Overexpressed fibroblast growth factor receptor 2 in the invasive front of colorectal cancer: A potential therapeutic target in colorectal cancer

Matsuda, Yoko; Ishiwata, Toshiyuki; Yamahatsu, Kazuya; Kawahara, Kiyoko; Hagio, Masahito; Peng, Wei‐Xia; Yamamoto, Tetsushi; Nakazawa, Naoki; Seya, Tomoko; Ohaki, Yoshiharu; Naito, Zenya

doi:10.1016/j.canlet.2011.06.009

Cited by 43 publications

(43 citation statements)

References 33 publications

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“…On the other hand, FGFR2IIIb expression in colorectal carcinomas did not correlate with survival or metastasis (7). We previously reported that FGFR2 expression, both of FGFR2IIIc and FGFR2IIIb, in colorectal carcinomas tended to correlate with distant metastasis (14); the present data indicate that expression levels of FGFR2IIIc, rather than FGFR2IIIb, may contribute to colorectal carcinoma progression.…”

Section: Discussionsupporting

confidence: 67%

“…Sixty-one polypectomy samples (hyperplastic polyps, adenomas, or colorectal carcinoma) and 95 surgically resected colorectal carcinoma samples were obtained at Nippon Medical School Hospital (Tokyo, Japan) from 2007 to 2008 and Chiba-Hokusoh Hospital (Chiba, Japan) from 2001 to 2003 (14). None of the patients received chemotherapy or radiation therapy before surgery or had inflammatory colorectal disease.…”

Section: Patients and Tissuesmentioning

confidence: 99%

“…For the nonradioactive cell proliferation assay, cells were plated at a density of 5 Â 10 3 cells per well in a 96-well plate (14). After 24, 48, and 72 hours, the cells were incubated with WST-8 cell counting reagent, and the optical density of the culture solution was measured using an ELISA plate reader (Bio-Rad Laboratory).…”

Section: Anchorage-dependent Cell Proliferation Assay Of Fgfr2iiic-trmentioning

confidence: 99%

“…Cell migration and invasion assays of FGFR2IIIc-transfected DLD-1 cells Migration assays were carried out using a modified Boyden chamber technique (14). Cells were placed onto the upper component, and the lower compartment was filled with 750 mL medium containing 10% FBS or 100 ng/mL FGF-1, -2, or -7.…”

Section: Cell Adhesion To Extracellular Matrices Of Fgfr2iiic-transfementioning

confidence: 99%

“…FGF-1, -3, -7, -10, and -22 reportedly bind to FGFR2IIIb, whereas FGF-1, -2, -4, -6, -9, -17, and -18 bind to FGFR2IIIc with high affinity (11)(12)(13). We recently reported that FGFR2 overexpression in colorectal carcinomas is associated with distant metastasis; furthermore, decreasing FGFR2 expression inhibited colorectal carcinoma cell growth, FGF-7-induced cell migration and invasion, and tumor growth in nude mice (14). FGFR2IIIb overexpression is correlated with well-differentiated histologic type (7), and FGF7-a specific ligand of FGFR2IIIb-induces tumor angiogenesis through VEGF-A expression (5) and adhesion to type IV collagen in colorectal carcinomas (15).…”

Section: Introductionmentioning

confidence: 99%

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Fibroblast Growth Factor Receptor 2 IIIc as a Therapeutic Target for Colorectal Cancer Cells

Matsuda

Hagio

Seya

et al. 2012

Molecular Cancer Therapeutics

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A high percentage of colorectal carcinomas overexpress a lot of growth factors and their receptors, including fibroblast growth factor (FGF) and FGF receptor (FGFR). We previously reported that FGFR2 overexpression was associated with distant metastasis and that FGFR2 inhibition suppressed cell growth, migration, and invasion. The FGFR2 splicing isoform FGFR2IIIb is associated with well-differentiated histologic type, tumor angiogenesis, and adhesion to extracellular matrices. Another isoform, FGFR2IIIc, correlates with the aggressiveness of various types of cancer. In the present study, we examined the expression and roles of FGFR2IIIc in colorectal carcinoma to determine the effectiveness of FGFR2IIIc-targeting therapy. In normal colorectal tissues, FGFR2IIIc expression was weakly detected in superficial colorectal epithelial cells and was not detected in proliferative zone cells. FGFR2IIIc-positive cells were detected by immunohistochemistry in the following lesions, listed in the order of increasing percentage: hyperplastic polyps < low-grade adenomas < high-grade adenomas < carcinomas. FGFR2IIIc immunoreactivity was expressed in 27% of colorectal carcinoma cases, and this expression correlated with distant metastasis and poor prognosis. FGFR2IIIc-transfected colorectal carcinoma cells showed increased cell growth, soft agar colony formation, migration, and invasion, as well as decreased adhesion to extracellular matrices. Furthermore, FGFR2IIIc-transfected colorectal carcinoma cells formed larger tumors in subcutaneous tissues and the cecum of nude mice. Fully human anti-FGFR2IIIc monoclonal antibody inhibited the growth and migration of colorectal carcinoma cells through alterations in cell migration, cell death, and development-related genes. In conclusion, FGFR2IIIc plays an important role in colorectal carcinogenesis and tumor progression. Monoclonal antibody against FGFR2IIIc has promising potential in colorectal carcinoma therapy.

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Section: Discussionsupporting

confidence: 67%

Section: Patients and Tissuesmentioning

confidence: 99%

Section: Anchorage-dependent Cell Proliferation Assay Of Fgfr2iiic-trmentioning

confidence: 99%

Section: Cell Adhesion To Extracellular Matrices Of Fgfr2iiic-transfementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Fibroblast Growth Factor Receptor 2 IIIc as a Therapeutic Target for Colorectal Cancer Cells

Matsuda

Hagio

Seya

et al. 2012

Molecular Cancer Therapeutics

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FGF Receptors: Cancer Biology and Therapeutics

2013

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Fibroblast growth factors (FGFs) are involved in a variety of cellular processes, such as stemness, proliferation, anti-apoptosis, drug resistance, and angiogenesis. Here, FGF signaling network, cancer genetics/genomics of FGF receptors (FGFRs), and FGFR-targeted therapeutics will be reviewed. FGF signaling to RAS-MAPK branch and canonical WNT signaling cascade mutually regulate transcription programming. FGF signaling to PI3K-AKT branch and Hedgehog, Notch, TGFβ, and noncanonical WNT signaling cascades regulate epithelial-to-mesenchymal transition (EMT) and invasion. Gene amplification of FGFR1 occurs in lung cancer and estrogen receptor (ER)-positive breast cancer, and that of FGFR2 in diffuse-type gastric cancer and triple-negative breast cancer. Chromosomal translocation of FGFR1 occurs in the 8p11 myeloproliferative syndrome and alveolar rhabdomyosarcoma, as with FGFR3 in multiple myeloma and peripheral T-cell lymphoma. FGFR1 and FGFR3 genes are fused to neighboring TACC1 and TACC3 genes, respectively, due to interstitial deletions in glioblastoma multiforme. Missense mutations of FGFR2 are found in endometrial uterine cancer and melanoma, and similar FGFR3 mutations in invasive bladder tumors, and FGFR4 mutations in rhabdomyosarcoma. Dovitinib, Ki23057, ponatinib, and AZD4547 are orally bioavailable FGFR inhibitors, which have demonstrated striking effects in preclinical model experiments. Dovitinib, ponatinib, and AZD4547 are currently in clinical trial as anticancer drugs. Because there are multiple mechanisms of actions for FGFR inhibitors to overcome drug resistance, FGFR-targeted therapy is a promising strategy for the treatment of refractory cancer. Whole exome/transcriptome sequencing will be introduced to the clinical laboratory as the companion diagnostic platform facilitating patient selection for FGFR-targeted therapeutics in the era of personalized medicine.

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