Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc +/min mice

Son

et al. 2009

Intl Journal of Cancer

Tristetraprolin (TTP) is an AU‐rich element‐binding protein that regulates mRNA stability. Here, we report that TTP suppress the growth of human colon cancer cells both in vivo and in vitro by regulating of the expression of vascular endothelial growth factor (VEGF). TTP protein expression in human colonic tissues was markedly decreased in colonic adenocarcinoma compared with in normal mucosa and adenoma. VEGF expression was higher in colonic adenocarcinoma than in normal mucosa and adenoma. Specific inhibition of TTP expression by RNA‐interference increased the expression of VEGF in cultured human colon cancer cells, and TTP overexpression markedly decreased it. In addition, elevated expression of TTP decreased the expression level of luciferase linked to a 3′ terminal AU‐rich element (ARE) of VEGF mRNA. Colo320/TTP cells overexpressing TTP grew slowly in vitro and became tumors small in size when xenografted s.c into nude mice. These findings demonstrate that TTP acts as a negative regulator of VEGF gene expression in colon cancer cells, suggesting that it can be used as novel therapeutic agent to treat colon cancer.

Section: Discussionmentioning

confidence: 88%

Tristetraprolin regulates expression of VEGF and tumorigenesis in human colon cancer

Son

et al. 2009

Intl Journal of Cancer

“…The expression of VEGF in cancer is controlled by both oncogenic signalling (such as Wnt-signalling in colorectal cancer; Zhang et al, 2001) and hypoxia (Mizukami et al, 2004). Although there is redundancy among pro-angiogenic factors in advanced cancer (Relf et al, 1997;Hanrahan et al, 2003), many early cancers (Hanrahan et al, 2003;Jubb et al, 2003) and in vivo cancer models (Bergers et al, 1999;Hanrahan et al, 2003;Joyce et al, 2003;Goodlad et al, 2006;Korsisaari et al, 2007) are VEGF dependent. This observation has been exploited by the addition of an anti-VEGF monoclonal antibody (bevacizumab) to first-line chemotherapy in metastatic colorectal cancer, which prolonged the median overall survival (from 15.6 to 20.3 months, P ¼ 0.001; Hurwitz et al, 2004).…”

mentioning

confidence: 99%

“…The early growth of colorectal tumours requires angiogenesis (Goodlad et al, 2006;Korsisaari et al, 2007), the consequence of increased expression of pro-angiogenic factors (e.g., vascular endothelial growth factor-A (VEGF-A); Ferrara et al, 1991;Kim et al, 1993;Jubb et al, 2003;Korsisaari et al, 2007). The expression of VEGF in cancer is controlled by both oncogenic signalling (such as Wnt-signalling in colorectal cancer; Zhang et al, 2001) and hypoxia (Mizukami et al, 2004).…”

mentioning

confidence: 99%

Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer

Turley

et al. 2009

Br J Cancer

Background: Delta-like ligand 4 (Dll4) is a Notch ligand that is upregulated by hypoxia and vascular endothelial growth factor-A (VEGF-A) and is reported to have a role in tumor angiogenesis. Evidence from xenograft studies suggests that inhibiting Dll4–Notch signalling may overcome resistance to anti-VEGF therapy. The aim of this study was to characterise the expression of Dll4 in colon cancer and to assess whether it is associated with markers of hypoxia and prognosis. Method: In all, 177 colon cancers were represented in tissue microarrays. Immunohistochemistry was performed using validated antibodies against Dll4, VEGF, hypoxia-inducible factor (HIF)-1 α , HIF-2 α , prolyl hydroxylase (PHD)1, PHD2, PHD3 and carbonic anhydrase 9 (CA9). Results: The expression of Dll4 was observed preferentially in the endothelium of 71% (125 out of 175) of colon cancers, but not in the endothelium adjacent to normal mucosa (none out of 107, P <0.0001). The expression of VEGF was significantly associated with HIF-2 α ( P <0.0001) and Dll4 ( P =0.010). Only HIF-2 α had a significant multivariate prognostic effect (hazard ratio 1.61, 95% confidence interval 1.01–2.57). Delta-like ligand 4 was also expressed by neoplastic cells, particularly neoplastic goblet cells. Conclusion: Endothelial expression of Dll4 is not a prognostic factor, but is significantly associated with VEGF. Assessing endothelial Dll4 expression may be critical in predicting response to anti-VEGF therapies.

“…The suppression of VEGF-A derived from the myeloid has reduced vascularization in solid tumors. [64] When TAM reaches hypoxic areas, hypoxia directs them to a pro-tumorigenic phenotype by altering gene expression profiles. Hypoxia-inducible factor (HIF)-1α is a key transcription factor that regulates hypoxia-induced gene expression [65,66] .…”

Section: Roles Of Extracellular Matrix (Ecm) Components and Their Framentioning

confidence: 99%

Macrophages as a Key Factor in the Process of Tumour From the Initiation to the Therapy of Cancer.

Yang¹

2017

WJPR