Molecular basis of angiogenesis and cancer

Tonini, Tiziana; Rossi, Francesca; Claudio, Pier Paolo

doi:10.1038/sj.onc.1206816

Cited by 300 publications

(218 citation statements)

References 91 publications

(85 reference statements)

Supporting

Mentioning

208

Contrasting

Unclassified

Order By: Relevance

“…The first, arising through a process termed 'angiogenesis', originates from the sprouting of new capillaries from pre-existing vessels in geographical proximity to the tumor. The second, known as 'vasculogenesis', arises from the recruitment into the tumor bed of bone marrow-derived hematopoietic/EPCs and their subsequent differentiation into endothelial cells (Tonini et al, 2003;Folkman, 2007;Verfaillie, 2008).…”

Section: Introductionmentioning

confidence: 99%

IL-3 is a novel target to interfere with tumor vasculature

et al. 2011

View full text Add to dashboard Cite

Angiogenesis inhibiting agents are currently integral component of anticancer therapy. However, tumors, initially responsive to anti-angiogenic drugs or vascular targeting agents, can acquire resistance. The limited clinical efficacy might result from the heterogeneous nature of tumors or alternatively from the unique phenotype of tumor vascular cells, widely diverse from so-called 'normal' endothelium. Hence, defining the molecular mechanisms driving this diversity might provide a rational basis to design combinatory therapies that should be more effective in avoiding resistance. Herein, we demonstrated that tumor-derived endothelial cells (TECs) isolated from breast and kidney carcinomas retained an endothelial phenotype, but outspread independently of growth factors. Applying small interfering RNA approach, we demonstrated that interleukin (IL)-3, but not vascular endothelial growth factor, released by TECs, supports their autocrine growth and promotes in vivo vessel formation and tumor angiogenesis. Meanwhile, we found that the expression of the membrane-bound kit ligand (mbKitL) depends on IL-3, and it is crucial for adhesion of endothelial progenitor cells (EPCs) and inflammatory cells to TECs. These events required Akt activation. Finally, the finding that depletion of the mbKitL prevented EPC and inflammatory cell trafficking into vascular microenvironment, indicates that, as in bone marrow, the mbKitL can act as a membrane/adhesion molecule for c-Kit-expressing cells. These data provide evidences that an IL-3 autocrine loop can drive a tumor endothelial switch and that targeting IL-3 might confer a significant therapeutic advantage to hamper tumor angiogenesis.

show abstract

Section: Introductionmentioning

confidence: 99%

IL-3 is a novel target to interfere with tumor vasculature

et al. 2011

View full text Add to dashboard Cite

show abstract

“…pRb2/p130 is mainly expressed and active in differentiated and arrested cells in the G 0 / G 1 phase of the cell cycle. Genetic and functional inactivation of pRb2/p130 allow cells to bypass the G 0 / G 1 checkpoint, enabling them to undergo mitosis (Lee et al, 1987;Ewen et al, 1991;Mayol et al, 1993;Claudio et al, 2002a;Tonini et al, 2002Tonini et al, , 2003. pRb2/ p130 acts by repressing transcription via binding to E2F4 and E2F5 members of E2F transcription factors (La Thangue, 1996;Sidle et al, 1996;Macaluso et al, 2003;Sanseverino et al, 2003), which have binding sites for promoters of genes important for progression of cells from G1 to S phase.…”

Section: Introductionmentioning

confidence: 99%

Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A

et al. 2004

Self Cite

View full text Add to dashboard Cite

The polycomb group (PcG) proteins are known to be involved in maintaining the silenced state of several developmentally regulated genes. Enhancer of zeste homolog 2 (Ezh2), a member of this large protein family, has also been shown to be deregulated in different tumor types and its role, both as a potential primary effector and as a mediator of tumorigenesis, has become a subject of increased interest. We observed that Ezh2 binds to pRb2/ p130, a member of the retinoblastoma family; as such, we were led to consider the possible ability of Ezh2 to modulate cell cycle progression. Both Ezh2 and pRb2/ p130 repress gene expression by recruiting histone deacetylase (HDAC1), which decreases DNA accessibility for activating transcription factors. Additionally, we observed that Ezh2 interacts with the C-terminal region of pRb2/p130, essential for interaction with HDAC1. We show that Ezh2 is able to reverse pRb2/p130-HDAC1-mediated repression of the cyclin A promoter. This indicates a functional role of this complex in regulating cyclin A expression, known to be crucial in mediating cell cycle advancement. We also detected a significant decrease in the retention of HDAC1 activity associated with pRb2/p130 when Ezh2 was overexpressed. Finally, electromobility shift assays (EMSA) demonstrated that overexpression of Ezh2 caused the abrogation of the pRb2/p130-HDAC1 complex on the cyclin A promoter. These data, taken together, suggest that Ezh2 competes with HDAC1 in binding to pRb2/p130, disrupting their occupancy on the cyclin A promoter. In this study, we propose a new mechanism for the functional inactivation of pRb2/p130 that ultimately contributes to cell cycle progression and malignant transformation.

show abstract

“…In pathological conditions, unregulated angiogenesis is seen, such as diabetic retinopathy, rheumatoid arthritis and cancer. 7 The construction of a vesicular network requires several sequential steps, including endothelial cell activation, degradation of the basement membrane, endothelial cell migration, proliferation and stabilization into mature blood vessels. 16 These processes are mediated by a wide variety of angiogenic inducers such as growth factors, chemokines, angiogenic enzymes, endothelial specific receptors and adhesion molecules.…”

Section: Angiogenesismentioning

confidence: 99%

“…3,4 Owing to the fact that cancers cannot grow beyond a certain size and spread without a blood vessel that provides sufficient supplement such as nutrients and oxygen, as well as pipelines to move out, angiogenesis plays a critical role in solid tumor progression and the development of metastasis. [5][6][7] Thus, antiangiogenic therapy designed to prevent tumor angiogenesis has emerged as a non-invasive and safe option for cancer treatment. 8,9 Furthermore, the fact that angiogenic endothelial cells overexpress integrin cell surface receptors that are known to bind arginine-glycineaspartate (RGD)-containing peptides 10 makes them prime candidates for RGD-based targeted cancer gene therapy.…”

Section: Introductionmentioning

confidence: 99%

A review of RGD-functionalized nonviral gene delivery vectors for cancer therapy

et al. 2012

View full text Add to dashboard Cite

The development of effective treatments that enable many patients suffering from cancer to be successfully cured is highly demanded. Angiogenesis, which is a process for the formation of new capillary blood vessels, has a crucial role in solid tumor progression and the development of metastasis. Antiangiogenic therapy designed to prevent tumor angiogenesis, thereby arresting the growth or spread of tumors, has emerged as a non-invasive and safe option for cancer treatment. Due to the fact that integrin receptors are overexpressed on the surface of angiogenic endothelial cells, various strategies have been made to develop targeted delivery systems for cancer gene therapy utilizing integrin-targeting peptides with an exposed arginine-glycine-aspartate (RGD) sequence. The aim of this review is to summarize the progress and prospect of RGD-functionalized nonviral vectors toward targeted delivery of genetic materials in order to achieve an efficient therapeutic outcome for cancer gene therapy, including antiangiogenic therapy.

show abstract

Molecular basis of angiogenesis and cancer

Cited by 300 publications

References 91 publications

IL-3 is a novel target to interfere with tumor vasculature

IL-3 is a novel target to interfere with tumor vasculature

Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A

A review of RGD-functionalized nonviral gene delivery vectors for cancer therapy

Contact Info

Product

Resources

About