pancreas (Maitra et al, 2002), breast (Grothey et al, 2000;Yoder et al, 2005), skin (Goncharuk et al, 2002), lung (Pelosi et al, 2003a, b;Choi et al, 2006), urinary bladder (Tong et al, 2005), and ovary (Hu et al, 2000) and the protein has been recently proposed as a novel biomarker for aggressive tumour behaviour (Hashimoto et al, 2005b(Hashimoto et al, , 2006Zhang et al, 2006). In colonic adenocarcinoma cell lines, fascin overexpression correlates with an increase in the formation of dynamic cell protrusions, proliferation, and invasiveness (Jawhari et al, 2003).…”

Fascin overexpression in intraductal papillary mucinous neoplasms (adenomas, borderline neoplasms, and carcinomas) of the pancreas, correlated with increased histological grade

“…It is required for the formation of actin-based cell-surface protrusions that are essential for cellular migration and cellmatrix adhesion. [15][16][17] In normal epithelial cells, fascin expression is usually absent or very low, but it is significantly upregulated in transformed epithelial cells and several types of human carcinoma such as lung, 18,19 breast, [20][21][22][23] esophagus, 24,25 stomach, 26 colon, 27 pancreas, [28][29][30][31] biliary tract and ampulla, 31,32 ovary, 33 urinary bladder, 34 and skin. 35 Among the above neoplasms, fascin upregulation is most frequently observed in pancreatic infiltrating adenocarcinoma.…”

“…35 Among the above neoplasms, fascin upregulation is most frequently observed in pancreatic infiltrating adenocarcinoma. 28,30,31 It is interesting that PanIN shows fascin expression despite being an intraepithelial neoplasia. 29,30 In general, in tumors of other organs, expression of fascin is especially strong in areas of infiltration, or is limited to such areas.…”

“…28,30,31 It is interesting that PanIN shows fascin expression despite being an intraepithelial neoplasia. 29,30 In general, in tumors of other organs, expression of fascin is especially strong in areas of infiltration, or is limited to such areas. Fascin expression in IPMN and its relationship with the clinicopathological features remain unclear, though IPMN has much in common with PanIN.…”