Expression of basic fibroblast growth factor, transforming growth factor β1 and their 3 receptors in osteosarcoma and its relationship to angiogenesis

Objective: To investigate the expression of angiogenic factors, basic fibroblast, growth factor (bFGF) and transforming growth factor (TGF)-β₁ in osteosarcoma, its association with neovascularization and prognosis. Methods: The expression of bFGF, β₁ and their receptors, as well as intratumoral microvessel count (MVD) were studied in 80 osteosarcomas by immunohistochemical staining and morphometry. The relationship between the angiogenic factors expression and prognosis was evaluated by a multivariate analysis using Cox proportion hazard model. Results: Among 80 cases of osteosarcoma, 46 cases were positive for TGF/TGF-β (57.5%), and 31 cases for β₁, (RI)(38.8%) respectively. The MVD and bFGF, TGFβ_{1 1} were important indicators to predict the prognosis of patients with osteosarcoma by the Cox proportion hazard model analysis. Conclusion: The angiogenic factors bFGF and TGF-β₁ are involved in the angiogenesis of osteosarcoma, and the angiogenesis influences the prognosis. Also they may be useful in the evaluation of the prognosis of patients with osteosarcoma. This work was supported by a grant from the Youth Scientific Research Foundation of the 9th Five-year Plan of the PLA.     

Immunohistochemical localization of transforming growth factor-α and epithelial growth factor receptor in human fetal developing skin, psoriasis and restrictive dermopathy

Keratinocytes release a number of cytokines interacting with other intra- and subepidermal cells during the initiation and the perpetuation of skin inflammatory reactions. Cultured human keratinocytes overexpressing the transforming growth factor alpha (TGF-alpha) assumed a spindled morphology and displayed increased locomotion. Moreover, the receptor for TGF-alpha, the epithelial growth factor receptor (EGFR), is important for autocrine growth, promotion of cell survival, and regulation of cell migration. The expression of TGF-alpha and EGFR has not been widely studied in human developing skin and their roles in geno-dermatosis are not known. In this study, we investigated the expression of TGF-alpha and EGFR by immunohistochemistry in human developing skin at different gestational ages (14 th week, 20 th week, and 34 th week), in six patients with psoriasis, and, for the first time, in an infant affected with restrictive dermopathy, a very rare lethal genodermatosis, characterized by abnormal skin growth and differentiation with thin, tightly adherent skin. TGF-alpha and EGFR were expressed in the basal layer at the 14 th week and in all epidermal layers at the 20 th and 34 th week of gestation. In psoriasis, TGF-alpha was overexpressed in all layers of epidermis, while EGFR was expressed in the basal and first suprabasal layers. In restrictive dermopathy, we observed no expression of both TGF-alpha and EGFR at the level of the skin. The other organs showed comparable patterns to those of an age-matched infant. In conclusion, TGF-alpha and EGFR interact strictly to promote skin development during the intrauterine life. An interactive autocrine growth cycle between TGF-alpha and EGFR is present in psoriasis. A skin-localized alteration of the expression of TGF-alpha and EGFR may be at the basis of restrictive dermopathy. The delay of growth and differentiation of the skin in restrictive dermopathy may be related to the absent expression of TGF-alpha, which is probably due to a down regulation of EGFR by an abnormal autocrine mechanism.     

Mutant epidermal growth factor receptor contributes to head and neck cancer growth and resistance to EGFR targeting

Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous-cell carcinoma (HNSCC) and its expression levels correlate with decreased patient survival. Nonetheless, therapies aiming at blocking EGFR has shown limited efficacy in a proportion of patients with HNSCC in clinical trials. Sok et al. in a recent paper (Clin Cancer Res, 2006, 12:5064-5073 ) attempted to ascertain whether it is due to mutation of EGFR. As the most common form of mutation of EGFR seen in several other types of cancer is a truncation mutation, EGFR     

Are basic fibroblast growth factor and vascular endothelial growth factor prognostic indicators in pediatric patients with malignant solid tumors?

Angiogenesis plays an important role in the growth, progression, and metastasis of solid tumors. Among angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) appear to be useful markers in adults with cancer. The aim of this pilot study was to determine the levels of VEGF in serum and bFGF in serum and urine of children with solid tumor at diagnosis (as measured by ELISA), and to investigate whether these parameters provide prognostic information. Forty consecutive patients with different types of cancer were prospectively included in this study. Median values of all studied angiogenic factors were higher in patients than in controls (n = 40), and the differences were statistically significant for bFGF in serum and urine: 10 versus 3 pg/ml (P = 0.0004) and 6406 versus 0 pg/g of creatinine (P < 0.0001), respectively. Among patients, median serum values of bFGF and VEGF were higher in children with metastatic disease (n = 14) than in those with localized disease (n = 26). The difference was statistically significant for serum bFGF: 17.5 versus 6 pg/ml (P = 0.02). Serum angiogenic factor levels correlated with outcome. The estimated event-free survival at 3 years was 79% for patients with normal bFGF values (n = 13) versus 42% (n = 26; P = 0.02) for those with high levels, and 71% in case of normal VEGF values (n = 20) versus 38% (n = 19; P = 0.04) for those with high levels. No benefit of normal urinary bFGF values was observed. Our results provide a rationale for exploring the clinical interest of bFGF and VEGF measurements in body fluids of a larger group of children with cancer.     

Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib.

The epidermal growth factor receptor （EGFR） tyrosine kinase inhibitor erlotinib （also known as Tarceva or OSI-774） has shown pronfising response rates in malignant gliomas. We investigated the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylafing agent temozolomide.     

Epidermal growth factor receptor regulates β-catenin location,stability, and transcriptional activity in oral cancer

Background  

Many cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in the nuclei of oral cancer cells.     

Basic fibroblast growth factor and vascular endothelial growth factor serum levels in breast cancer patients and healthy women: useful as diagnostic tools?

Introduction  

The aim of the present study was to analyze the relationship between the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in breast cancer cells and the corresponding serum levels in individual patients. The study also evaluated the potential of serum levels of the two growth factors as diagnostic markers in a case–control study.     

Targeting the epidermal growth factor receptor in non-small-cell lung cancer: Who,which, when,and how?

Aberrations in the signaling cascade of the epidermal growth factor receptor are common to several solid tumors. Compounds aimed at targeting this pathway have been approved for use by the US Food and Drug Administration for lung, head and neck, pancreas, and colorectal carcinomas. Unfortunately, only the minority of patients treated with this class of agents will have responses or improvements in survival. This article reviews the data on agents that exploit tumor dependency on epidermal growth factor receptor cascade and describes the knowledge on how to discern the appropriate patient population for receiving these agents.     

Expression of basic fibroblast growth factor,CD31, and α-smooth muscle actin and esophageal cancer recurrence after definitive chemoradiation

There is cumulative evidence that stromal reaction in cancer has an important diagnostic and prognostic significance. The aims of this study were to analyze the expression of basic fibroblast growth factor (FGF-2), CD31, and α-smooth muscle actin (SMA) in esophageal cancer patients and to establish their significance as indicators of disease recurrence after definitive chemoradiation (CRT). Protein expressions of FGF-2, CD31, and SMA were evaluated by immunohistochemistry and Western blot analysis in 70 patients, 20 with esophageal squamous cell carcinoma (ESCC) and 50 with locally recurrent ESCC after definitive CRT. Twenty matched normal esophageal squamous epithelium were also studied as controls. Esophageal cancer tissues showed positive expression of FGF-2, CD31, and SMA; in contrast, FGF-2 expression was not detected and only little staining for CD31 and SMA was noted in normal epithelium. Protein levels of FGF-2, CD31, and SMA were significantly elevated in recurrent ESCC. Among the patients with locally recurrent disease, expression of FGF-2 and SMA was notably high in whom the tumor recurred locally within 24 months after definitive CRT. The 2- and 5-year local recurrence-free survival rate was 15.4 % and 0 in patients with high FGF-2 expression, compared with 45.8 and 33.3 % in those who expressed low FGF-2, respectively (P?=?0.005). Of patients who expressed high SMA, the 2- and 5-year local recurrence-free survival rate was 21.7 and 8.7 %, respectively, compared to those with low SMA expression which was 37.0 and 22.2 %, respectively (P?=?0.016). Overexpression of FGF-2 and SMA is associated with local recurrence and reduced recurrence-free survival after definitive CRT for ESCC. The data also suggest that targeting stromal cells may be an attractive approach for esophageal cancer therapy strategies.     

Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity

The transforming growth factor β (TGFβ) stimulates tumor progression and metastasis. Secretion of TGFβ by tumor cells also suppresses an antitumor immune response in which dendritic cells (DCs) play an important role to activate cytotoxic T lymphocytes (CTLs). Herein we report that the small molecule TGFβ signaling inhibitor SB-431542, induces DC maturation in vitro and triggers antitumor activity in vivo. We added SB-431542 to cultures of murine bone-marrow derived DCs (BM-DCs) derived from BALB/c mice and human DCs generated from peripheral monocytes (human DCs) at different concentrations in triplicates and examined expression of co-stimulatory molecules by FACS and production of Interleukin-12 (IL-12) by ELISA. SB induced phenotypic maturation of BM-DCs and human DCs and improved their abilities to produce IL-12 in a dose-dependent manner. SB-431542 also augmented capacity of murine and human DCs to activate naive T cells in allogeneic mixed lymphocyte reaction. Interestingly, SB-431542 augmented the capacity of BM-DCs and human DCs to incorporate FITC-conjugated dextran. Intraperitoneal administration of SB-431542 initiated 3 and 7 days after the implantation of colon-26 cancer cells into the peritoneal cavity of BALB/c mice significantly induced CTL activity against colon-26. We incubated human DCs with SB-431542 and cell lysate of scirrhous gastric cancer cell line OCUM-8, and then examined CTL activities against OCUM-8. CD8 T cells activated by human DCs treated with SB-431542 showed modest augmentation CTL activity against cancer cells. Furthermore, pretreatment of human DCs with SB-431542 upregulated cytotoxic activity against K562 cells, suggesting SB should have potential to activate DCs to natural killer cells. In conclusion, TGFβ receptor I kinase inhibitor such as SB-431542 might induce anti-tumor immune response in immuno-tolerant patients associated with TGFβ activity.     

Insulin receptor substrate-1 involvement in epidermal growth factor receptor and insulin-like growth factor receptor signalling: implication for Gefitinib (‘Iressa’) response and resistance

Classically the insulin receptor substrate-1 (IRS-1) is an essential component of insulin-like growth factor type 1 receptor (IGF-IR) signalling, providing an interface between the receptor and key downstream signalling cascades. Here, however, we show that in tamoxifen-resistant MCF-7 (Tam-R) breast cancer cells, that are highly dependent on epidermal growth factor receptor (EGFR) for growth, IRS-1 can interact with EGFR and be preferentially phosphorylated on tyrosine (Y) 896, a Grb2 binding site. Indeed, phosphorylation of this site is greatly enhanced by exposure of these cells, and other EGFR-positive cell lines, to EGF. Importantly, while IGF-II promotes phosphorylation of IRS-1 on Y612, a PI3-K recruitment site, it has limited effect on Y896 phosphorylation in Tam-R cells. Furthermore, EGF and IGF-II co-treatment, reduces the ability of IGF-II to phosphorylate Y612, whilst maintaining Y896 phosphorylation, suggesting that the EGFR is the dominant recruiter of IRS-1 in this cell line. Significantly, challenge of Tam-R cells with the EGFR-selective tyrosine kinase inhibitor gefitinib, for 7 days, reduces IRS-1/EGFR association and IRS-1 Y896 phosphorylation, while promoting IRS-1/IGF-IR association and IRS-1 Y612 phosphorylation. Furthermore, gefitinib significantly enhances IGF-II-mediated phosphorylation of IRS-1 Y612 and AKT in Tam-R cells. Importantly, induction of this pathway by gefitinib can be abrogated by inhibition/downregulation of the IGF-IR. Our data would therefore suggest a novel association exists between the EGFR and IRS-1 in several EGFR-positive cancer cell lines. This association acts to promote phosphorylation of IRS-1 at Y896 and drive MAPK signalling whilst preventing recruitment of IRS-1 by the IGF-IR and inhibiting signalling via this receptor. Treatment with gefitinib alters the dynamics of this system, promoting IGF-IR signalling, the dominant gefitinib-resistant growth regulatory pathway in Tam-R cells, thus, potentially limiting its efficacy.     

Immunohistochemical analysis of the mutant epidermal growth factor, ΔEGFR,in glioblastoma

The naturally occurring mutated form of the epidermal growth factor receptor, ΔEGFR (also named EGFRvIII and de2-7EGFR), greatly enhances glioblastoma (GBM) cell growth in vivo through several activities, such as down-regulating p27 and up-regulating BclX(L) while increasing signaling through the RAS-MAPK and PI3-K cascades. More than half of GBMs, especially of the de novo type, overexpress EGFR, and 50%–70% of these express ΔEGFR. However, little is known about the distribution of ΔEGFR-expressing tumor cells within surgical specimens. In order to address this clinically important issue, we performed immunohistochemical analyses of 53 GBMs obtained during surgery using the anti-ΔEGFR monoclonal antibody, DH8.3. We also simultaneously analyzed wild-type EGFR expression in these tissues using the anti-EGFR monoclonal antibody, EGFR. 113. ΔEGFR and wild-type EGFR expression were observed in 20/53 (38%) and 29/53 (55%), respectively. Nineteen (95%) of the ΔEGFR-positive tumors also expressed wild-type EGFR; one case was ΔEGFR-positive but wild-type EGFR-negative. In 13/20 (65%) of the ΔEGFR-positive tumors, tumor cells were scattered diffusely within the tumors, 6/20 showed geographical distribution of ΔEGFR-positive tumor cells, and one case showed homogeneous staining. In the wild-type EGFR-positive cases, almost all tumor cells expressed EGFR. The differential distribution of cells expressing the two receptors observed here may suggest either that ΔEGFR arises at a low frequency from wild-type EGFR-expressing cells, perhaps during the process of gene amplification, or that there is a paracrine-type of interaction between them.     

Vascular endothelial growth factor -634G/C and vascular endothelial growth factor -2578C/A polymorphisms and lung cancer risk: a case–control study and meta-analysis

Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis in the process of tumor growth and metastasis. In present study, we conducted a case–control study and meta-analysis to evaluate the genetic effects of VEGF -634G/C and VEGF -2578C/A polymorphisms and risk of lung cancer. A total of 175 subjects were recruited for case–control study and seven studies were included in the meta-analysis. Our case–control study showed that VEGF -634G/C polymorphism had no association with lung cancer risk (CC vs. GG: OR?=?0.88, 95 % CI?=?0.37–2.11), whereas there was an association between VEGF -2578CC genotype and decrease in lung cancer risk (CC vs. CA/AA: OR?=?0.52, 95 % CI?=?0.28–0.96). A meta-analysis was further performed and statistically similar results were obtained (CC vs. GG: OR?=?0.91, 95 % CI?=?0.60–1.39 for VEGF ?634; CC vs. AA: OR?=?0.53, 95 % CI?=?0.32–0.89 for VEGF ?2578). Our study showed that the variant genotypes of the VEGF -2578C/A polymorphism, but not the VEGF -634G/C polymorphism, was associated with lung cancer risk. More studies are needed to detect VEGF -634G/C and VEGF ?2578 polymorphisms and their association with lung cancer in different ethnic populations incorporated with environmental exposures.     

In-utero exposures and breast cancer risk: joint effect of estrogens and insulin-like growth factor?

Initial evidence from observational studies led to the suggestion that high maternal estrogens in-utero are central factors in the development of adult breast cancer. Subsequently, several studies attempted to illuminate this hypothesis, but few of the more detailed observational studies show a clear and strong association between prenatal estrogen exposure and breast cancer risk in adulthood. To date, the potential underlying biological mechanisms remain unclear and controversial. However, recent observations of a relation between insulin-like growth factor-1 (IGF-1) and breast cancer risk may shed new light on the role of in-utero exposure, early growth, and risk of breast cancer. More research is needed to elucidate this potential mechanism.     

Integrin-mediated activation of latent transforming growth factor β

Members of the integrin family recognize a variety of spatially-restricted extracellular ligands. Classically, ligation of integrins activates cytoplasmic signals in the integrin-expressing cell and contributes to cell adhesion, migration, proliferation and survival. At least two members of this family, αvβ6 and αvβ8 perform an additional function, activation of latent complexes of transforming growth factor β. In effect, this process allows integrins on one cell to activate signals on adjacent (in the case of αvβ6) or nearby cells (in the case of αvβ8). Integrin-mediated TGFβ activation has been shown to play important roles in modulating tissue fibrosis, acute lung injury and pulmonary emphysema. Given the important roles that TGFβ plays in modulating epithelial cell growth, epithelial-to-mesenchymal transformation and tumor invasion and metastasis, integrin-mediated TGFβ activation is likely to play important roles in tumor growth ad metastasis.     

Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, growth hormone, and mammographic density in the Nurses’ Health Studies

Higher circulating insulin-like growth factor I (IGF-1) levels have been associated with higher mammographic density among women in some, but not all studies. Also, few studies have examined the association between mammographic density and circulating growth hormone (GH) in premenopausal women. We conducted a cross-sectional study among 783 premenopausal women and 436 postmenopausal women who were controls in breast cancer case?Ccontrol studies nested in the Nurses?? Health Study (NHS) and NHSII. Participants provided blood samples in 1989?C1990 (NHS) or in 1996?C1999 (NHSII), and mammograms were obtained near the time of blood draw. Generalized linear models were used to assess the associations of IGF-1, IGF-binding protein-3 (IGFBP-3), IGF-1:IGFBP-3 ratio, and GH with percent mammographic density, total dense area, and total non-dense area. Models were adjusted for potential confounders including age and body mass index (BMI), among others. We also assessed whether the associations varied by age or BMI. In both pre- and postmenopausal women, percent mammographic density was not associated with plasma levels of IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 ratio. In addition, GH was not associated with percent density among premenopausal women in the NHSII. Similarly, total dense area and non-dense area were not significantly associated with any of these analytes. In postmenopausal women, IGF-1 was associated with higher percent mammographic density among women with BMI?<25?kg/m², but not among overweight/obese women. Overall, plasma IGF-1, IGFBP-3, and GH levels were not associated with mammographic density in a sample of premenopausal and postmenopausal women.