Gene Summary

Gene:FGF7; fibroblast growth factor 7
Aliases: KGF, HBGF-7
Summary:The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein is a potent epithelial cell-specific growth factor, whose mitogenic activity is predominantly exhibited in keratinocytes but not in fibroblasts and endothelial cells. Studies of mouse and rat homologs of this gene implicated roles in morphogenesis of epithelium, reepithelialization of wounds, hair development and early lung organogenesis. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:fibroblast growth factor 7
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • FGF2
  • Western Blotting
  • Cell Division
  • Stomach Cancer
  • Thyroid Cancer
  • Transfection
  • Chromosome 15
  • Growth Substances
  • Tumor Microenvironment
  • Fibroblast Growth Factor 10
  • Cell Proliferation
  • Immunohistochemistry
  • Breast Cancer
  • Vascular Endothelial Growth Factors
  • Epithelial Cells
  • Messenger RNA
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
  • Neoplasm Proteins
  • Cultured Cells
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • Cell Differentiation
  • Pancreatic Cancer
  • Signal Transduction
  • Bladder Cancer
  • Oligonucleotide Array Sequence Analysis
  • Fibroblast Growth Factor 7
  • Prostate Cancer
  • Fibroblast Growth Factors
  • FGFR2
  • Disease Progression
  • Receptors, Fibroblast Growth Factor
  • Molecular Sequence Data
  • Wnt Proteins
  • Cancer RNA
  • Base Sequence
  • Tumor Stem Cell Assay
  • Fibroblasts
  • Gene Expression
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FGF7 (cancer-related)

Eiro N, González L, Martínez-Ordoñez A, et al.
Cancer-associated fibroblasts affect breast cancer cell gene expression, invasion and angiogenesis.
Cell Oncol (Dordr). 2018; 41(4):369-378 [PubMed] Related Publications
PURPOSE: It has been reported that stromal cell features may affect the clinical outcome of breast cancer patients. Cancer associated fibroblasts (CAFs) represent one of the most abundant cell types within the breast cancer stroma. Here, we aimed to explore the influence of CAFs on breast cancer gene expression, as well as on invasion and angiogenesis.
METHODS: qRT-PCR was used to evaluate the expression of several cancer progression related genes (S100A4, TGFβ, FGF2, FGF7, PDGFA, PDGFB, VEGFA, IL-6, IL-8, uPA, MMP2, MMP9, MMP11 and TIMP1) in the human breast cancer-derived cell lines MCF-7 and MDA-MB-231, before and after co-culture with CAFs. Stromal mononuclear inflammatory cell (MIC) MMP11 expression was used to stratify primary tumors. In addition, we assessed the in vitro effects of CAFs on both MDA-MB-231 breast cancer cell invasion and endothelial cell (HUVEC) tube formation.
RESULTS: We found that the expression levels of most of the genes tested were significantly increased in both breast cancer-derived cell lines after co-culture with CAFs from either MMP11+ or MMP11- MIC tumors. IL-6 and IL-8 showed an increased expression in both cancer-derived cell lines after co-culture with CAFs from MMP11+ MIC tumors. We also found that the invasive and angiogenic capacities of, respectively, MDA-MB-231 and HUVEC cells were increased after co-culture with CAFs, especially those from MMP11+ MIC tumors.
CONCLUSIONS: Our data indicate that tumor-derived CAFs can induce up-regulation of genes involved in breast cancer progression. Our data additionally indicate that CAFs, especially those derived from MMP11+ MIC tumors, can promote breast cancer cell invasion and angiogenesis.

Turczyk L, Kitowska K, Mieszkowska M, et al.
FGFR2-Driven Signaling Counteracts Tamoxifen Effect on ERα-Positive Breast Cancer Cells.
Neoplasia. 2017; 19(10):791-804 [PubMed] Free Access to Full Article Related Publications
Signaling mediated by growth factors receptors has long been suggested as one of the key factors responsible for failure of endocrine treatment in breast cancer (BCa). Herein we present that in the presence of tamoxifen, FGFs (Fibroblast Growth Factors) promote BCa cell growth with the strongest effect being produced by FGF7. FGFR2 was identified as a mediator of FGF7 action and the FGFR2-induced signaling was found to underlie cancer-associated fibroblasts-dependent resistance to tamoxifen. FGF7/FGFR2-triggered pathway was shown to induce ER phosphorylation, ubiquitination and subsequent ER proteasomal degradation which counteracted tamoxifen-promoted ER stabilization. We also identified activation of PI3K/AKT signaling targeting ER-Ser167 and regulation of Bcl-2 expression as a mediator of FGFR2-promoted resistance to tamoxifen. Analysis of tissue samples from patients with invasive ductal carcinoma revealed an inversed correlation between expression of FGFR2 and ER, thus supporting our in vitro data. These results unveil the complexity of ER regulation by FGFR2-mediated signaling likely to be associated with BCa resistance to endocrine therapy.

Di Domenico M, Giordano A
Signal transduction growth factors: the effective governance of transcription and cellular adhesion in cancer invasion.
Oncotarget. 2017; 8(22):36869-36884 [PubMed] Free Access to Full Article Related Publications
Giulio Bizzozero classified the tissues concerning their capacity to self-renew during the adult life in labile, stable and permanent tissues. In 1940 Viktor Hamburger and Rita Levi Montalcini exposed the possibility to induce the growth of permanent cells thanks to a specific ligand Nerve Growth Factor (NGF). Stanley Cohen purified a protein the Epidermal Growth Factor (EGF), able to induce epidermis proliferation and to elicit precocious eye disclosure and teeth eruption, establishing the "inverse" relationships between the proliferation and differentiation. These two biological effects induced by EGF were according to EGFR signaling is involved in a large array of cellular functions such as proliferation, survival, adhesion, migration and differentiation. This review is focused on the key role of growth factors signaling and their downstream effectors in physiological and in pathological phenomena, the authors highlight the governance of Growth factors during the EMT in cancer invasion.

Huang T, Wang L, Liu D, et al.
FGF7/FGFR2 signal promotes invasion and migration in human gastric cancer through upregulation of thrombospondin-1.
Int J Oncol. 2017; 50(5):1501-1512 [PubMed] Free Access to Full Article Related Publications
Fibroblast growth factor 7 (FGF7) is a mesenchyme-specific heparin-binding growth factor that binds FGF receptor 2 (FGFR2) to regulate numerous cellular and physiological processes. FGF7/FGFR2 signal is associated with gastric cancer progression. In the present study, we investigated the molecular mechanism by which FGF7/FGFR2 promotes invasion and migration in human gastric cancer. We first demonstrated that increased FGFR2 expression in human gastric cancer tissues was significantly associated with tumor depth and clinical stage in human gastric cancer tissues. Thrombospondin 1 (THBS1) is an extracellular glycoprotein that plays multiple roles in cell-matrix and cell-cell interactions. Increased expression of THBS1 significantly correlated with tumor differentiation. FGFR2 and THBS1 expression were both increased in cancer tissues as compared with adjacent normal tissues and their expression was positively correlated. In vitro, FGF7 stimulation of cell invasion and migration was partially suppressed by the FGFR2 knockdown. In addition, FGF7/FGFR2 upregulated THBS1, and cell invasion and migration were decreased by knockdown of THBS1. Furthermore, the PI3K/Akt/mTOR signaling pathway was predominantly responsible for FGF7/FGFR2-induced THBS1 upregulation. Taken together, our data suggest that FGF7/FGFR2/THBS1 is associated with the regulation of invasion and migration in human gastric cancer.

de Bessa Garcia SA, Pavanelli AC, Cruz E Melo N, Nagai MA
Prostate apoptosis response 4 (PAR4) expression modulates WNT signaling pathways in MCF7 breast cancer cells: A possible mechanism underlying PAR4-mediated docetaxel chemosensitivity.
Int J Mol Med. 2017; 39(4):809-818 [PubMed] Free Access to Full Article Related Publications
Docetaxel is an effective drug for the treatment of metastatic breast cancer. However, the exact mechanisms and/or markers associated with chemosensitivity or resistance to docetaxel remain unclear. We previously showed that the expression of prostate apoptosis response 4 (PAR4) inhibits the growth of MCF7 breast cancer cells and increases their sensitivity to docetaxel. Using cDNA microarray analysis, we evaluated transcriptome changes in MCF7 cells expressing increased levels of PAR4 and control cells before and after docetaxel treatment. Some of the top gene networks generated from the differentially expressed genes were related to the wingless‑type MMTV integration 1 (WNT) canonical (WNT/β-catenin) and non‑canonical (β‑catenin‑independent) pathways. The Human WNT signaling pathway RT2 profiler™ PCR array was used to validate the effects of PAR4 on the expression pattern of genes involved in the WNT pathway. CACNAD2A3, GDF5 and IL6 were upregulated and NANOG was downregulated in the MCF7 breast cancer cells expressing increased levels of PAR4 after treatment with docetaxel, likely indicating inactivation of the WNT/β-catenin pathway. Upregulation of FGF7, LEF1 and TWIST1 indicated activation of the WNT/β‑catenin pathway. Although preliminary, our findings could be of particular interest for understanding the action of PAR4 in chemosensitivity, particularly to increase the specificity and effectiveness of drug treatment and overcome resistance to chemotherapy. Further studies are needed to better understand the biological roles of PAR4 in the regulation of WNT pathways in breast cancer cells in response to docetaxel and other chemotherapeutic agents.

Eiro N, Fernandez-Gomez J, Sacristán R, et al.
Stromal factors involved in human prostate cancer development, progression and castration resistance.
J Cancer Res Clin Oncol. 2017; 143(2):351-359 [PubMed] Related Publications
PURPOSE: To detect new predictive markers from the prostate cancer tissue, to study the expression by cultured cancer-associated fibroblasts (CAFs) of stromal factors implicated in prostate carcinogenesis, and to compare their expressions in localized, metastatic, castration-sensitive (CSCP), castration-resistant prostate tumors (CRCP) as well as in fibroblasts from benign prostatic hyperplasia (BPH).
MATERIALS AND METHODS: The genomic expression of 20 stroma-derived factors, including the androgen receptor (AR), growth factors (FGF2, FGF7, FGF10, HGF, TGFβ, PDGFB), protein implicated in invasion (MMP-2, MMP-9 and MMP-11), inflammation (IL-6, IL-17, STAT-3 and NFκB), stroma/epithelium interaction (CDH11, FAP, CXCL12 and CXCL14) and chaperones (HPA1A and HSF1), was evaluated in cultured fibroblasts both from BHP and prostate carcinomas (PCa). After isolation and culture of fibroblasts by biopsy specimens, RNA was isolated and genomic studies performed.
RESULTS: Finally, 5 BPH and 37 PCa specimens were selected: clinically localized (19), metastatic (5), CSCP (7) and CRPC (6). Interleukin-17 receptor (IL-17RB) was highly expressed in CAFs compared with fibroblasts from BPH. However, metalloproteinase-2 and chemokine ligand 14 (CXCL14) were expressed at higher levels by fibroblasts from BPH. The fibroblastic growth factor-7 was highly expressed by CAFs from localized tumors, but metalloproteinase-11 in metastatic tumors. MMP-11, androgen receptor (AR) and heat-shock-70kda-protein-1A (HSPA1A) expressions were significantly higher in CAFs from CRPC.
CONCLUSIONS: These results demonstrate a CAFs heterogeneity among prostate carcinomas with regard to some molecular profile expressions that may be relevant in tumor development (IL-17RB), progression (MMP-11) and castration resistance (AR, MMP-11 and HSPA1A).

Qi L, Song W, Li L, et al.
FGF4 induces epithelial-mesenchymal transition by inducing store-operated calcium entry in lung adenocarcinoma.
Oncotarget. 2016; 7(45):74015-74030 [PubMed] Free Access to Full Article Related Publications
Several fibroblast growth factor (FGF) isoforms act to stimulate epithelial-mesenchymal transition (EMT) during cancer progression. FGF4 and FGF7 are two ligands of FGF receptor 2 (FGFR2). Using two lung adenocarcinoma (ADC) cell lines, A549 and H1299, we showed that FGF4, but not FGF7, altered cell morphology, promoted EMT-associated protein expression, and enhanced cell proliferation, migration/invasion and colony initiation. In addition, FGF4 increased store-operated calcium entry (SOCE) and expression of the calcium signal-associated protein Orai1. The SOCE inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or Orai1 knockdown reversed all of the EMT-promoting effects of FGF4. BHQ also inhibited FGF4-induced EMT in a mouse xenograft model. Finally, 60 human lung ADC samples and 21 sets of matched specimens (primary and metastatic foci in lymph nodes from one patient) were used to confirm the clinicopathologic significance of FGF4 and its correlation with E-cadherin, Vimentin and Orai1 expression. Our study thus shows that FGF4 induces EMT by elevating SOCE in lung ADC.

Katoh M
FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review).
Int J Mol Med. 2016; 38(1):3-15 [PubMed] Free Access to Full Article Related Publications
Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor-associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients.

Zou Q, Cui D, Liang S, et al.
Aging up-regulates ARA55 in stromal cells, inducing androgen-mediated prostate cancer cell proliferation and migration.
J Mol Histol. 2016; 47(3):305-15 [PubMed] Related Publications
Stromal cells in the peripheral zone (PZ) of the prostate from older males (PZ-old) could significantly promote Prostate cancer (PCa) growth compared with stromal cells from young males (PZ-young). But the mechanism is still unknown. In the co-culture system with PZ-old cells, Pc3/Du145 cells showed advanced proliferation and migration after Dihydrotestosterone (DHT) incubation, but DHT didn't show the similar effect in PZ-young co-culture system. Also, higher androgen/AR signal pathway activity and AR-related cytokines secretion (FGF-2, KGF, IGF-1) were found in PZ-old cells. As AR exprssison was equivalent in PZ-old and PZ-young cells, we focused on Androgen receptor associated protein-55(ARA55), a stromal-specific androgen receptor (AR) coactivator. ARA55 expression was higher in PZ-old cells compared with PZ-young cells in vitro. After knocking down ARA55 expression in PZ-old cells, the PCa growth- promoting effect from the PZ-old cells was diminished, which may be explained by the decreased the progressive cytokines secretion (FGF-2, KGF, IGF-1) from PZ-old stromal cells. In vivo, the consistent results were also found: PZ-old cells promoted prostate cancer cells growth, but this effect receded when knocking down ARA55 expression in PZ-old cells. From our study, we found PZ stromal cells presented age-related effects in proliferation and migration of prostate cancer cells in the androgen/AR dependent manner. As aging increased, more ARA55 were expressed in PZ stromal cells, leading to more sensitive androgen/androgen receptor (AR) signal pathway, then constituting a more feasible environment to cancer cells.

Yeh CR, Ou ZY, Xiao GQ, et al.
Infiltrating T cells promote renal cell carcinoma (RCC) progression via altering the estrogen receptor β-DAB2IP signals.
Oncotarget. 2015; 6(42):44346-59 [PubMed] Free Access to Full Article Related Publications
Previous studies indicated the T cells, one of the most common types of immune cells existing in the microenvironment of renal cell carcinoma (RCC), may influence the progression of RCC. The potential linkage of T cells and the estrogen receptor beta (ERβ), a key player to impact RCC progression, however, remains unclear. Our results demonstrate that RCC cells can recruit more T cells than non-malignant kidney cells. Using an in vitro matrigel invasion system, we found infiltrating T cells could promote RCC cells invasion via increasing ERβ expression and transcriptional activity. Mechanism dissection suggested that co-culturing T cells with RCC cells released more T cell attraction factors, including IFN-γ, CCL3 and CCL5, suggesting a positive regulatory feed-back mechanism. Meanwhile, infiltrating T cells may also promote RCC cell invasion via increased ERβ and decreased DAB2IP expressions, and knocking down DAB2IP can then reverse the T cells-promoted RCC cell invasion. Together, our results suggest that infiltrating T cells may promote RCC cell invasion via increasing the RCC cell ERβ expression to inhibit the tumor suppressor DAB2IP signals. Further mechanism dissection showed that co-culturing T cells with RCC cells could produce more IGF-1 and FGF-7, which may enhance the ERβ transcriptional activity. The newly identified relationship between infiltrating T cells/ERβ/DAB2IP signals may provide a novel therapeutic target in the development of agents against RCC.

Yin J, Sheng B, Pu A, et al.
Keratinocyte Growth Factor Regulation of Aryl Hydrocarbon Receptor Activation in Colorectal Cancer Cells.
Dig Dis Sci. 2016; 61(2):444-52 [PubMed] Related Publications
BACKGROUND: Keratinocyte growth factor (KGF) stimulates normal growth, development and intestinal epithelial cell proliferation. Cyclin D1 promotes the cell cycle by inhibiting retinoblastoma protein (RB1). The activated aryl hydrocarbon receptor (AhR) has an important influence on the development of tumors through its interactions with the cell cycle.
AIM: The aim of the present study was to explore a new role for AhR in KGF-induced colon cancer cell growth.
MATERIALS AND METHODS: Real-time PCR, western blot or immunofluorescence analysis were used to detect the expression of KGF, AhR, cyclin D1 and CYP1A1. Immunohistochemistry was used to observe the localization of AhR. MTT assay and flow cytometric analyses were performed to measure cell viability and the cell cycle.
RESULTS: Real-time PCR analysis revealed that KGF, AhR, and CYP1A1 mRNAs were overexpressed in colorectal cancer tissues. Meanwhile, overexpression of AhR was primarily observed in epithelial cells. In in vitro assay, KGF promoted colon cancer cell growth, as well as up-regulated and activated AhR. At the same time, AhR-knockdown colon cancer cells were less responsive to KGF. Western blot analysis, real-time PCR, or immunofluorescence data indicated that cyclin D1 expression was up-regulated by KGF but this up-regulation was compromised when AhR was silenced, and the cell cycle was arrested in the G0/G1 stage in these cells.
CONCLUSIONS: Our study suggests that KGF, AhR, and CYP1A1 are overexpressed in colorectal cancer tissues. Moreover, we reveal a new mechanism by which KGF promotes cell proliferation through the AhR-cyclin D1 pathway in colon cancer cells.

Zhang Q, Wang P, Shao M, et al.
Clinicopathological correlation of keratinocyte growth factor and matrix metalloproteinase-9 expression in human gastric cancer.
Tumori. 2015 Sep-Oct; 101(5):566-71 [PubMed] Related Publications
AIMS AND BACKGROUND: Keratinocyte growth factor (KGF) is reported to be implicated in the growth of some cancer cells. Matrix metalloproteinase 9 (MMP-9) is thought to enhance the tumor invasion and metastasis ability. This study was aimed at analyzing the relationship between KGF and MMP-9 expression and patients' clinicopathological characteristics to clarify the clinical significance of the expression of KGF and MMP-9 in gastric cancer.
METHODS: Tissue samples from 161 patients with primary gastric cancer were investigated using immunohistochemistry. The relationship between KGF and/or MMP-9 expression and clinicopathological characteristics was analyzed.
RESULTS: KGF expression and MMP-9 expression in gastric cancer tissue were observed in 62 cases (38.5%) and 97 cases (60.2%), respectively. MMP-9 was significantly associated with depth of invasion, lymph node metastasis and TNM stage. The prognosis of MMP-9-positive patients was significantly poorer than that of MMP-9-negative patients (p = 0.009). KGF expression was positively correlated with MMP-9 expression in gastric cancer, and the prognosis of patients with both KGF- and MMP-9-positive tumors was significantly worse than that of patients with negative tumors for either factor (p = 0.045). Expression of MMP-9 was revealed to be an independent prognostic factor (p = 0.026).
CONCLUSIONS: Coexpression of KGF and MMP-9 in gastric cancer could be a useful prognostic factor, and MMP-9 might also serve as a novel target for both prognostic prediction and therapeutics.

Fu ZC, Wang FM, Cai JM
Gene expression changes in residual advanced cervical cancer after radiotherapy: indicators of poor prognosis and radioresistance?
Med Sci Monit. 2015; 21:1276-87 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Different sensitivity of advanced cervical cancer to irradiation can decrease effectiveness of radiotherapy in some cases. We attempted to identify the differentially expressed genes in residual cervical cancer after radiotherapy that might be associated with poor prognosis and radioresistance.
MATERIAL/METHODS: Differential genes expression was identified by an oligonucleotide microarray in cervical cancer tissues before radiation and after a 50-Gy dose of radiation. The microarray results were validated by quantitative real-time PCR. CXCL12 was validated by immunohistochemistry in paraffin-embedded cervical cancer tissues before radiotherapy. The relationship between the differentiated gene and prognosis was validated by survival analysis.
RESULTS: Hierarchic cluster analysis identified 238 differentiated genes that exhibited ≥3.0-fold change and p<0.05. We found 111 genes that were in persistent up-regulation and 127 in persistent down-regulation after a 50-Gy dose of radiation when compared with the control group. These genes were involved in processes such as cell growth and death, cell-apoptosis, cell cycle regulation, cell signaling, DNA synthesis and repair, and cell adhesion. High differential expression of CXCL12, CD74, FGF7, COL14A1, PRC1, and RAD54L genes was validated by quantitative PCR before and after radiotherapy. Survival analysis results showed that the high expression of CXCL12 was closely related to poor prognosis.
CONCLUSIONS: The higher expression of CXCL12 might be informative regarding poor prognosis in patients undergoing radical radiotherapy. The differentially expressed genes identified in our study might provide a new method for diagnosis and treatment of radioresistance in cervical cancer.

Belleudi F, Nanni M, Raffa S, Torrisi MR
HPV16 E5 deregulates the autophagic process in human keratinocytes.
Oncotarget. 2015; 6(11):9370-86 [PubMed] Free Access to Full Article Related Publications
Autophagy plays key roles during host defense against pathogens, but viruses have evolved strategies to block the process or to exploit it for replication and successful infection. The E5 oncoprotein of human papillomavirus type 16 (HPV16 E5) perturbs epithelial homeostasis down-regulating the expression of the keratinocyte growth factor receptor (KGFR/FGFR2b), whose signaling induces autophagy. Here we investigated the possible effects of 16E5 on autophagy in human keratinocytes expressing the viral protein. The 16E5 presence strongly inhibited the autophagic process, while forced expression and activation of KGFR counteracted this effect, demonstrating that the viral protein and the receptor exert opposite and interplaying roles not only on epithelial differentiation, but also in the control of autophagy. In W12 cells, silencing of the 16E5 gene in the context of the viral full length genome confirmed its role on autophagy inhibition. Finally, molecular approaches showed that the viral protein interferes with the transcriptional regulation of autophagy also through the impairment of p53 function, indicating that 16E5 uses parallel mechanisms for autophagy impairment. Overall our results further support the hypothesis that a transcriptional crosstalk among 16E5 and KGFR might be the crucial molecular driver of epithelial deregulation during early steps of HPV infection and transformation.

Fan EW, Li CC, Wu WJ, et al.
FGF7 Over Expression is an Independent Prognosticator in Patients with Urothelial Carcinoma of the Upper Urinary Tract and Bladder.
J Urol. 2015; 194(1):223-9 [PubMed] Related Publications
PURPOSE: Urothelial carcinoma of the bladder and upper tract is the most common tumor type in the urinary tract but its molecular pathogenesis and survival determinants remain obscure. By data mining a published transcriptomic database of bladder urothelial carcinoma (GSE31684) we identified FGF7 as the most significant gene up-regulated during urothelial carcinoma progression. We then used our well characterized urothelial carcinoma cohort to analyze FGF7 transcript and protein expression, and its clinicopathological significance.
MATERIALS AND METHODS: We performed real-time reverse transcriptase-polymerase chain reaction assay to determine the FGF7 transcript level in 30 fresh samples each of upper tract and bladder urothelial carcinoma. Immunohistochemistry evaluated by H-score was used to determine FGF7 protein expression in 340 upper tract and 295 bladder urothelial carcinomas. Transcript and protein expression were correlated with clinicopathological features. We further evaluated the prognostic significance of FGF7 protein expression for disease specific and metastasis-free survival.
RESULTS: An increased FGF7 transcript level was associated with higher pT stage in upper tract and bladder urothelial carcinoma (p = 0.003 and <0.001, respectively). In the upper tract and bladder carcinoma groups FGF7 protein over expression was also significantly associated with advanced pT status (each p <0.001), lymph node metastasis (p = 0.002 and <0.001), high histological grade (p = 0.019 and <0.001), vascular invasion (each p <0.001), perineural invasion (p = 0.002 and 0.021) and frequent mitoses (p = 0.002 and 0.042, respectively). FGF7 over expression predicted dismal disease specific and metastasis-free survival on univariate and multivariate analysis.
CONCLUSIONS: Our study shows that FGF7 over expression is associated with advanced clinical features in patients with upper tract and bladder urothelial carcinoma, justifying its potential prognostic value for urothelial carcinoma.

Kinney AY, Butler KM, Schwartz MD, et al.
Expanding access to BRCA1/2 genetic counseling with telephone delivery: a cluster randomized trial.
J Natl Cancer Inst. 2014; 106(12) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The growing demand for cancer genetic services underscores the need to consider approaches that enhance access and efficiency of genetic counseling. Telephone delivery of cancer genetic services may improve access to these services for individuals experiencing geographic (rural areas) and structural (travel time, transportation, childcare) barriers to access.
METHODS: This cluster-randomized clinical trial used population-based sampling of women at risk for BRCA1/2 mutations to compare telephone and in-person counseling for: 1) equivalency of testing uptake and 2) noninferiority of changes in psychosocial measures. Women 25 to 74 years of age with personal or family histories of breast or ovarian cancer and who were able to travel to one of 14 outreach clinics were invited to participate. Randomization was by family. Assessments were conducted at baseline one week after pretest and post-test counseling and at six months. Of the 988 women randomly assigned, 901 completed a follow-up assessment. Cluster bootstrap methods were used to estimate the 95% confidence interval (CI) for the difference between test uptake proportions, using a 10% equivalency margin. Differences in psychosocial outcomes for determining noninferiority were estimated using linear models together with one-sided 97.5% bootstrap CIs.
RESULTS: Uptake of BRCA1/2 testing was lower following telephone (21.8%) than in-person counseling (31.8%, difference = 10.2%, 95% CI = 3.9% to 16.3%; after imputation of missing data: difference = 9.2%, 95% CI = -0.1% to 24.6%). Telephone counseling fulfilled the criteria for noninferiority to in-person counseling for all measures.
CONCLUSIONS: BRCA1/2 telephone counseling, although leading to lower testing uptake, appears to be safe and as effective as in-person counseling with regard to minimizing adverse psychological reactions, promoting informed decision making, and delivering patient-centered communication for both rural and urban women.

Amer M, Elhefnawi M, El-Ahwany E, et al.
Hsa-miR-195 targets PCMT1 in hepatocellular carcinoma that increases tumor life span.
Tumour Biol. 2014; 35(11):11301-9 [PubMed] Related Publications
MicroRNAs are small 19-25 nucleotides which have been shown to play important roles in the regulation of gene expression in many organisms. Downregulation or accumulation of miRNAs implies either tumor suppression or oncogenic activation. In this study, differentially expressed hsa-miR-195 in hepatocellular carcinoma (HCC) was identified and analyzed. The prediction was done using a consensus approach of tools. The validation steps were done at two different levels in silico and in vitro. FGF7, GHR, PCMT1, CITED2, PEX5, PEX13, NOVA1, AXIN2, and TSPYL2 were detected with high significant (P < 0.005). These genes are involved in important pathways in cancer like MAPK signaling pathway, Jak-STAT signaling pathways, regulation of actin cytoskeleton, angiogenesis, Wnt signaling pathway, and TGF-beta signaling pathway. In vitro target validation was done for protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1). The co-transfection of pmirGLO-PCMT1 and pEGP-miR-195 showed highly significant results. Firefly luciferase was detected using Lumiscensor and t test analysis was done. Firefly luciferase expression was significantly decreased (P < 0.001) in comparison to the control. The low expression of firefly luciferase validates the method of target prediction that we used in this work by working on PCMT1 as a target for miR-195. Furthermore, the rest of the predicted genes are suspected to be real targets for hsa-miR-195. These target genes control almost all the hallmarks of liver cancer which can be used as therapeutic targets in cancer treatment.

Meng QH, Xu E, Hildebrandt MA, et al.
Genetic variants in the fibroblast growth factor pathway as potential markers of ovarian cancer risk, therapeutic response, and clinical outcome.
Clin Chem. 2014; 60(1):222-32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The fibroblast growth factor (FGF) and FGF receptor (FGFR) axis plays a critical role in tumorigenesis, but little is known of its influence in ovarian cancer. We sought to determine the association of genetic variants in the FGF pathway with risk, therapeutic response, and survival of patients with ovarian cancer.
METHODS: We matched 339 non-Hispanic white ovarian cancer cases with 349 healthy controls and genotyped them for 183 single-nucleotide polymorphisms (SNPs) from 24 FGF (fibroblast growth factor) and FGFR (fibroblast growth factor receptor) genes. Genetic associations for the main effect, gene-gene interactions, and the cumulative effect were determined.
RESULTS: Multiple SNPs in the FGF-FGFR axis were associated with an increased risk of ovarian cancer. In particular, FGF1 [fibroblast growth factor 1 (acidic)] SNP rs7727832 showed the most significant association with ovarian cancer (odds ratio, 2.27; 95% CI, 1.31-3.95). Ten SNPs were associated with a reduced risk of ovarian cancer. FGF18 (fibroblast growth factor 18) SNP rs3806929, FGF7 (fibroblast growth factor 7) SNP rs9920722, FGF23 (fibroblast growth factor 23) SNP rs12812339, and FGF5 (fibroblast growth factor 5) SNP rs3733336 were significantly associated with a favorable treatment response, with a reduction of risk of nonresponse of 40% to 60%. Eleven SNPs were significantly associated with overall survival. Of these SNPs, FGF23 rs7961824 was the most significantly associated with improved prognosis (hazard ratio, 0.55; 95% CI, 0.39-0.78) and was associated with significantly longer survival durations, compared with individuals with the common genotype at this locus (58.1 months vs. 38.0 months, P = 0.005). Survival tree analysis revealed FGF2 rs167428 as the primary factor contributing to overall survival.
CONCLUSIONS: Significant associations of genetic variants in the FGF pathway were associated with ovarian cancer risk, therapeutic response, and survival. The discovery of multiple SNPs in the FGF-FGFR pathway provides a molecular approach for risk assessment, monitoring therapeutic response, and prognosis.

Ishino R, Minami K, Tanaka S, et al.
FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro.
Biochem Biophys Res Commun. 2013; 440(1):125-31 [PubMed] Related Publications
FGF1 and FGF2 support hematopoietic stem and progenitor cells (HSPCs) under stress conditions. In this study, we show that fibroblast growth factor (FGF7) may be a novel niche factor for HSPC support and leukemic growth. FGF7 expression was attenuated in mouse embryonic fibroblasts (MEFs) deficient for the MED1 subunit of the Mediator transcriptional coregulator complex. When normal mouse bone marrow (BM) cells were cocultured with Med1(+/+) MEFs or BM stromal cells in the presence of anti-FGF7 antibody, the growth of BM cells and the number of long-time culture-initiating cells (LTC-ICs) decreased significantly. Anti-FGF7 antibody also attenuated the proliferation and cobblestone formation of MB1 stromal cell-dependent myeloblastoma cells. The addition of recombinant FGF7 to the coculture of BM cells and Med1(-/-) MEFs increased BM cells and LTC-ICs. FGF7 and its cognate receptor, FGFR2IIIb, were undetectable in BM cells, but MEFs and BM stromal cells expressed both. FGF7 activated downstream targets of FGFR2IIIb in Med1(+/+) and Med1(-/-) MEFs and BM stromal cells. Taken together, we propose that FGF7 supports HSPCs and leukemia-initiating cells indirectly via FGFR2IIIb expressed on stromal cells.

Ramsey MR, Wilson C, Ory B, et al.
FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma.
J Clin Invest. 2013; 123(8):3525-38 [PubMed] Free Access to Full Article Related Publications
Oncogenic transcription factors drive many human cancers, yet identifying and therapeutically targeting the resulting deregulated pathways has proven difficult. Squamous cell carcinoma (SCC) is a common and lethal human cancer, and relatively little progress has been made in improving outcomes for SCC due to a poor understanding of its underlying molecular pathogenesis. While SCCs typically lack somatic oncogene-activating mutations, they exhibit frequent overexpression of the p53-related transcription factor p63. We developed an in vivo murine tumor model to investigate the function and key transcriptional programs of p63 in SCC. Here, we show that established SCCs are exquisitely dependent on p63, as acute genetic ablation of p63 in advanced, invasive SCC induced rapid and dramatic apoptosis and tumor regression. In vivo genome-wide gene expression analysis identified a tumor-survival program involving p63-regulated FGFR2 signaling that was activated by ligand emanating from abundant tumor-associated stroma. Correspondingly, we demonstrate the therapeutic efficacy of extinguishing this signaling axis in endogenous SCCs using the clinical FGFR2 inhibitor AZD4547. Collectively, these results reveal an unanticipated role for p63-driven paracrine FGFR2 signaling as an addicting pathway in human cancer and suggest a new approach for the treatment of SCC.

Chen G, Qiu H, Ke SD, et al.
Emodin regulating excision repair cross-complementation group 1 through fibroblast growth factor receptor 2 signaling.
World J Gastroenterol. 2013; 19(16):2481-91 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the molecular mechanisms underlying the reversal effect of emodin on platinum resistance in hepatocellular carcinoma.
METHODS: After the addition of 10 μmol/L emodin to HepG2/oxaliplatin (OXA) cells, the inhibition rate (IR), 50% inhibitory concentration (IC₅₀) and reversal index (IC₅₀ in experimental group/IC₅₀ in control group) were calculated. For HepG2, HepG2/OXA, HepG2/OXA/T, each cell line was divided into a control group, OXA group, OXA + fibroblast growth factor 7 (FGF7) group and OXA + emodin group, and the final concentrations of FGF7, emodin and OXA in each group were 5 ng/mL, 10 μg/mL and 10 μmol/L, respectively. Single-cell gel electrophoresis was conducted to detect DNA damage, and the fibroblast growth factor receptor 2 (FGFR2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and excision repair cross-complementing gene 1 (ERCC1) protein expression levels in each group were examined by Western blotting.
RESULTS: Compared with the IC₅₀ of 120.78 μmol/L in HepG2/OXA cells, the IC₅₀ decreased to 39.65 μmol/L after treatment with 10 μmol/L emodin; thus, the reversal index was 3.05. Compared with the control group, the tail length and Olive tail length in the OXA group, OXA + FGF7 group and OXA + emodin group were significantly increased, and the differences were statistically significant (P < 0.01). The tail length and Olive tail length were lower in the OXA + FGF7 group than in the OXA group, and this difference was also statistically significant. Compared with the OXA + FGF7 group, the tail extent, the Olive tail moment and the percentage of tail DNA were significantly increased in the OXA + emodin group, and these differences were statistically significant (P < 0.01). In comparison with its parental cell line HepG2, the HepG2/OXA cells demonstrated significantly increased FGFR2, p-ERK1/2 and ERCC1 expression levels, whereas the expression of all three molecules was significantly inhibited in HepG2/OXA/T cells, in which FGFR2 was silenced by FGFR2 shRNA. In the examined HepG2 cells, the FGFR2, p-ERK1/2 and ERCC1 expression levels demonstrated increasing trends in the OXA group and OXA + FGF7 group. Compared with the OXA group and OXA + FGF7 group, the FGFR2, p-ERK1/2, and ERCC1 expression levels were significantly lower in the OXA + emodin group, and these differences were statistically significant. In the HepG2/OXA/T cell line that was transfected with FGFR2 shRNA, the FGFR2, p-ERK1/2 and ERCC1 expression levels were significantly inhibited, but there were no significant differences in these expression levels among the OXA, OXA + FGF7 and OXA + emodin groups.
CONCLUSION: Emodin markedly reversed OXA resistance by enhancing OXA DNA damage in HepG2/OXA cells, and the molecular mechanism was related to the inhibitory effect on ERCC1 expression being mediated by the FGFR2/ERK1/2 signaling pathway.

Haapa-Paananen S, Chen P, Hellström K, et al.
Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation.
PLoS One. 2013; 8(4):e60930 [PubMed] Free Access to Full Article Related Publications
Cancer initiation and progression involve microRNAs that can function like tumor suppressors and oncogenes. The functional significance of most miRNAs is currently unknown. To determine systematically which microRNAs are essential for glioma growth, we screened a precursor microRNA library in three human glioblastoma and one astroglial cell line model systems. The most prominent and consistent cell proliferation-reducing hits were validated in secondary screening with an additional apoptosis endpoint. The functional screening data were integrated in the miRNA expression data to find underexpressed true functional tumor suppressor miRNAs. In addition, we used miRNA-target gene predictions and combined siRNA functional screening data to find the most probable miRNA-target gene pairs with a similar functional effect on proliferation. Nine novel functional miRNAs (hsa-miR-129, -136, -145, -155, -181b, -342-5p, -342-3p, -376a/b) in GBM cell lines were validated for their importance in glioma cell growth, and similar effects for six target genes (ROCK1, RHOA, MET, CSF1R, EIF2AK1, FGF7) of these miRNAs were shown functionally. The clinical significance of the functional hits was validated in miRNA expression data from the TCGA glioblastoma multiforme (GBM) tumor cohort. Five tumor suppressor miRNAs (hsa-miR-136, -145, -342, -129, -376a) showed significant underexpression in clinical GBM tumor samples from the TCGA GBM cohort further supporting the role of these miRNAs in vivo. Most importantly, higher hsa-miR-145 expression in GBM tumors yielded significantly better survival (p<0.005) in a subset of patients thus validating it as a genuine tumor suppressor miRNA. This systematic functional profiling provides important new knowledge about functionally relevant miRNAs in GBM biology and may offer new targets for treating glioma.

Tani H, Saito N, Kobayashi M, Kameoka S
Clinical significance of keratinocyte growth factor and K-sam gene expression in gastric cancer.
Mol Med Rep. 2013; 7(5):1381-6 [PubMed] Free Access to Full Article Related Publications
Although gastric cancer is increasingly being detected at an early stage of development, diffuse growth‑type malignant tumors, such as scirrhous gastric cancer, are usually at an advanced stage at the time of diagnosis, resulting in poor treatment outcomes. The aim of this study was to determine whether the K-sam gene and keratinocyte growth factor (KGF) expression may be used to identify malignant tumors with a poor prognosis. K-sam and KGF expression was retrospectively evaluated in samples from 86 patients with early and advanced gastric cancer according to type, by examining serum levels and using immunohistochemical staining. The associations with clinicopathological characteristics and survival were also examined. The mean serum KGF levels were 11.191±3.808 pg/ml in early stage and 10.715±3.4991 pg/ml in advanced gastric cancer patients. KGF levels were significantly higher in types 4 and 5 (14.498±3.812 pg/ml, n=6) compared with types 1, 2 and 3 (10.747±3.571 pg/ml, n=80; P=0.028). Stage classification was identified as the only significant factor which determined overall survival. Patients with KGF-positive tumors had significantly higher serum KGF levels compared with those who had KGF-negative tumors. Patients with K-sam‑positive tumors had significantly higher KGF levels compared with those who had K-sam-negative tumors. Pathological KGF expression was not significantly correlated with the degree of differentiation; however, there was a positive correlation between high K-sam expression in scirrhous gastric tumors and serum KGF levels. The present study revealed that high serum KGF levels are a risk factor for diffuse infiltrative gastric cancer and may provide a simple method of identifying patients with a poor prognosis among previously diagnosed preoperative gastric cancer patients.

Sun JZ, Ha XQ, Zhang LM, et al.
Attenuated Salmonella typhimurium carrying the hepatocyte growth factor and keratinocyte growth factor genes repairs gastrointestinal mucosal damage caused by chemotherapy.
Med Oncol. 2013; 30(1):453 [PubMed] Related Publications
Radiotherapy and chemotherapy are the main therapeutic approaches for patients with malignant tumours, especially advanced tumours. However, they can cause adverse effects, one of which is gastrointestinal mucosal damage, which can greatly affect patients' quality of life. Until now, there have been no effective therapies to avoid or treat these adverse effects. In this study, we used attenuated Salmonella typhimurium (S. typhimurium) to deliver the hepatocyte growth factor (HGF) or keratinocyte growth factor (KGF) to murine gastrointestinal mucosa. We found that attenuated S. typhimurium carrying the HGF or KGF genes can effectively reduce the ratio of tumour to non-tumour carcass weight, repair damage to the gastrointestinal mucosal from chemotherapy, improve the immune response, and reduce the mortality rate of mice. Oral administration of attenuated S. typhimurium with HGF and KGF may be promising as a way of improving the quality of life of patients undergoing radiotherapy and chemotherapy.

Masunaga A, Nagashio R, Iwamoto S, et al.
A case of pulmonary papillary adenoma: possible relationship between tumor histogenesis/tumorigenesis and fibroblast growth factor receptor 2 IIIb.
Pathol Int. 2012; 62(9):640-5 [PubMed] Related Publications
Pulmonary papillary adenoma is a rare tumor. We analyzed a tumor which appeared in a 16-year-old Japanese woman. The tumor histologically showed papillary proliferation of one-layered tumor cells coating inflammatory fibrovascular cores. At the periphery of the tumor, the tumor cells grew in a lepidic fashion. The tumor cells were confirmed as type-II pneumocytes with electron-microscope. In this study, using immunohistochemistry, in situ hybridization and real-time reverse transcription polymerase chain reaction, we examined the expressions and quantities of fibroblast growth factor 10 (FGF10), keratinocyte growth factor (KGF) and fibroblast growth factor receptor 2 (FGFR2) IIIb, based on the extent of their abilities of proliferation and differentiation of type II pneumocytes. The tumor cells expressed FGFR 2 and produced 350 times more FGFR2IIIb messenger RNA (mRNA) than did the nontumorous lung. The quantity of KGF mRNA in the tumor tissue was twice that of the nontumorous lung. Moreover, there was dysregulation of FGFR2IIIb transcription in the tumor. According to these findings, we expect overexpression of FGFR2IIIb to play an important role in causing tumor. Because FGFR is suspected to be connected with lung carcinoma, we also treat similar tumorigenesis via FGFR as carcinoma; complete resection of adenoma might be indicated.

Toriseva M, Ala-aho R, Peltonen S, et al.
Keratinocyte growth factor induces gene expression signature associated with suppression of malignant phenotype of cutaneous squamous carcinoma cells.
PLoS One. 2012; 7(3):e33041 [PubMed] Free Access to Full Article Related Publications
Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes.

Zhang J, Sarkar S, Cua R, et al.
A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis.
Carcinogenesis. 2012; 33(2):312-9 [PubMed] Related Publications
Glioma cells in situ are surrounded by microglia, suggesting the potential of glioma-microglia interactions to produce various outcomes. As chemokines are important mediators of cell-cell communication, we sought first to identify commonly expressed chemokines in 16 human glioma lines. We found CCL2 (macrophage chemoattractant protein-1) messenger RNA to be expressed by the majority of glioma lines. However, these lines did not express the CCL2 receptor, CCR2, which was found on microglia. Next, we overexpressed CCL2 in the U87 glioma line, which has low basal level of CCL2, to investigate the hypothesis that glioma-secreted CCL2 interacts with microglia to affect glioma growth. Stable clones with 10- to 12-fold elevation of CCL2 have similar growth rate and invasive capacity as vector controls when cultured in isolation. However, in coculture with microglia in a three-dimensional collagen gel matrix, the invasiveness of CCL2-overexpressing clones was increased. Gene array analyses were then undertaken and they revealed that interleukin (IL)-6 was consistently increased in the coculture. Recombinant IL-6 enhanced the invasiveness of glioma cells when these were cultured alone, whereas a neutralizing antibody to IL-6 attenuated the microglia-stimulated glioma invasiveness. Finally, we found that human glioma specimens in situ contained IL-6 immunoreactivity that was expressed on CD68+ cells. This study has uncovered a mechanism by which glioma cells exploit microglia for increased invasiveness. Specifically, glioma-derived CCL2 acts upon CCR2-bearing microglia, which then produces IL-6 to stimulate gliomas. The CCL2/CCR2/IL-6 loop is a potential therapeutic target for the currently incurable malignant gliomas.

Ishii K, Mizokami A, Tsunoda T, et al.
Heterogenous induction of carcinoma-associated fibroblast-like differentiation in normal human prostatic fibroblasts by co-culturing with prostate cancer cells.
J Cell Biochem. 2011; 112(12):3604-11 [PubMed] Related Publications
In the tumor microenvironment, carcinoma-associated fibroblasts (CAFs) are considered to play a critical role in the promotion of tumorigenesis. However, the mechanisms that generate CAFs are not well elucidated. To understand how CAFs are generated during primary cancer progression, we investigated the biochemical characteristics of normal human prostate stromal cells (PrSC) co-cultured with human prostate cancer (PCa) cells in vitro. In primary cultures of human PCa-derived stromal cells (PCaSC-8 and PCaSC-9), expression of TNC, ACTA2, EGF, FGF7, and IGF1 mRNA was generally higher than PrSC but gene expression patterns were not uniform between PCaSC-8 and PCaSC-9 cells. Transforming growth factor β (TGFβ) and vascular endothelial growth factor (VEGF) protein levels in both PCaSC-8 and PCaSC-9 cells were generally higher than PrSC but levels of both secreted proteins were not same. When PrSCs were co-cultured with androgen-sensitive LNCaP cells or its sublines, androgen-low-sensitive E9 cells and androgen-insensitive AIDL cells, mRNA expression of IGF1 was significantly increased in all combinations. In contrast, expression of COL1A1, TNC, and ACTA2 mRNA was significantly increased only in LNCaP + PrSC and E9 + PrSC co-cultures. Protein production of VEGF was significantly increased only in LNCaP + PrSC and E9 + PrSC co-cultures. Increase of TGFβ protein was observed only in E9 + PrSC co-cultures. These biochemical characteristics of PrSC were partially recapitulated in TGFβ-treated PrSC. We have demonstrated that normal fibroblasts co-cultured with cancer cells become activated and exhibit biochemical characteristics of CAFs in a heterogenous manner. Our results suggest that heterogenous induction of CAF-like differentiation might be strongly dependent on biochemical characteristics of adjacent cancer cells.

Zheng C, Cotrim AP, Rowzee A, et al.
Prevention of radiation-induced salivary hypofunction following hKGF gene delivery to murine submandibular glands.
Clin Cancer Res. 2011; 17(9):2842-51 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Salivary glands are significantly affected when head and neck cancer patients are treated by radiation. We evaluated the effect of human keratinocyte growth factor (hKGF) gene transfer to murine salivary glands on the prevention of radiation-induced salivary hypofunction.
EXPERIMENTAL DESIGN: A hybrid serotype 5 adenoviral vector encoding hKGF (AdLTR(2)EF1α-hKGF) was constructed. Female C3H mice, 8 weeks old, were irradiated by single (15 Gy) or fractionated (6 Gy for 5 days) doses to induce salivary hypofunction. AdLTR(2)EF1α-hKGF or AdControl was administered (10(8) - 10(10) particles per gland) to both submandibular glands (SG) by retrograde ductal instillation before irradiation (IR). Salivary flow was measured following pilocarpine stimulation. Human KGF levels were measured by ELISA. SG cell proliferation was measured with bromodeoxyuridine labeling. Endothelial and progenitor or stem cells in SGs were measured by flow cytometry. The effect of SG hKGF production on squamous cell carcinoma (SCC VII) tumor growth was assessed.
RESULTS: In 3 separate single-dose IR experiments, salivary flow rates of mice administered the AdLTR(2)EF1α-hKGF vector were not significantly different from nonirradiated control mice (P > 0.05). Similarly, in 3 separate fractionated IR experiments, the hKGF-expressing vector prevented salivary hypofunction dramatically. Transgenic hKGF protein was found at high levels in serum and SG extracts. AdLTR(2)EF1α-hKGF-treated mice showed increased cell proliferation and numbers of endothelial cells, compared with mice treated with AdControl. hKGF gene transfer had no effect on SCC VII tumor growth ± radiation.
CONCLUSIONS: hKGF gene transfer prevents salivary hypofunction caused by either single or fractionated radiation dosing in mice. The findings suggest a potential clinical application.

Ware KE, Marshall ME, Heasley LR, et al.
Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression.
PLoS One. 2010; 5(11):e14117 [PubMed] Free Access to Full Article Related Publications
Despite initial and sometimes dramatic responses of specific NSCLC tumors to EGFR TKIs, nearly all will develop resistance and relapse. Gene expression analysis of NSCLC cell lines treated with the EGFR TKI, gefitinib, revealed increased levels of FGFR2 and FGFR3 mRNA. Analysis of gefitinib action on a larger panel of NSCLC cell lines verified that FGFR2 and FGFR3 expression is increased at the mRNA and protein level in NSCLC cell lines in which the EGFR is dominant for growth signaling, but not in cell lines where EGFR signaling is absent. A luciferase reporter containing 2.5 kilobases of fgfr2 5' flanking sequence was activated after gefitinib treatment, indicating transcriptional regulation as a contributing mechanism controlling increased FGFR2 expression. Induction of FGFR2 and FGFR3 protein as well as fgfr2-luc activity was also observed with Erbitux, an EGFR-specific monoclonal antibody. Moreover, inhibitors of c-Src and MEK stimulated fgfr2-luc activity to a similar degree as gefitinib, suggesting that these pathways may mediate EGFR-dependent repression of FGFR2 and FGFR3. Importantly, our studies demonstrate that EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF2 and FGF7 stimulated ERK activation as well as FGF-stimulated transformed growth in the setting of EGFR TKIs. In conclusion, this study highlights EGFR TKI-induced FGFR2 and FGFR3 signaling as a novel and rapid mechanism of acquired resistance to EGFR TKIs and suggests that treatment of NSCLC patients with combinations of EGFR and FGFR specific TKIs may be a strategy to enhance efficacy of single EGFR inhibitors.

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