Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?

Rafii, Shahin; Lyden, David; Benezra, Robert; Hattori, Koichi; Heissig, Beate

doi:10.1038/nrc925

Cited by 639 publications

(443 citation statements)

References 91 publications

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“…In terms of direct anti-vascular effects, a wealth of preclinical data has demonstrated that anti-VEGF agents alone can block angiogenesis and regress tumors or delay tumor progression [41,42]. Recent studies have proposed an 'anti-vasculogenic' effect of VEGF blockers, manifested through the blockade of blood-borne endothelial precursor cell recruitment in tumors [43]. Finally, based on preclinical observations, it has been suggested that anti-VEGF agents can 'normalize' tumor vasculature [9,44] (Figure 1).…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…Interestingly, blood CPCs (defined as CD133 + CD34 bright CD45 dim cells) are transiently decreased in number by bevacizumab treatment in rectal cancer patients [45,46,50], and CPC elevation is correlated with the relapse of glioblastomas after cediranib treatment interruption [51]. Subsets of CPCs might express not only VEGF receptors, but also c-KIT and plateletderived growth factor (PDGF) receptors [43,52], which are also key targets of many of the anti-VEGF receptor TKI agents.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

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VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

Duda

Batchelor

Willett

et al. 2007

Trends in Molecular Medicine

123

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Despite setbacks, the clinical development of antiangiogenic agents has accelerated remarkably over the past 3-4 years. Consequently, there are currently three direct inhibitors of the VEGF pathway approved for use in cancer therapy. Other agents that block the VEGF pathway are in advanced stages of clinical development and have shown promising results. With these exciting developments come crucial questions regarding the use of these new molecular-targeted agents, alone or in combination with standard cytotoxic or targeted agents. Importantly, the mechanisms of action of anti-VEGF therapy remain unknown. Here, we discuss several potential mechanisms of action such as tumor vascular normalization, bone marrow-derived cell recruitment blockade and cytostatic effects of anti-VEGF therapy. We review the current progress, the major stumbling blocks and the future directions for anti-cancer therapy using anti-VEGF agents, emphasizing clarification of the underlying molecular mechanisms of action and biomarker identification and validation.

show abstract

Section: Mechanisms Of Actionmentioning

confidence: 99%

Section: Mechanisms Of Actionmentioning

confidence: 99%

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

Duda

Batchelor

Willett

et al. 2007

Trends in Molecular Medicine

123

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“…The nature and exact functions of these mobilized BM-derived cells have been under intense scrutiny and are the subject of recent reviews [3,4]. Recruitment of EPCs and supporting cells contributes to the acceleration of ischemic revascularization and augments neo-angiogenesis in specific tumors, including lymphomas [5,6].…”

mentioning

confidence: 99%

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Petit

Jin

Rafii

2007

Trends in Immunology

Self Cite

520

378

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Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4 + BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4 + VEGFR1 + hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1-CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively.

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“…Tumour expansion is mainly supported by angiogenesis (sprouting cells and co-option of neighbouring preexisting vessels) (Folkman, 2006). However, emerging evidences indicate that bone marrow -derived EPCs also contribute to this process (Rafii et al, 2002). Expansion and differentiation of endothelial progenitors are recognized as a dynamic multistage process, in most cases requiring the engagement of adhesion molecules (Bellik et al, 2005), as well as growth factor and cytokine receptors.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of β1 integrin and IL-3Rβ common subunit interaction hinders tumour angiogenesis

et al. 2010

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Integrin/cytokine receptor interaction provides permissive signals leading to neoangiogenesis, and integrins are crucial for differentiation of endothelial progenitor cells (EPCs). It is known that the inflammatory interleukin-3 (IL-3), released in the tumoral microenvironment, contributes to both angiogenesis and vasculogenic processes. Herein, we generated IL-3 receptor beta common (IL-3Rbc) extracellular domain-derived fusion proteins (Fc) to elucidate the molecular mechanisms regulating these processes. Three different Fc were generated, containing the entire extracellular domain of IL-3Rbc (Fc1.4), a fragment corresponding to domains 1-3 (Fc1.3) and a fragment corresponding to domain 4 (Fc4), respectively. The ability of the fusion proteins to interfere with IL-3Rbc/b1 integrin interaction was assessed on endothelial cells (ECs), EPCs and murine-derived ECs. Pull-down experiments showed that Fc1.4 and Fc4 fusion proteins specifically interacted with b1 integrin. Fc4 and Fc1.4 fragments prevented IL-3-mediated EPC expansion, arterial morphogenesis and tumour-derived EC migration, without affecting cell adhesion. Fc4 in vivo inhibited the IL-3-mediated vasculogenic process, as well as inflammatory and tumour vascular growth. In conclusion, these data identify the b1 integrininteracting domain in the juxta-membrane IL-3Rbc extracellular domain, and provide the rational for targeting this interaction to impair vascular growth.

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Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?

Cited by 639 publications

References 91 publications

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Inhibition of β1 integrin and IL-3Rβ common subunit interaction hinders tumour angiogenesis

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