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Enhanced expression of fibroblast growth factor receptor 2 IIIc promotes human pancreatic cancer cell proliferation.

ABSTRACT: In pancreatic ductal adenocarcinoma (PDAC), the fibroblast growth factor receptor 1 (FGFR-1) IIIb isoform correlates with the inhibition of cancer cell proliferation, migration, and invasion, whereas FGFR-1 IIIc enhances cancer cell proliferation. The FGFR-2 IIIb isoform is expressed in PDAC, and its expression correlates with increased venous invasion. We examined the role of FGFR-2 IIIc in PDAC. FGFR-2 IIIc was expressed in all six pancreatic cancer cell lines examined and was highest in PANC-1 cells. FGFR-2 IIIc was abundant in the cancer cells from 83 of 117 PDAC cases, which correlated with decreased duration to development of liver metastasis after surgery. FGFR-2 IIIc-transfected cells exhibited increased proliferation in vitro and formed larger subcutaneous and orthotopic tumors, the latter producing more liver metastases. Moreover, FGF-2 exerted a more rapid stimulatory effect on the levels of phosphorylated extracellular signal-regulated kinase (p-ERK) in FGFR-2 IIIc stably transfected PANC-1 cells, compared with control cells. FGFR-2 IIIc-transfected cells also formed more spheres and contained more side population cells. Suppression of FGFR-2 IIIc expression inhibited the proliferation of PANC-1 cells, whereas an anti-FGFR-2 IIIc antibody inhibited the proliferation and migration of PANC-1 cells. Thus, high FGFR-2 IIIc levels in PDAC contribute to disease aggressiveness and confer to pancreatic cancer cells features suggestive of cancer stem cells, indicating that FGFR-2 IIIc may be a novel and important therapeutic target in PDAC.

SUBMITTER: Ishiwata T

PROVIDER: S-EPMC3349828 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Enhanced expression of fibroblast growth factor receptor 2 IIIc promotes human pancreatic cancer cell proliferation.

Ishiwata Toshiyuki T Matsuda Yoko Y Yamamoto Tetsushi T Uchida Eiji E Korc Murray M Naito Zenya Z

The American journal of pathology 20120319 5

In pancreatic ductal adenocarcinoma (PDAC), the fibroblast growth factor receptor 1 (FGFR-1) IIIb isoform correlates with the inhibition of cancer cell proliferation, migration, and invasion, whereas FGFR-1 IIIc enhances cancer cell proliferation. The FGFR-2 IIIb isoform is expressed in PDAC, and its expression correlates with increased venous invasion. We examined the role of FGFR-2 IIIc in PDAC. FGFR-2 IIIc was expressed in all six pancreatic cancer cell lines examined and was highest in PANC- ...[more]

PMID: 22440254

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Project description:Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer striking 200 000 Americans annually. Further, in organ transplant patients, there is a 65- to 100-fold increased incidence of cSCC compared to the general population. Excision of cSCC of the head and neck results in significant facial disfigurement. Therefore, increased understanding of the mechanisms involved in the pathogeneses of cSCC could identify means to prevent, inhibit, and reverse this process. In our previous studies, inhibition of fibroblast growth factor receptor (FGFR) significantly decreased ultraviolet B-induced epidermal hyperplasia and hyperproliferation in SKH-1 mice, suggesting an important role for FGFR signaling in skin cancer development. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR in cSCC cells and normal epidermal keratinocytes revealed protein overexpression and increased FGFR2 activation in cSCC cells compared to normal keratinocytes. Further, tumor cell-specific overexpression of FGFR2 was detected in human cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Pretreatment with the pan-FGFR inhibitor; AZD4547 significantly decreased cSCC cell-cycle traverse, proliferation, migration, and motility. Interestingly, AZD4547 also significantly downregulated mammalian target of rapamycin complex 1 and AKT activation in cSCC cells, suggesting an important role of these signaling pathways in FGFR-mediated effects. To further bolster the in vitro studies, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice with SCC12A tumor xenografts treated with AZD4547 (15 mg/kg/bw, twice weekly oral gavage) exhibited significantly decreased tumor volume compared to the vehicle-only treatment group. The current studies provide mechanistic evidence for the role of FGFR and selectively FGFR2 in the early progression of cSCC and identifies FGFR as a putative therapeutic target in the treatment of skin cancer.

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Enhanced expression of fibroblast growth factor receptor 2 IIIc promotes human pancreatic cancer cell proliferation.

Publications

Enhanced expression of fibroblast growth factor receptor 2 IIIc promotes human pancreatic cancer cell proliferation.

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