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.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

The role of transforming growth factor Β in glioma progression

This review examines the apparently paradoxical conversion of transforming growth factor 's (TGF) regulatory role as a growth inhibitor among normal glial cells to that of a progression factor among glioblastomas (GM). In vitro, TGF functions as an autocrine growth inhibitor of near-diploid gliomas of any grade. In contrast, hyperdiploid glioblastoma multiforme (HD-GM) cultures proliferate in response to TGF, which is mediated by induction of platelet-derived growth factor B chain (PDGF-BB). The dominant hypothesis of TGF's pathogenetic association with malignant transformation has been predicated upon acquisition of resistance to its growth inhibitory effects. However, the lack of obvious correlation with TGF receptor (TR) expression (or loss) between the HD-GM and the TGF-inhibited GM cultures suggests the existence of intrinsically opposed regulatory mechanisms influenced by TGF. The mechanism of conversion might be explained either by the loss of a putative tumor suppressor gene (TSG) which mediates TGF's inhibition of growth or by enhancement of an active oncogenic pathway among the HD-GM. The frequency of mutations within glioma-associated TSG, such as TP53 and RB, suggests that defects in TGF's inhibitory signaling pathway may have analogous effects in the progression to HD-GM, and TGF's conversion to a mitogen. Alternative sites of inactivation which might explain the loss of TGF's inhibitory effect include inactivating mutation/loss of the TR type II, alterations in post-receptor signal transmission or the cyclin/cyclin dependent kinase system which regulates the phosphorylation of pRB. Loss or inactivation of a glial TSG with a consequent failure of inhibition appears to allow TGF's other constitutive effects, such as induction of c-sis, to become functionally dominant. Mechanistically, TGF's conversion from autocrine inhibitor to mitogen promotes 'clonal dominance' by conferring a Darwinian advantage to the hyperdiploid subpopulations through qualitative and quantitative differences in its modulation of PDGF-A and c-sis, with concomitant paracrine inhibition of competing, near-diploid elements. Abbreviations: transforming growth factor (TGF) and receptor (TR); retinoblastoma gene (RB) and protein (pRB); platelet-derived growth factor (PDGF) and receptor (PDGFR); epidermal growth factor (EGF) and receptor (EGFR); fibroblast growth factor (FGF); malignant glioma (MG), astrocytoma (AST), anaplastic astrocytoma (AAST), glioblastoma (GM); hyperdiploid glioblastoma (HD-GM); glioblastoma multiforme (GM); normal rat kidney (NRK); tumor suppressor gene (TSG); loss of heterozygosity (LOH); TP53 wild type (TP53wt); TP53 mutant (TP53m)     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Potent inhibition of tumoral hypoxia-inducible factor 1α by albendazole

Background  

Emerging reports suggest resistance, increased tumor invasiveness and metastasis arising from treatment with drugs targeting vascular endothelial growth factor (VEGF). It is believed that increased tumoral hypoxia plays a prominent role in the development of these phenomena. Inhibition of tumoral hypoxia inducible factor (HIF-1α) is thus becoming an increasingly attractive therapeutic target in the treatment of cancer. We hypothesized that the anti-VEGF effect of albendazole (ABZ) could be mediated through inhibition of tumoral HIF-1α.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Fludarabine: risk factor for aggressive behaviour of squamous cell carcinoma of the skin?

Fludarabine, a purine analogue, is effective in the therapyof low-grade non-Hodgkin's lymphomas. Side-effects include fever,peripheral neuropathy, pulmonary toxicity and significant depletionof T-lymphocyte populations. In addition, flare up and aggressivebehaviour of squamous cell carcinoma (SCC) during fludarabinetherapy has been observed [1]. We report on a     

Inhibition of hypoxia inducible factor 1α expression suppresses the progression of esophageal squamous cell carcinoma

Hypoxia inducible factor 1α (HIF-1α) is highly expressed and is implicated in the progression of esophageal squamous cell carcinoma. To investigate the potential mechanism by which HIF-1α contributes to the progression of esophageal squamous cell carcinoma, here we established stable esophageal carcinoma cell lines Eca-109 and TE- 13 in which HIF-1α was depleted by shRNA mediated gene silencing. In additon, we used specific inhibitor YC-1 to inhibit HIF-1α expression. Our in vitro studies demonstrated that shRNA or chemical mediated inhibition of HIF-1α led to reduced proliferation and increased apoptosis of esophageal carcinoma cells, as well as the downregulatuion of HIF-1α targets VEGF, MMP2 and BCL2. Furthermore, we employed xenograft nude mice model to validate the in vitro findings and proved that depletion of HIF-1α suppressed the tumorigenicity of esophageal carcinoma cells in vivo. In conclusion, our results provide new insight into the potential role of HIF-1α in esophageal squamous cell carcinoma and open up the possibility of inhibiting HIF-1α for targeted therapy of esophageal squamous cell carcinoma.     

Effect of vascular endothelial growth factor on remodeling of C6 glioma tissue in vivo

Pathological characteristics and biological behaviors of tumor are considered to result from pathological tissue remodeling regulated by the interaction of factors in the tumor microecosystem (TMES). Vascular endothelial growth factor (VEGF) is one of the factors that probably play an important role in the process of tissue remodeling. This study was a comprehensive investigation of the effects of VEGF on remodeling of glioma tissue in vivo. C6 cells with expression vectors containing sense (C6/VEGF+) or antisense (C6/VEGF−) VEGF₁₆₄ complementary DNA (cDNA) or an empty vector (C6/vec) were implanted into athymic mice, which served as an in vivo model with different levels of VEGF expression. VEGF expression, water content, and morphological characteristics of these tumor tissues were assayed. Expression of VEGF and water content in C6/VEGF− glioma (C6/VEGF−G) tissues were lower than in C6, C6/VEGF+, and C6/vec glioma (C6G, C6/VEGF+G, C6/vecG) (P < 0.01, P < 0.05); water content correlated with VEGF expression (r = 0.791, P = 0.000). In C6/VEGF−G, tumor cells were not tightly adhered to vascular walls, and the basal lamina surrounded by collagen fibers was monolayer and not continuous. However, in C6G, C6/VEGF+G, and C6/vecG, tumor cells were very close to the vascular walls, with some extending their processes to the wall. Generally, loose basal laminae surrounded by small amounts of collagen fibers were multilayer, integrated, and continuous. Vesicular vacuolar organelle (VVO) structures were observed in plasma of vascular endothelial cells (VECs), and significant correlation was found between VEGF expression level and VVO density (Spearman’s r = 0.642, P = 0.007). No correlation was found between VEGF expression and fenestrae formation in VECs (Pearson’s correlation r = −0.053, P = 0.846), and fenestrae in neither VECs nor intercellular clefts correlated with water content of tumor tissue (Pearson’s correlation r = 0.018, P = 0.947). These results demonstrate that VEGF can aggravate edema in tumor tissues by increasing VVOs and plays critical roles in the stickiness of tumor cells to vessel wall and in the integrity and continuity of the basal lamina of vessels. Our data indicate a possible mechanism of remodeling of glioma tissue and suggest that blocking VEGF might contribute to a therapeutic strategy for glioma.