Characterization of Keratinocyte Growth Factor and Receptor Expression in Human Pancreatic Cancer

Abstract

Keratinocyte growth factor (KGF) is an angiogenic and mitogenic polypeptide that has been implicated in cancer growth and tissue development and repair. Its actions are dependent on its binding to a specific cell-surface KGF receptor (KGFR) , which is encoded by the fibroblast growth factor (FGF) receptor type II (FGFR-2) gene. In the present study , we compared the immunohistochemical localization of KGF and KGFR/ FGFR-2 in the normal and cancerous pancreas using specific antibodies that recognize KGF and KGFR/ FGFR-2 and examined the expression of KGF , KGFR, and FGFR-2 in human pancreatic cancer by in situ hybridization with the corresponding riboprobes. In the normal pancreas , KGF immunoreactivity was present principally in the islet cells , whereas KGFR/ FGFR-2 immunoreactivity was present both in the islet and ductal cells. In the pancreatic cancers , moderate KGF and moderate to strong KGFR/FGFR-2 immunoreactivity was present in many of the cancer cells. Furthermore , the ductal and acinar cells adjacent to the cancer cells exhibited moderate to strong KGF and KGFR/FGFR-2 immunoreactivity. By in situ hybridization , KGF , KGFR , and FGFR-2 were overexpressed and co-localized in the cancer cells within the pancreatic tumor mass but were even more abundant in the acinar and ductal cells adjacent to the cancer cells. These findings indicate that KGF , KGFR, and FGFR-2 are overexpressed in both the cancer cells and the adjacent pancreatic parenchyma and raise the possibility that KGF may act in an autocrine and paracrine manner to enhance pancreatic cancer cell growth in vivo. (Am J Pathol 1998, 153:213-222) Pancreatic ductal adenocarcinoma is the fifth leading cause of cancer death in the Western world with an overall 5-year survival rate of less than 1% and a median survival after diagnosis of 4 months.

Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors

“…Using immunostaining and in situ hybridization techniques as well as RNase protection assays, we previously reported that FGFR -1, FGFR -2, and the related keratinocyte growth factor receptor (KGFR ) are expressed at relatively high levels in pancreatic cancer cells within the pancreatic tumor mass. 21,22 Using laser capture microdissection and real -time PCR, in the present study we were able to assess the expression levels of all four high -affinity FGFRs in the pancreatic cancer cells from seven different PDAC samples (Fig 9). Three samples exhibited relatively high levels of FGFR -1 ( samples 1, 5, and 6 ), and two of these three samples also exhibited high levels of FGFR -2 and moderate levels of FGFR -3 and -4 (samples 1 and 6 ).…”

“…21,22 RNA ( 10 g per sample ) was hybridized overnight at 428C with [ -32 P]CTP -labeled riboprobes, and single-stranded RNA was subsequently digested with RNAse A /T1 according to Ambion's RNase protection assay kit RPA II. Yeast tRNA ( 10 g ) was used as a negative control.…”

“…Total RNA was then extracted from these cells by using the single-step acid -guanidine -thiocyanate phenol chloroform method, as previously described, 21,22 but with the addition of glycogen to enhance the quantitative precipitation of the RNA during the extraction procedure. RNA was then analyzed for FGFR mRNA expression levels using realtime quantitative PCR as described above.…”

“…17 Pancreatic cancer cells are susceptible to transduction of adenoviral -mediated delivery of the HSV-TK gene. 10,13,16,20 In addition, PDACs overexpress the two Ig -like variants of the FGFR -1 and FGFR -2 21,22 and multiple FGFs. 23 We therefore sought to determine whether an adenoviral -based gene delivery system targeting FGF receptors may be of potential benefit in PDAC, by studying six human pancreatic cancer cell lines and by characterizing FGFR expression in PDAC samples.…”

Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells

“…In the pancreas, previous works have shown the effect of KGF in ductal-cell proliferation [5]. The expression of this growth factor and its receptors is up-regulated in pancreatic carcinomas [17]. Studies in transgenic mice expressing KGF alone [18] or both KGF and EGF [19] in their beta cells showed that ectopic expression of KGF in the pancreas induces increased ductal-cell proliferation, profound changes in pancreatic morphology and the appearance of hepatocytes within the Fig.…”